Solid forms of delgocitinib and methods thereof

Abstract

The present disclosure relates to solid forms of delgocitinib, methods for preparing same, pharmaceutical compositions thereof, and methods of use thereof.

Description

[Technical Field]

[0001] The present disclosure relates to solid forms of delgocitinib, in embodiments, crystalline polymorphs or salts of delgocitinib, methods for their preparation, pharmaceutical compositions thereof, and methods of use thereof. [Background technology]

[0002] Delgocitinib (JTE-052), chemically named 3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile, is a pan-Janus kinase (JAK) inhibitor and is approved in Japan for the treatment of atopic dermatitis (AD). As described in U.S. Patent No. 8,609,647, delgocitinib has the following chemical structure: [ka]

[0003] The preparation of delgocitinib is disclosed in US Pat. Nos. 10,822,354 and 8,609,647, and delgocitinib polymorphs are described in US Pat. Nos. 11,339,181 and 11,312,728.

[0004] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single compound, such as delgocitinib, can have a unique crystalline structure, as well as melting points, thermal behavior (e.g., measured by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC)), X-ray powder diffraction (XRPD) patterns, infrared absorption fingerprints, Raman absorption fingerprints, and solid-state ( 13 C) Various polymorphs may occur, which have physical properties in the NMR spectrum. One or more of these techniques may be used to distinguish various polymorphs of a compound.

[0005] Various salts and solid forms (including solvated forms) of an active pharmaceutical ingredient can have different properties. Such variations in the properties of various salts and solid forms can provide a basis for improving formulations, for example, by improving better processing or handling characteristics, improving dissolution profiles, or improving stability (polymorphic and chemical stability) and shelf life. These variations in the properties of various salts and solid forms can also improve the final dosage form, for example, if they serve to improve bioavailability. Various salts and solid forms of an active pharmaceutical ingredient can also result in various polymorphs or crystalline forms, which may provide further opportunities to exploit variations in the properties and characteristics of the solid active pharmaceutical ingredient to provide improved products.

[0006] The discovery of new salts and solid forms of pharmaceutical products can result in materials with desirable processing characteristics, such as ease of handling, processing, storage stability, and purification, or intermediate crystalline forms that facilitate the desired transformation to other polymorphs. New polymorphs and new salts of pharmaceutically useful compounds also provide opportunities to improve the performance characteristics (dissolution profile, bioavailability, etc.) of pharmaceutical products. The forms can provide products with different properties, such as different crystal habits, higher crystallinity, or polymorphic stability, thereby providing better processing or handling characteristics, improved dissolution profile, or improved shelf life, thereby expanding the repertoire of materials available to pharmaceutical scientists for formulation optimization. For at least these reasons, there is a need for additional salts and solid forms (including solvated forms) of delgocitinib. Summary of the Invention

[0007] The present disclosure relates to solid forms of delgocitinib, its crystalline polymorphs or amorphous forms, methods for preparing same, and pharmaceutical compositions comprising said solid forms.

[0008] In particular, the present disclosure provides crystalline forms of delgocitinib designated Forms DL1 to DL13 and crystalline delgocitinib hydrochloride (as defined herein).

[0009] The present disclosure provides methods for preparing delgocitinib and its solid forms or crystalline polymorphs.

[0010] In another aspect, the present disclosure encompasses the above solid forms or crystalline polymorphs of delgocitinib and crystalline delgocitinib hydrochloride for use in the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating atopic dermatitis (AD).

[0011] In another aspect, the present disclosure encompasses the above solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride for the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating atopic dermatitis (AD). In yet another embodiment, the present disclosure encompasses a pharmaceutical composition comprising any one of the solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride.

[0012] In specific embodiments, the present disclosure encompasses pharmaceutical formulations comprising any one of the above solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure further encompasses a method for preparing said pharmaceutical formulations of delgocitinib and delgocitinib hydrochloride, comprising combining any one of the above solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride, or a pharmaceutical composition comprising same, with at least one pharmaceutically acceptable excipient.

[0014] The solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride disclosed herein, as well as pharmaceutical compositions or formulations containing same, can be used as pharmaceuticals, particularly for treating complement-mediated diseases, preferably for treating atopic dermatitis, comprising administering a therapeutically effective amount of the solid form of the disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from atopic dermatitis or otherwise in need of treatment.

[0015] The present disclosure also provides a method for treating atopic dermatitis, comprising administering a therapeutically effective amount of any one of the solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, to a subject suffering from or otherwise in need of treatment for atopic dermatitis.

[0016] The present disclosure further provides the use of at least one of the solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride of the present disclosure, or the pharmaceutical compositions or formulations described above, in the manufacture of a medicament for treating atopic dermatitis. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline delgocitinib form DL1.

[0018] [Figure 2] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL2.

[0019] [Figure 3] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL3.

[0020] [Figure 4] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL4.

[0021] [Figure 5] FIG. 1 shows the XRPD pattern of amorphous delgocitinib.

[0022] [Figure 6] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL5.

[0023] [Figure 7] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL6.

[0024] [Figure 8] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL7.

[0025] [Figure 9] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL8.

[0026] [Figure 10] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL9.

[0027] [Figure 11] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL10.

[0028] [Figure 12] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL11.

[0029] [Figure 13] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL12.

[0030] [Figure 14] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form DL13.

[0031] [Figure 15]FIG. 1 shows the XRPD pattern of crystalline delgocitinib hydrochloride.

[0032] [Figure 16] FIG. 1 shows the XRPD pattern of crystalline delgocitinib form alpha. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present disclosure relates to solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride, methods for preparing same, and pharmaceutical compositions comprising at least one of these solid forms, or a combination thereof. In particular, the present disclosure relates to solid forms of delgocitinib and delgocitinib hydrochloride (as defined herein) designated Forms DL1 to DL13.

[0034] The solid form of delgocitinib of the present disclosure may have advantageous properties selected from at least one of chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability (chemical stability, as well as thermal and mechanical stability against polymorphic transformation, stability against dehydration and / or storage stability), low hygroscopicity, low residual solvent content, tendency to sticking, and advantageous processing and handling properties, such as compressibility and bulk density.

[0035] As used herein, crystalline forms may be referred to as being characterized by graphical data "shown 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 for further defining each solid form (a so-called "fingerprint") that cannot necessarily be described by reference to numerical values ​​or peaks alone. In any event, those skilled in the art will understand that such graphical representations of data may be subject to slight variations in, for example, the relative intensities and peak positions of peaks due to certain factors, such as variations in instrument response and variations in sample concentration and purity, which are well known to those skilled in the art. Nevertheless, those skilled in the art can readily compare the graphical data of a figure herein with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms.

[0036] Thus, it will be understood that any crystalline form of delgocitinib referred to herein as being characterized by graphical data "shown in" a figure also includes any crystalline form of delgocitinib characterized using graphical data with such slight variations, as would be known to one of skill in the art, in comparison to the figure.

[0037] The solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride described in any aspect or embodiment of the present disclosure may be polymorphically pure or may be substantially free of other solid forms of delgocitinib and delgocitinib hydrochloride.

[0038] A solid form (or polymorph) may be referred to herein as being polymorphically pure or as being substantially free of any other solid (or polymorphic) form. As used herein in this context, the phrase "substantially free of any other form" is understood to mean that the solid form contains no more than about 20% (w / w), no more than about 10% (w / w), no more than about 5% (w / w), no more than about 2% (w / w), no more than about 1% (w / w), or no more than about 0% (w / w) of any form of the subject compound, as measured, for example, by XRPD. Thus, a solid form of delgocitinib or delgocitinib hydrochloride described herein as being substantially free of any other solid form 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 solid form of delgocitinib or delgocitinib hydrochloride. Thus, in some embodiments of the present disclosure, the described solid forms of delgocitinib and delgocitinib hydrochloride may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more solid forms of delgocitinib and delgocitinib hydrochloride.

[0039] The solid forms or crystalline polymorphs of delgocitinib and delgocitinib hydrochloride described in any aspect or embodiment of the present disclosure may be chemically pure or substantially free of other compounds.

[0040] Compounds may be referred to herein as chemically pure or purified compounds, or compounds that are substantially free of other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of other compounds" refer to compounds that are substantially free of any impurities, including enantiomers, diastereomers, or other isomers of the subject compound. A chemically pure or purified compound, or a compound that is substantially free of other compounds, is understood to mean containing less than about 10% (w / w), less than about 5% (w / w), less than about 4% (w / w), less than about 3% (w / w), less than about 2% (w / w), less than about 1.5% (w / w), less than about 1% (w / w), less than about 0.8% (w / w), less than about 0.6% (w / w), less than about 0.4% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w), or less than about 0% of other compounds, for example, as measured by HPLC. Alternatively, a chemically pure or purified compound, or a compound that is substantially free of other compounds, is understood to mean containing less than about 10% area percent, less than about 5% area percent, less than about 4% area percent, less than about 3% area percent, less than about 2% area percent, less than about 1.5% area percent, less than about 1% area percent, less than about 0.8% area percent, less than about 0.6% area percent, less than about 0.4% area percent, less than about 0.2% area percent, less than about 0.1% area percent, or less than about 0% of other compounds as measured by HPLC. Thus, pure or purified delgocitinib and delgocitinib hydrochloride described herein as being substantially free of compounds will be understood to contain more than about 90% (w / w), more than about 95% (w / w), more than about 96% (w / w), more than about 97% (w / w), more than about 98% (w / w), more than about 98.5% (w / w), more than about 99% (w / w), more than about 99.2% (w / w), more than about 99.4% (w / w), more than about 99.6% (w / w), more than about 99.8% (w / w), more than about 99.9% (w / w), or about 100% of the subject delgocitinib and delgocitinib hydrochloride.Alternatively, pure or purified delgocitinib and delgocitinib hydrochloride described herein as being substantially free of compounds will 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 delgocitinib and delgocitinib hydrochloride.

[0041] As used herein, unless otherwise specified, XRPD peaks reported herein are preferably measured using CuKα radiation, λ=1.5418 Å, and preferably, XRPD peaks reported herein are measured using CuKα radiation, λ=1.5418 Å at a temperature of 25±3° C.

[0042] As used herein, the term "isolated" with respect to the solid forms of delgocitinib and delgocitinib hydrochloride of the present disclosure corresponds to a solid form of delgocitinib and delgocitinib hydrochloride that is physically separated from the reaction mixture in which it is formed.

[0043] As used herein, an object, such as a reaction mixture, may be characterized as being at or allowed to come to "room temperature" (often abbreviated as "RT"). This means that the object's temperature 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.

[0044] A method or process may be referred to herein as being performed "overnight." This refers, for example, to a method or process, to a time period spanning overnight hours during which the method or process may not be actively observed. This time period may be from about 8 hours to about 20 hours, or from about 10 hours to about 18 hours, and typically is about 16 hours.

[0045] As used herein, unless otherwise stated, the term "anhydrous" with respect to crystalline delgocitinib and delgocitinib hydrochloride means not containing any water of crystallization (or other solvent) in a defined stoichiometric amount within the crystal. Furthermore, the "anhydrous" form does not contain more than about 1% (w / w) of either water or organic solvent, as measured, for example, by TGA, Karl Fischer method, or other suitable technique.

[0046] As used herein, the term "solvate," unless otherwise specified, refers to a crystalline form that incorporates a solvent into the crystalline structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate can be present in either stoichiometric or non-stoichiometric amounts.

[0047] 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, such that 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 other contexts, 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 (methyl tert-butyl ether) MTBE (1.5 v / v) to 100 mL of a reaction mixture indicates that 150 mL of MTBE has been added.

[0048] As used herein, the term non-hygroscopic with respect to crystalline delgocitinib and delgocitinib hydrochloride refers to the absorption of less than about 1.0% (w / w) water at about 25°C and about 80% relative humidity (RH), as measured, for example, by TGA or other suitable technique.

[0049] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar.

[0050] As used herein, delgocitinib form alpha is delgocitinib form alpha ("form alpha") as described by XRPD (Figure 1) in U.S. Patent No. 11,339,181 and as described herein by an XRPD pattern (Figure 16). Form alpha can be prepared according to Example 1 described in U.S. Patent No. 11,339,181 and by Example 19 below.

[0051] As used herein, unless otherwise specified, the term "thermodynamic stability" with respect to a solid form or crystalline polymorph of delgocitinib and delgocitinib hydrochloride refers to the resistance of the solid form or crystalline polymorph to polymorphic transformation under certain conditions (e.g., heating, melting, or dissolution). In some embodiments, the term refers to less than about 20% (w / w), about 10% (w / w), about 5% (w / w), about 1% (w / w), about 0.5% (w / w), or about 0% (w / w) of the transformation of crystalline delgocitinib and delgocitinib hydrochloride to other solid forms of delgocitinib and delgocitinib hydrochloride, as measured by XRPD. In some embodiments, the transition is between about 1% (w / w) and about 20% (w / w), between about 1% (w / w) and about 10% (w / w), or between about 1% (w / w) and about 5% (w / w).

[0052] The present disclosure includes crystalline delgocitinib designated as Form DL1. Delgocitinib crystalline Form DL1 can be characterized by one or more of the following: an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 °2θ±0.2 °2θ; and an XRPD pattern substantially as shown in Figure 1; or a combination of these data.

[0053] Crystalline delgocitinib form DL1 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ ± 0.2 degrees 2θ, and further having one, two, or three additional peaks selected from 9.0, 19.1, and 27.4 degrees 2θ ± 0.2 degrees 2θ; or a combination of these data.

[0054] Crystalline delgocitinib form DL1 may alternatively be characterized by an XRPD pattern having peaks at 9.0, 9.5, 12.6, 14.3, 16.8, 18.1, 19.1, and 27.4 degrees 2θ±0.2 degrees 2θ.

[0055] Crystalline delgocitinib form DL1 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at any one, two, three, four, five, six, or seven of: 3.0-6.5°2θ ± 0.2°2θ; 7.8-8.5°2θ ± 0.2°2θ; 10.0-10.6°2θ ± 0.2°2θ; 11.6-12.0°2θ ± 0.2°2θ; 13.6-13.8°2θ ± 0.2°2θ; 19.9-20.2°2θ ± 0.2°2θ; and 22.9-23.4°2θ ± 0.2°2θ.

[0056] Crystalline delgocitinib form DL1 may be characterized by each of the above properties alone or in any possible combination, for example, by an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ±0.2 degrees 2θ, and the XRPD pattern shown in FIG. 1, and combinations thereof.

[0057] Crystalline delgocitinib form DL1 may be characterized as a hydrate, preferably a monohydrate.

[0058] The delgocitinib form DL1 described above in any aspect or embodiment of the present disclosure can be prepared by a method comprising suspending delgocitinib (preferably Form Alpha, Form DL7, or Form DL3 described in any aspect or embodiment of the present disclosure) in water, optionally with stirring, preferably at a temperature of about 30° C. to about 70° C., about 40° C. to about 65° C., about 50° C. to about 65° C., about 55° C. to about 65° C., or about 60° C. Delgocitinib form DL1 is optionally isolated and optionally dried.

[0059] According to any aspect or embodiment of the method, water can be used in an amount of about 20 to about 40 vol, about 25 to about 35 vol, and in some embodiments, about 30 vol. The mixture can be heated, optionally with stirring, to a temperature of about 30°C to about 70°C, about 40°C to about 65°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C.

[0060] According to any aspect or embodiment of the method, the mixture may be maintained for about 2 to about 20 hours, about 6 to about 20 hours, about 8 to about 20 hours, about 10 to about 20 hours, preferably about 16 hours. The mixture may be cooled to a temperature of preferably about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. Form DL1 may optionally be isolated by any suitable method, for example, by centrifugation, decantation, or filtration, preferably by filtration. Form DL1 may be dried at a temperature of preferably about 20°C to about 80°C, about 20°C to about 70°C, about 25°C to about 65°C, 25°C to about 60°C, about 20°C to about 60°C, or about 35°C to about 60°C, or about 40°C to about 50°C, or about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. Preferably, drying is performed under vacuum or reduced pressure. When drying is carried out under reduced pressure, a pressure of about 1 mbar or about 200 mbar, about 1 mbar to about 100 mbar, about 1 mbar to about 50 mbar, particularly about 5 mbar to about 40 mbar, or more particularly about 20 mbar can be used.

[0061] According to any aspect of the disclosed methods, delgocitinib form DL1 can be prepared by a process comprising: (i) stirring a suspension of delgocitinib (preferably, Form Alpha, Form DL3, or Form DL7 described in any aspect or embodiment of the present disclosure) at a temperature of about 40°C to about 65°C (preferably, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C) for about 2 to about 20 hours (preferably, about 6 to about 20 hours, about 8 to about 20 hours, about 10 to about 20 hours, or preferably, about 16 hours); (ii) cooling the mixture to a temperature of about 15°C to about 35°C (preferably, about 20°C to about 30°C, or about 25°C); (iii) isolating delgocitinib form DL1 (preferably by filtration); and, optionally, (iv) drying delgocitinib form DL1. Preferably, drying is performed under vacuum or reduced pressure. Drying can be carried out at a temperature of about 20°C to about 80°C, about 20°C to about 70°C, about 25°C to about 65°C, about 25°C to about 60°C, about 35°C to about 60°C, about 40°C to about 50°C, about 35°C to about 60°C, about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C. Preferably, drying is carried out for an appropriate time, particularly about 30 minutes to about 3 hours, about 30 minutes to about 2 hours, or about 1 hour. When drying is carried out under reduced pressure, a pressure of about 1 mbar or about 200 mbar, about 1 mbar to about 100 mbar, about 1 mbar to about 50 mbar, particularly about 5 mbar to about 40 mbar, or more particularly about 20 mbar can be used.

[0062] The above methods for preparing delgocitinib form DL1 may further comprise combining delgocitinib form DL1 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0063] The present disclosure includes a crystalline form of delgocitinib designated Form DL2. Crystalline Form DL2 of delgocitinib can be characterized by one or more of the following: an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 2; or a combination of these data.

[0064] Crystalline delgocitinib form DL2 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.3, 22.2, and 25.5 °2θ ± 0.2 °2θ; or a combination of these data.

[0065] Crystalline delgocitinib form DL2 may alternatively be characterized by an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 19.3, 22.2, 25.5, 28.5, and 29.3 degrees 2θ±0.2 degrees 2θ.

[0066] The crystalline delgocitinib form DL2 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at one, two, three, four, or five of: 3.6-4.0°2θ ± 0.2°2θ; 5.0-8.2°2θ ± 0.2°2θ; 9.2-12.6°2θ ± 0.2°2θ; 13.7-14.1°2θ ± 0.2°2θ; and 18.7-18.8°2θ ± 0.2°2θ.

[0067] Crystalline delgocitinib form DL2 may be characterized by each of the above properties alone or in all possible combinations, for example, an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ±0.2 °2θ; the XRPD pattern shown in Figure 2, and combinations thereof.

[0068] Crystalline delgocitinib form DL2 can be characterized as an anhydrous form.

[0069] Delgocitinib form DL2 according to any aspect or embodiment of the present disclosure can be prepared by a process comprising suspending delgocitinib (preferably amorphous delgocitinib) in a solvent selected from dimethylformamide, isopropyl acetate, tert-butanol and cyclohexane, particularly cyclohexane, optionally isolating delgocitinib form DL2, and optionally drying.

[0070] According to any aspect or embodiment of the method, the solvent can be used in an amount of about 20 to about 200 vol, about 50 to about 150 vol, about 70 to about 130 vol, about 90 to about 110 vol, or about 100 vol. The mixture can be heated, optionally with stirring, to a temperature of about 30°C to about 70°C, about 40°C to about 65°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C.

[0071] According to any aspect or embodiment of the method, the mixture may be heated for about 6 to about 48 hours, about 10 to about 48 hours, about 20 to about 30 hours, and in embodiments, about 24 hours. The mixture may be cooled to a temperature of preferably about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. Form DL2 may optionally be isolated by any suitable method, for example, by centrifugation, decantation, or filtration, preferably by filtration. Form DL2 may be dried at a temperature of preferably about 20°C to about 80°C, about 20°C to about 70°C, about 25°C to about 65°C, about 35°C to about 60°C, or about 40°C to about 50°C, or about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. Preferably, drying is performed under vacuum or reduced pressure. When drying is carried out under reduced pressure, a pressure of about 1 mbar or about 200 mbar, about 1 mbar to about 100 mbar, about 1 mbar to about 50 mbar, particularly about 5 mbar to about 40 mbar, or more particularly about 20 mbar can be used.

[0072] In any aspect or embodiment of the method, delgocitinib form DL2 can be prepared by (i) stirring a suspension of delgocitinib (preferably amorphous form) in cyclohexane at a temperature of preferably about 30°C to about 70°C (preferably about 40°C to about 65°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C) for 6 to about 48 hours (preferably about 10 to about 48 hours, about 20 to about 30 hours, in embodiments, about 24 hours); (ii) stirring the mixture at a temperature of about 15°C to about 35°C (iii) isolating delgocitinib form DL2 (preferably by filtration); and, optionally, (iv) drying delgocitinib form DL2 (preferably under reduced pressure at a temperature of about 20°C to about 80°C, about 20°C to about 70°C, about 25°C to about 65°C, or about 35°C to about 60°C, about 40°C to about 50°C, or about 20°C to about 50°C).

[0073] The above methods for preparing delgocitinib form DL2 can further comprise combining delgocitinib form DL2 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0074] The present disclosure includes crystalline delgocitinib designated as Form DL3. Delgocitinib crystalline Form DL3 can be characterized by one or more of the following: an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 3; or a combination of these data.

[0075] Crystalline delgocitinib form DL3 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 14.1, 22.3, 24.4, and 25.3 °2θ ± 0.2 °2θ; or a combination of these data.

[0076] Crystalline delgocitinib form DL3 may alternatively be characterized by an XRPD pattern having peaks at 9.1, 14.1, 18.6, 21.6, 22.3, 24.4, 25.3, 26.6, and 28.8 degrees 2θ±0.2 degrees 2θ.

[0077] The crystalline delgocitinib form DL3 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at any one, two, or three of: 2.8-3.8°2θ±0.2°2θ; 5.2-7.7°2θ±0.2°2θ; and 12.0-12.6°2θ±0.2°2θ.

[0078] Crystalline delgocitinib form DL3 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 3, and combinations thereof.

[0079] Crystalline delgocitinib form DL3 can be characterized as an anhydrous form.

[0080] The delgocitinib Form DL3 described above according to any aspect or embodiment of the present disclosure can be prepared by exposing delgocitinib (preferably Form DL1 or Form DL3, more preferably Form DL1) to a temperature of about 110°C to about 140°C, about 115°C to about 125°C, or about 120°C for a time suitable to prepare Form DL3. Preferably, according to any embodiment of the method, delgocitinib can be exposed to this temperature for about 2 to about 10 hours, about 3 to about 8 hours, about 3 to 6 hours, or 4 hours. Preferably, in any embodiment of the method, Form DL3 can be prepared by exposing delgocitinib (preferably Form DL1) to a temperature of about 115°C to about 125°C, or about 120°C in an air tray dryer (ATD) for about 3 to about 8 hours, or about 3 to 6 hours. Form DL3 can be cooled to room temperature.

[0081] The above methods for preparing delgocitinib form DL3 can further comprise combining delgocitinib form DL3 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0082] The present disclosure includes crystalline delgocitinib designated as Form DL4. Delgocitinib crystalline Form DL4 can be characterized by one or more of the following: an XRPD pattern having peaks at 7.6, 15.1, 16.1, 22.8, and 23.4 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 4; or a combination of these data.

[0083] Crystalline delgocitinib form DL4 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.6, 15.1, 16.1, 22.8, and 23.4 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 9.3, 25.2, and 28.3 °2θ ± 0.2 °2θ; or a combination of these data.

[0084] Crystalline delgocitinib form DL4 may alternatively be characterized by an XRPD pattern having peaks at 7.6, 9.3, 15.1, 16.1, 22.8, 25.2, 23.4, and 28.3 degrees 2θ±0.2 degrees 2θ.

[0085] Crystalline delgocitinib form DL4 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at any one, two, three, four, or five of: 2.5-6.8°2θ±0.2°2θ; 8.2-8.7°2θ±0.2°2θ; 10.0-13.2°2θ±0.2°2θ; 26.0-27.7°2θ±0.2°2θ.

[0086] Crystalline delgocitinib form DL4 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 7.6, 15.1, 16.1, 22.8, and 23.4 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 4, and combinations thereof.

[0087] Crystalline delgocitinib form DL4 can be characterized as a hydrate form.

[0088] The present disclosure includes crystalline delgocitinib designated as Form DL5. Delgocitinib crystalline Form DL5 can be characterized by one or more of the following: an XRPD pattern having peaks at 9.8, 16.8, 22.4, 25.7, and 26.5 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 6; or a combination of these data.

[0089] Crystalline delgocitinib form DL5 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.8, 16.8, 22.4, 25.7, and 26.5 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 13.0, 14.3, 19.5, and 25.2 °2θ ± 0.2 °2θ; or a combination of these data.

[0090] Crystalline delgocitinib form DL5 may alternatively be characterized by an XRPD pattern having peaks at 9.8, 13.0, 14.3, 16.8, 19.5, 22.4, 25.2, 25.7, and 26.5 degrees 2θ±0.2 degrees 2θ.

[0091] The crystalline delgocitinib form DL5 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 4.0 and 9.0 degrees 2θ ± 0.2 degrees 2θ; and 10.5 and 12.2 degrees 2θ ± 0.2 degrees 2θ.

[0092] Crystalline delgocitinib form DL5 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 9.8, 16.8, 22.4, 25.7, and 26.5°2θ±0.2°2θ, and the XRPD pattern shown in FIG. 6, and combinations thereof.

[0093] Crystalline delgocitinib form DL5 can be characterized as a hydrate form.

[0094] The present disclosure includes crystalline delgocitinib designated as Form DL6. Delgocitinib crystalline Form DL6 can be characterized by one or more of the following: an XRPD pattern having peaks at 6.5, 10.9, 13.5, 15.4, and 18.0 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 7; or a combination of these data.

[0095] Crystalline delgocitinib form DL6 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.5, 10.9, 13.5, 15.4, and 18.0 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.6, 22.4, and 27.0 °2θ ± 0.2 °2θ; or a combination of these data.

[0096] Crystalline delgocitinib form DL6 may alternatively be characterized by an XRPD pattern having peaks at 6.5, 10.9, 13.5, 15.4, 18.0, 19.6, 22.4, and 27.0 degrees 2θ±0.2 degrees 2θ.

[0097] The crystalline delgocitinib form DL6 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 3.5 and 5.2 degrees 2θ ± 0.2 degrees 2θ; and 7.2 and 10.0 degrees 2θ ± 0.2 degrees 2θ.

[0098] Crystalline delgocitinib form DL6 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 6.5, 10.9, 13.5, 15.4, and 18.0 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 7, and combinations thereof.

[0099] Crystalline delgocitinib form DL6 can be characterized as a hydrate form.

[0100] The present disclosure includes crystalline delgocitinib designated as Form DL7. Delgocitinib crystalline Form DL7 can be characterized by one or more of the following: an XRPD pattern having peaks at 4.5, 8.8, 10.5, 14.0, 15.3, and 15.8 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 8; or a combination of these data.

[0101] Crystalline delgocitinib form DL7 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.5, 8.8, 10.5, 14.0, 15.3, and 15.8 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 17.4, 23.6, and 27.1 °2θ ± 0.2 °2θ; or a combination of these data.

[0102] Crystalline delgocitinib form DL7 may alternatively be characterized by an XRPD pattern having peaks at 4.5, 8.8, 10.5, 14.0, 15.3, 15.8, 17.4, 23.6, and 27.1 degrees 2θ±0.2 degrees 2θ.

[0103] The crystalline delgocitinib form DL7 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between 5.2 and 7.0 degrees 2θ ± 0.2 degrees 2θ.

[0104] Crystalline delgocitinib form DL7 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 4.5, 8.8, 10.5, 14.0, 15.3, and 15.8 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 8, and combinations thereof.

[0105] Crystalline delgocitinib form DL7 can be characterized as a hydrate form.

[0106] The present disclosure includes crystalline delgocitinib designated as Form DL8. Delgocitinib crystalline Form DL8 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 6.5, 12.9, 17.8, and 25.7 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 9; or a combination of these data.

[0107] Crystalline delgocitinib form DL8 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 6.5, 12.9, 17.8, and 25.7 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 12.0, 14.8, 18.5, and 20.9 °2θ ± 0.2 °2θ; or a combination of these data.

[0108] Crystalline delgocitinib form DL8 may alternatively be characterized by an XRPD pattern having peaks at 5.9, 6.5, 12.0, 12.9, 14.8, 17.8, 18.5, 20.9, and 25.7 degrees 2θ±0.2 degrees 2θ.

[0109] The crystalline delgocitinib form DL8 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 2.7 and 4.6 degrees 2θ ± 0.2 degrees 2θ; and 7.6 and 10.8 degrees 2θ ± 0.2 degrees 2θ.

[0110] Crystalline delgocitinib form DL8 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 5.9, 6.5, 12.9, 17.8, and 25.7 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 9, and combinations thereof.

[0111] Crystalline delgocitinib form DL8 can be characterized as an acetone solvate.

[0112] The present disclosure includes crystalline delgocitinib designated as Form DL9. Delgocitinib crystalline Form DL9 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.7, 17.2, 18.0, 24.6, and 26.1 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 10; or a combination of these data.

[0113] Crystalline delgocitinib form DL9 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.7, 17.2, 18.0, 24.6, and 26.1 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 15.8, 19.6, 20.4, and 29.8 °2θ ± 0.2 °2θ; or a combination of these data.

[0114] Crystalline delgocitinib form DL9 may alternatively be characterized by an XRPD pattern having peaks at 5.7, 15.8, 17.2, 18.0, 19.6, 20.4, 24.6, 26.1, and 29.8 degrees 2θ±0.2 degrees 2θ.

[0115] The crystalline delgocitinib form DL9 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 3.5-4.8°2θ±0.2°2θ; and 7.0-7.5°2θ±0.2°2θ.

[0116] Crystalline delgocitinib form DL9 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 5.7, 17.2, 18.0, 24.6, and 26.1 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 10, and combinations thereof.

[0117] Crystalline delgocitinib form DL9 may be characterized as an isopropyl alcohol solvate, preferably a hemi-isopropyl alcohol solvate.

[0118] The present disclosure includes crystalline delgocitinib designated as Form DL10. Delgocitinib crystalline Form DL10 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ, and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, 23.6 °2θ ± 0.2 °2θ; an XRPD pattern substantially as shown in Figure 11; or a combination of these data.

[0119] Crystalline delgocitinib form DL10 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ, no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, 23.6 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.6, 21.4, and 26.4 °2θ ± 0.2 °2θ; or a combination of these data.

[0120] Crystalline delgocitinib form DL10 may alternatively be characterized by an XRPD pattern having peaks at 9.1, 13.1, 18.4, 19.6, 21.4, 25.1, 26.4, and 28.6 °2θ ± 0.2 °2θ and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, 23.6 °2θ ± 0.2 °2θ.

[0121] The crystalline delgocitinib form DL10 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at one, two, three, or four of the following angles: 3.5-7.0°2θ±0.2°2θ; 8.0-8.6°2θ±0.2°2θ; 11.2-12.4°2θ±0.2°2θ.

[0122] Crystalline delgocitinib form DL10 may be characterized by each of the above properties alone or in all possible combinations, for example, an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ, and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, 23.6 °2θ ± 0.2 °2θ, and the XRPD pattern shown in Figure 11, and combinations thereof.

[0123] Crystalline delgocitinib form DL10 can be characterized as an anhydrous form.

[0124] Delgocitinib form DL10 described in any aspect or embodiment of the present disclosure can be prepared by a method comprising solvent / antisolvent crystallization. In any aspect or embodiment of the method, delgocitinib form DL10 can be prepared by crystallizing delgocitinib from a mixture of dimethylformamide (DMF) and isobutyl acetate, optionally isolating, and optionally drying. Preferably, the method can include combining a mixture of delgocitinib form DL10 in DMF with isobutyl acetate to crystallize delgocitinib form DL10 from the mixture.

[0125] In any aspect or embodiment of the method, DMF can be used in an amount of about 1.5 vol to about 5 vol, about 2 vol to about 4 vol, or about 2.6 vol relative to delgocitinib. Isobutyl acetate can be used in an amount of about 30 vol to about 100 vol, about 40 vol to about 80 vol, preferably about 50 vol relative to delgocitinib. In any aspect or embodiment of the method, the volume ratio of DMF to isobutyl acetate can be about 1:5 to about 1:30, about 1:10 to about 1:25, or about 1:19 or about 1:20.

[0126] In any aspect or embodiment of the method for preparing delgocitinib form DL10, isobutyl acetate may be combined with a mixture of delgocitinib in DMF, and preferably, the mixture of delgocitinib in DMF is heated, preferably with stirring, to a temperature of about 40°C to about 80°C, about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C.

[0127] In any aspect or embodiment, the method may include adding isobutyl acetate to a solution of delgocitinib, or preferably, adding the delgocitinib solution to isobutyl acetate. In any embodiment of the method, the solution of delgocitinib in DMF is added to isobutyl acetate, preferably at a temperature of about 40°C to about 80°C, about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C. Preferably, the isobutyl acetate is at a temperature of about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 5°C, about -2°C to about 2°C, or about 0°C. The addition may be carried out over a period of about 1 to about 30 minutes, about 1 to about 20 minutes, about 2 to about 10 minutes, about 3 to about 8 minutes, or about 5 minutes.

[0128] According to any embodiment of the above-described method for preparing Form DL10, the reaction mixture comprising delgocitinib, DMF, and isobutyl acetate can be maintained at a temperature of about −10° C. to about 10° C., about −5° C. to about 5° C., about −2° C. to about 5° C., about −2° C. to about 2° C., or about 0° C. The mixture can be maintained at this temperature for about 1 to about 30 hours, about 10 to about 25 hours, about 15 to about 20 hours, or about 18 hours, preferably with stirring.

[0129] In any of the embodiments of the above-described methods for preparing Form DL10, delgocitinib Form DL10 may be isolated. Isolation can be carried out by any suitable means, such as centrifugation, decantation, or filtration, preferably by filtration. Preferably, filtration is carried out at a temperature of about 10°C to about 40°C, preferably about 20°C to about 30°C, or at about room temperature. After isolation, the product may be washed and optionally dried. Drying may be carried out with nitrogen or air, or under vacuum. Drying may be carried out at a temperature of about 20°C to about 50°C, or about 20°C to about 40°C, or about 20°C to about 30°C, or about 25°C. Drying may be carried out for a time sufficient to remove Form DL10, preferably about 5 minutes to 2 hours, in embodiments 10 to 15 minutes. When drying is carried out under vacuum, a pressure of about 1 mbar or about 200 mbar, about 1 mbar to about 100 mbar, about 1 mbar to about 50 mbar, particularly about 5 mbar to about 40 mbar, or more particularly about 20 mbar can be used.

[0130] Delgocitinib form DL10 according to any aspect or embodiment of the present disclosure can be prepared by (i) combining a delgocitinib solution in DMF (preferably at a temperature of about 30°C to about 70°C (preferably, about 40°C to about 65°C, about 50°C to about 65°C, about 55°C to about 65°C, or about 60°C) with isobutyl acetate (preferably, the temperature of the isobutyl acetate is about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 5°C, about -2°C to about 2°C, or about 0°C); and (ii) incubating the mixture for about 2 to about 24 hours (preferably, about 6 to about 22 hours, about 8 to about 20 hours, about 10 to about 20 hours, or about 18 hours), preferably at about -10°C to about 10°C, about -5°C to about 5°C. , (ii) maintaining the mixture at a temperature of about -2°C to about 5°C, about -2°C to about 2°C, or about 0°C; (ii) cooling the mixture to a temperature of about 15°C to about 35°C (preferably, a temperature of about 20°C to about 30°C, or about 25°C); (iii) isolating delgocitinib form DL10 (preferably by filtration); and, optionally, (iv) drying delgocitinib form DL10 (preferably under reduced pressure at a temperature of about 20°C to about 80°C, about 20°C to about 70°C, about 25°C to about 65°C, or about 35°C to about 60°C, or about 40°C to about 50°C), or at about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C).

[0131] When drying is carried out under reduced pressure, a pressure of about 1 mbar or about 200 mbar, about 1 mbar to about 100 mbar, about 1 mbar to about 50 mbar, particularly about 5 mbar to about 40 mbar, or more particularly about 20 mbar can be used.

[0132] The above methods for preparing delgocitinib form DL10 may further comprise combining delgocitinib form DL10 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0133] The present disclosure includes a crystalline form of delgocitinib designated Form DL11. Crystalline form DL11 of delgocitinib can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ, and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ; an XRPD pattern substantially as shown in Figure 12; or a combination of these data.

[0134] Crystalline delgocitinib form DL11 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ, no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ, and one, two, or three additional peaks selected from 11.0, 21.0, and 29.1 °2θ ± 0.2 °2θ; or a combination of these data.

[0135] Crystalline delgocitinib form DL11 may alternatively be characterized by an XRPD pattern having peaks at 11.0, 12.4, 14.6, 18.1, 21.0, 21.9, 26.9, and 29.1 °2θ ± 0.2 °2θ, and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ.

[0136] Crystalline delgocitinib form DL11 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern that does not have peaks at any one, two, three, or four of: 3.5-5.2°2θ±0.2°2θ; 3.5-5.2°2θ±0.2°2θ; 6.5-7.7°2θ±0.2°2θ; and 8.2-10.1°2θ±0.2°2θ.

[0137] Crystalline delgocitinib form DL11 may be characterized by each of the above properties alone or in all possible combinations, for example, an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ; the XRPD pattern shown in Figure 12, and combinations thereof.

[0138] Crystalline delgocitinib form DL11 can be characterized as an anhydrous form.

[0139] The delgocitinib form DL11 described in any aspect or embodiment of the present disclosure can be prepared by exposing delgocitinib (preferably, form DL6 described in any aspect or embodiment herein) to a temperature of about 95°C to about 105°C, or about 100°C, for a time appropriate to prepare form DL11. Delgocitinib can be exposed to this temperature for about 10 to about 60 minutes, about 20 to about 40 minutes, or about 30 minutes. Preferably, in any embodiment of the present method, form DL11 can be prepared by a method comprising exposing delgocitinib (preferably form DL6) to a temperature of about 95°C to about 105°C, or about 100°C, for about 10 to about 60 minutes, about 20 to about 40 minutes, or about 30 minutes in an air tray dryer. Form DL11 can be cooled to room temperature.

[0140] The above methods for preparing delgocitinib form DL11 may further comprise combining delgocitinib form DL11 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0141] The present disclosure includes crystalline delgocitinib designated as Form DL12. Delgocitinib crystalline Form DL12 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.9, 11.4, 12.9, 19.1, and 24.7 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 13; or a combination of these data.

[0142] Crystalline delgocitinib form DL12 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.9, 11.4, 12.9, 19.1, and 24.7 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 11.8, 16.5, 17.9, and 27.2 °2θ ± 0.2 °2θ; or a combination of these data.

[0143] Crystalline delgocitinib form DL12 may alternatively be characterized by an XRPD pattern having peaks at 4.9, 11.4, 11.8, 12.9, 16.5, 17.9, 19.1, 24.7, and 27.2 degrees 2θ±0.2 degrees 2θ.

[0144] The crystalline delgocitinib form DL12 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 3.8 and 4.5 degrees 2θ ± 0.2 degrees 2θ; and 5.5 and 9.0 degrees 2θ ± 0.2 degrees 2θ.

[0145] Crystalline delgocitinib form DL12 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 4.9, 11.4, 12.9, 19.1, and 24.7 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 13, and combinations thereof.

[0146] Crystalline delgocitinib form DL12 may be characterized as a benzyl solvate, preferably a monobenzyl solvate form.

[0147] The present disclosure includes crystalline delgocitinib designated as Form DL13. Delgocitinib crystalline Form DL13 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 15.2, 18.0, 19.8, 22.7, and 25.8 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 14; or a combination of these data.

[0148] Crystalline delgocitinib form DL13 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 15.2, 18.0, 19.8, 22.7, and 25.8 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 7.4, 20.7, 29.1, and 33.8 °2θ ± 0.2 °2θ; or a combination of these data.

[0149] Crystalline delgocitinib form DL13 may alternatively be characterized by an XRPD pattern having peaks at 7.4, 15.2, 18.0, 19.8, 20.7, 22.7, 25.8, 29.1, and 33.8 degrees 2θ±0.2 degrees 2θ.

[0150] The crystalline delgocitinib form DL13 described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks between one or both of 3.0-6.0°2θ±0.2°2θ; and 8.5-9.5°2θ±0.2°2θ.

[0151] Crystalline delgocitinib form DL13 may be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 15.2, 18.0, 19.8, 22.7, and 25.8 °2θ±0.2 °2θ, and the XRPD pattern shown in Figure 14, and combinations thereof.

[0152] Crystalline delgocitinib form DL13 can be characterized as an ethanol solvate.

[0153] The present disclosure includes crystalline delgocitinib hydrochloride. The crystalline delgocitinib hydrochloride can be characterized by one or more of the following data: an XRPD pattern having peaks at 6.6, 12.6, 19.5, 20.1, and 28.0 °2θ±0.2 °2θ; an XRPD pattern substantially as shown in Figure 15; or a combination of these data.

[0154] The crystalline delgocitinib hydrochloride may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.6, 12.6, 19.5, 20.1, and 28.0 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 14.0, 23.4, 24.2, and 24.9 °2θ ± 0.2 °2θ; or a combination of these data.

[0155] Crystalline delgocitinib hydrochloride may alternatively be characterized by an XRPD pattern having peaks at 6.6, 12.6, 14.0, 19.5, 20.1, 23.4, 24.2, 24.9, and 28.0 degrees 2θ±0.2 degrees 2θ.

[0156] The crystalline delgocitinib hydrochloride described in any aspect or embodiment disclosed herein may be further characterized by an XRPD pattern having no peaks at one or both of the ranges 4.0-5.5°2θ±0.2°2θ; and 7.2-8.5°2θ±0.2°2θ.

[0157] Crystalline delgocitinib hydrochloride can be characterized by each of the above properties alone or in all possible combinations, for example, by an XRPD pattern having peaks at 6.6, 12.6, 19.5, 20.1, and 28.0°2θ±0.2°2θ, and the XRPD pattern shown in Figure 15, and combinations thereof.

[0158] In another embodiment of the present disclosure, the crystalline delgocitinib forms DL1-DL13 and crystalline delgocitinib hydrochloride are polymorphically and chemically pure.

[0159] The present disclosure also relates to delgocitinib forms DL1-DL13 and crystalline delgocitinib hydrochloride crystalline forms obtainable by any of the methods described herein, which may include the methods described in the Examples herein below.

[0160] The present disclosure also relates to pharmaceutical compositions comprising crystalline delgocitinib Forms DL1-DL13 and crystalline delgocitinib hydrochloride as described herein, or obtainable by any of the processes described herein below.

[0161] The present invention further includes methods for preparing pharmaceutical compositions comprising crystalline delgocitinib Forms DL1-DL13 and crystalline delgocitinib hydrochloride, the methods comprising combining crystalline delgocitinib Forms DL1-DL13 and crystalline delgocitinib hydrochloride with at least one pharmaceutically acceptable excipient.The present invention further includes methods for preparing crystalline delgocitinib Forms DL1-DL13 and crystalline delgocitinib hydrochloride described herein below, further comprising combining crystalline delgocitinib Forms DL1-DL13 and crystalline delgocitinib hydrochloride with at least one pharmaceutically acceptable excipient.

[0162] The present disclosure also provides methods for preparing solid forms of delgocitinib and delgocitinib hydrochloride, which may include the methods described in the Examples herein below.

[0163] In another aspect, the present disclosure encompasses the above solid forms of delgocitinib and crystalline delgocitinib hydrochloride for use in the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating atopic dermatitis.

[0164] In another aspect, the present disclosure encompasses the use of the above solid forms of delgocitinib and crystalline delgocitinib hydrochloride for the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating atopic dermatitis.

[0165] In yet another embodiment, the present disclosure encompasses a pharmaceutical composition comprising a solid form of delgocitinib and crystalline delgocitinib hydrochloride.

[0166] In specific embodiments, the present disclosure encompasses pharmaceutical formulations comprising solid forms of delgocitinib and crystalline delgocitinib hydrochloride, and at least one pharmaceutically acceptable excipient.

[0167] The present disclosure further includes a method for preparing the pharmaceutical formulations of delgocitinib and crystalline delgocitinib hydrochloride, comprising combining the solid forms of delgocitinib and crystalline delgocitinib hydrochloride, or pharmaceutical compositions containing same, with at least one pharmaceutically acceptable excipient.

[0168] The present disclosure includes a method for preparing the above pharmaceutical composition, which comprises combining the delgocitinib and the above crystalline polymorph of crystalline delgocitinib hydrochloride of the present disclosure with at least one pharmaceutically acceptable excipient.

[0169] The pharmaceutical formulation of the present invention contains the crystalline polymorphs of delgocitinib of the present invention, particularly crystalline delgocitinib forms DL1 to DL13 and crystalline delgocitinib hydrochloride. In addition to the active ingredient, the pharmaceutical formulation of the present invention may contain one or more excipients. Excipients are added to the formulation for various purposes.

[0170] Diluents can increase the bulk of a solid pharmaceutical composition, making pharmaceutical dosage forms containing the composition 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.

[0171] 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, polymethacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0172] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition, including 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, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0173] Glidants can be added to improve the flowability of a non-compacted solid composition 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.

[0174] When a dosage form such as a tablet is produced by compressing a powder composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surface of the punch and die, which can cause the product to have pits and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the pigment. 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.

[0175] 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 compositions of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0176] The solid and liquid compositions may also be dyed using any pharmaceutically acceptable coloring agent to improve their appearance and / or to facilitate patient identification of the product and unit dosage levels.

[0177] In liquid pharmaceutical compositions of the present invention, delgocitinib and delgocitinib hydrochloride and other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0178] Liquid pharmaceutical compositions may contain emulsifiers to uniformly disperse active ingredients or other excipients that are not soluble in the liquid carrier 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.

[0179] 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, including 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, and xanthan gum.

[0180] Sweetening agents (eg, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar) may be added to improve taste.

[0181] Preservatives and chelating agents (e.g., alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid) may be added at levels safe for consumption to improve storage stability.

[0182] According to the present invention, 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.

[0183] The solid compositions of the present invention include powders, granules, aggregates, and compressed compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ocular administration. While the most appropriate administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of administration in the present invention 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.

[0184] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0185] The dosage form of the present invention may be a capsule containing the composition of the present invention, preferably a powdered or granular solid composition, within either a hard or soft shell. The shell may be made from gelatin and may optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[0186] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0187] 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.

[0188] 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.

[0189] As an alternative to dry granulation, the blended composition can be directly compressed into a compacted dosage form using direct compression technology. 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 appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art with experience and expertise in the specific formulation challenges of direct compression tableting.

[0190] The capsule filling of the present invention may include any of the foregoing blends and granules described with respect to tableting, but which are not subjected to a final tableting step.

[0191] The solid forms of delgocitinib and delgocitinib hydrochloride defined herein, as well as pharmaceutical compositions or formulations containing them, can be used as medicaments, in particular for treating atopic dermatitis, comprising administering a therapeutically effective amount of a solid form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from or otherwise in need of treatment for atopic dermatitis.

[0192] The present disclosure further provides the use of the solid forms of delgocitinib and delgocitinib hydrochloride of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, in the manufacture of a medicament for treating atopic dermatitis.

[0193] Although the present disclosure has been described with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art upon consideration of this specification. The present disclosure is further illustrated by reference to the following examples which describe in detail how to prepare and use the compositions of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

[0194] Analysis method Powder X-ray diffraction was performed using a Bruker D8 Advance X-ray powder diffractometer with Cu K radiation (λ = 1.5418 Å); a Lynx Eye detector; a laboratory temperature of 22–25 °C; and a PMMA sample holder. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was placed in the cavity of the sample holder, and the surface of the sample was smoothed with a cover glass.

[0195] Measurement parameters: scanning range: 2-40° 2θ; scanning mode: continuous; step size: 0.05°; time per step: 0.5 s; sample spin: 30 rpm; sample holder: PMMA sample holding ring with silicon low background.

[0196] All X-ray powder diffraction peak values ​​are calibrated with respect to standard silicon spiking in the sample. [Example]

[0197] Delgocitinib can be obtained by any procedure described in the literature, for example, the synthetic procedure reported in U.S. Patent No. 8,609,647 or U.S. Patent No. 10,822,354.The delgocitinib form alpha used in the following examples can be produced according to the procedure described in U.S. Patent No. 11,339,181 and the following procedure 19.

[0198] Example 1: Preparation of delgocitinib form DL1 Delgocitinib (Form alpha, 5.0 grams) and 150 mL of water were heated to 60° C. and maintained with stirring for about 16 hours. The reaction mass was cooled to about 25° C., filtered, dried under vacuum for 1 hour, and analyzed by XRPD to obtain delgocitinib designated as Form DL1 ( FIG. 1 ).

[0199] Example 2. Preparation of delgocitinib form DL2 Delgocitinib form DL1 (0.01 grams) was dried in a thermogravimetric analyzer at 190°C for 2 minutes (heated to 190°C at 10 degrees / min and held stable at 190°C for 2 minutes). The sample was cooled to about 25°C and analyzed by XRPD to obtain delgocitinib designated form DL2 (Figure 2).

[0200] Example 3. Preparation of delgocitinib form DL3 Delgocitinib form DL4 (0.1 grams) was dried in an air tray dryer (ATD) at 120° C. for 4 hours. The sample was cooled to about 25° C. and analyzed by XRPD to obtain delgocitinib designated as form DL3 ( FIG. 3 ).

[0201] Example 4. Preparation of delgocitinib form DL4 Delgocitinib (0.05 grams) and 2 mL of a buffer solution (pH 4.5) were heated to 80°C. The resulting clear solution was cooled to -20°C in about 1 hour and maintained at this temperature with stirring for 15 hours. The reaction mass was heated to 25°C, filtered, dried under vacuum for 20-25 minutes, and analyzed by XRPD to obtain delgocitinib, designated Form DL4 (Figure 4).

[0202] Example 5. Preparation of amorphous delgocitinib Delgocitinib (0.8 grams) was dissolved in acetone (80 mL) at 55 °C. The clear solution was distilled under high vacuum (less than 50 mbar) on a rotary evaporator at 55 °C for approximately 30-45 minutes. The resulting solid was isolated and analyzed by XRPD to obtain amorphous delgocitinib (Figure 5).

[0203] Example 6. Preparation of delgocitinib form DL4 Amorphous delgocitinib (0.1 gram) and water (4 mL) were stirred for approximately 4-5 hours at 25° C. The reaction mass was filtered, dried under vacuum for 20-25 minutes, and analyzed by XRPD, which confirmed that it contained Form DL4.

[0204] Example 7. Preparation of delgocitinib form DL5 Delgocitinib form DL4 (0.1 grams) was dried in an air tray dryer (ATD) for 30 minutes at 100° C. The sample was cooled to about 25° C. and the dried solid was assigned as form DL5 by XRPD ( FIG. 6 ).

[0205] Example 8. Preparation of delgocitinib form DL6 Amorphous delgocitinib (0.1 grams) was exposed to 100% relative humidity (RH) in a humidity chamber (ATD) for 7 days at 25° C. The analyzed solid was assigned as Form DL6 by XRPD ( FIG. 7 ).

[0206] Example 9. Preparation of delgocitinib form DL7 Delgocitinib form DL1 (0.1 grams) was dried in an air tray dryer (ATD) at 100° C. for 30 minutes. The dried sample was cooled to about 25° C. and analyzed by XRPD, and was assigned as form DL7 ( FIG. 8 ).

[0207] Example 10. Preparation of delgocitinib form DL8 Delgocitinib (1.0 gram) was dissolved in acetone (120 mL) at 50° C. The clear solution was distilled on a rotary evaporator under high vacuum (about 300 mbar) at 50° C. for about 1 hour. The solid was isolated and analyzed by XRPD and assigned as Form DL8 (FIG. 9).

[0208] Example 11. Preparation of delgocitinib form DL9 Amorphous delgocitinib (0.03 grams) was ground with isopropyl alcohol (0.05 mL) using a mortar and pestle for 2 minutes. The resulting solid was analyzed by XRPD and assigned as Form DL9 (FIG. 10).

[0209] Example 12. Preparation of delgocitinib form DL2 Amorphous delgocitinib (0.05 grams) and cyclohexane (5 mL) were heated with stirring to 60°C for 1 day. The reaction mass was cooled to about 25°C, filtered, and dried under vacuum for 20-25 minutes. The resulting solid was assigned as Form DL2 by XRPD.

[0210] Example 13. Preparation of delgocitinib form DL3 Delgocitinib form DL1 (2 grams) was dried in an air tray dryer (ATD) at 120° C. for 4 hours. The sample was cooled to about 25° C. The solid was analyzed by XRPD and assigned as form DL3.

[0211] Example 14: Preparation of crystalline delgocitinib form DL10 Delgocitinib (1 gram) was dissolved in DMF (2.6 mL) at 60°C to obtain a clear solution. The clear solution was added to 0°C pre-cooled isobutyl acetate (50 mL) in a reactor. The reaction mixture was maintained at about 0°C with stirring for about 18 hours. The hot reaction mixture was filtered, and the isolated solid was dried under vacuum for 10-15 minutes and analyzed by XRPD to obtain delgocitinib, designated Form DL10 (Figure 1).

[0212] Example 15. Preparation of crystalline delgocitinib form DL11 Delgocitinib form DL6 (0.1 grams) was dried in an air tray dryer (ATD) at 100° C. for 30 minutes. The sample was cooled to about 25° C. and analyzed by XRPD to obtain delgocitinib designated as form DL11 (FIG. 12).

[0213] Example 16. Preparation of crystalline delgocitinib form DL12 Delgocitinib (0.03 grams) was dissolved in benzyl alcohol (0.2 mL) at 60° C. to obtain a clear solution. The clear solution was added to tert-butyl acetate (3 mL) pre-cooled at 0° C. in a reactor. The reaction mixture was maintained under stirring at about 0° C. for about 18 hours, filtered to isolate the solid, dried under vacuum for 10-15 minutes, and analyzed by XRPD to obtain delgocitinib designated as Form DL12 (FIG. 13).

[0214] Example 17. Preparation of crystalline delgocitinib form DL13 Delgocitinib (Form alpha, 0.05 grams) was dissolved in ethanol (4 mL) at 60°C to obtain a clear solution. The clear solution was added to n-heptane (15 mL) preheated to 80°C (approximately 80°C) in a reactor. The reaction mixture was maintained under stirring at approximately 80°C for approximately 1 hour. The hot reaction mixture was filtered, and the isolated solid was dried under vacuum for 10-15 minutes and designated as delgocitinib Form DL13 by XRPD (Figure 14).

[0215] Example 18. Preparation of crystalline delgocitinib hydrochloride Delgocitinib (α form 500 mg) was added to 10 mL of isopropyl acetate at 25° C. IPA.HCl (0.425 mL) was added and maintained under stirring at about 25° C. for about 1 day. The reaction mass was filtered and the isolated solid was dried under vacuum for 20-25 minutes and analyzed by XRPD to obtain crystalline delgocitinib hydrochloride (FIG. 15).

[0216] Example 19. Preparation of crystalline form alpha Delgocitinib (0.03 grams) was dissolved in 1-butanol (1 mL) at 60°C to obtain a clear solution. The clear solution was added to n-decane (5 mL) pre-cooled at 0°C and maintained with stirring at about 0°C for about 18 hours. The reaction mixture was filtered, and the isolated solid was dried under vacuum for 10-15 minutes and designated as Form alpha by XRPD (Figure 16).

[0217] Example 20. Preparation of delgocitinib form DL4 A pH 4.5 buffer solution was prepared according to USP specifications (0.02 M sodium acetate solution and 2 N acetic acid solution). 27.20 grams of sodium acetate trihydrate was weighed into a 1-liter volumetric flask. 800 mL of deionized water was added. Mix and dissolve. The pH was reduced to 4.5 with glacial acetic acid. Finally, the volume was adjusted to 1 liter with deionized water to obtain 1000 mL of a solution with a pH of 4.50 ± 0.05.

[0218] A mixture of delgocitinib (0.05 grams) and buffer solution (2 mL) was heated to 80°C. The resulting solution was cooled to -20°C over approximately 1 hour and maintained at this temperature with stirring for 15 hours. The reaction mixture was allowed to warm to 25°C, and the mixture was filtered. The product was dried under vacuum at room temperature for 20-25 minutes. XRPD analysis confirmed the product to be delgocitinib, designated Form DL4.

[0219] Example 21: Preparation of crystalline delgocitinib form DL10 Delgocitinib (1 gram) was dissolved in DMF (2.6 mL) at 60°C to give a clear solution. The solution was added to pre-cooled isobutyl acetate (50 mL) at 0°C. The reaction mixture was maintained at about 0°C with stirring for about 18 hours. The mixture was allowed to cool, and the solid was isolated by filtration and dried under vacuum at room temperature for 10-15 minutes. XRPD confirmed the presence of Form DL10.

[0220] Example 22. Preparation of crystalline delgocitinib hydrochloride Delgocitinib form α (0.5 grams) was added to isopropyl acetate (10 mL) at 25° C. A solution of HCl (g) in isopropanol (18%, 0.425 mL) was added. The reaction mixture was stirred at about 25° C. for about 1 day. The solid was isolated by filtration, and the product, crystalline delgocitinib hydrochloride, was dried under vacuum at room temperature for 20-25 minutes.

[0221] Example 23. Stability test Storage stability at different relative humidities Samples of the crystalline form of delgocitinib according to the present disclosure 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] These results indicate that Forms DL1, DL2, DL3, DL10 and DL11 are stable after exposure to conditions of high and low relative humidity for at least 7 days.

[0222] Samples of delgocitinib polymorphic forms according to the present disclosure were subjected to different temperature and relative humidity conditions. Form DL1 was stored in a low-density polyethylene bag (twisted and tied) and further covered with a triple-layer laminate bag (heat-sealed). Forms DL2, DL3, DL10, and DL11 were stored in a low-density polyethylene bag (twisted and tied), covered with a triple-layer laminate bag (heat-sealed), and a 2-gram silica gel pouch was placed between the two bags. XRPD analysis was performed on the samples after 1, 2, 3, and 6 months of storage. The results are shown in Tables 2 and 3 below. [Table 2] [Table 3] The results show that Forms DL1, DL2, DL3, DL10, and DL11 are very storage stable.

[0223] Crushing experiment Samples of delgocitinib forms according to the present disclosure were subjected to vigorous grinding.In these experiments, approximately 20 mg of sample was placed in a mortar and crushed with a pestle for 2 minutes.After grinding experiments, XRPD analysis was carried out for each sample (Table 4). [Table 4] The results show that delgocitinib forms DL1, DL2, DL3, DL10, and D11 are resistant to polymorphic changes and are highly suitable for the preparation of pharmaceutical formulations.

[0224] Compression stability A sample of delgocitinib was subjected to 2 tons of pressure (Atlas® Autopress hydraulic press, set at 2 tons). After 2 minutes, XRPD analysis of the sample was performed. The results are shown in Table 5 below: [Table 5] Therefore, delgocitinib forms DL1, DL2, DL3, DL10, and DL11 are stable under high pressure conditions, making these forms highly suitable for pharmaceutical processing.

[0225] Further aspects and embodiments of the present disclosure are described in the following numbered sections. term 1. Crystalline delgocitinib designated as Form DL2, characterized by data selected from an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ±0.2 °2θ, or an XRPD pattern substantially as shown in Figure 2. 2. The crystalline delgocitinib form DL2 according to paragraph 1, characterized by an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.3, 22.2, and 25.5 °2θ ± 0.2 °2θ. 3. The crystalline delgocitinib form DL2 according to paragraph 1 or 2, characterized by an XRPD pattern with peaks at 4.5, 8.8, 14.5, 18.2, 19.3, 22.2, 25.5, 28.5 and 29.3 °2θ±0.2 °2θ. 4. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 3, characterized by an XRPD pattern having no peaks at 3.6 to 4.0°2θ±0.2°2θ. 5. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 4, characterized by an XRPD pattern having no peaks at 5.0 to 8.2°2θ±0.2°2θ. 6. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 5, characterized by an XRPD pattern having no peaks at 9.2 to 12.6°2θ±0.2°2θ. 7. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 6, characterized by an XRPD pattern having no peaks at 13.7 to 14.1°2θ±0.2°2θ. 8. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 7, characterized by an XRPD pattern having no peak at 18.7 to 18.8°2θ±0.2°2θ. 9. The crystalline delgocitinib form DL2 according to any one of paragraphs 1 to 8, which is an anhydrous form. 10. Crystalline delgocitinib designated as Form DL1, characterized by data selected from an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ±0.2 degrees 2θ, or an XRPD pattern substantially as shown in FIG. 1. 11. The crystalline delgocitinib form DL1 of paragraph 10, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ ± 0.2 degrees 2θ, and further having one, two, or three additional peaks selected from 9.0, 19.1, and 27.4 degrees 2θ ± 0.2 degrees 2θ. 12. The crystalline delgocitinib form DL1 according to paragraph 10 or 11, characterized by an XRPD pattern with peaks at 9.0, 9.5, 12.6, 14.3, 16.8, 18.1, 19.1, and 27.4 °2θ±0.2 °2θ. 13. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 12, characterized by an XRPD pattern having no peaks between 3.0 and 6.5°2θ±0.2°2θ. 14. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 13, characterized by an XRPD pattern having no peaks at 7.8 to 8.5°2θ±0.2°2θ. 15. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 14, characterized by an XRPD pattern having no peaks at 10.0 to 10.6° 2θ±0.2° 2θ. 16. The crystalline form of delgocitinib form DL1 according to any one of paragraphs 10 to 15, characterized by an XRPD pattern having no peaks at 11.6 to 12.0° 2θ±0.2° 2θ. 17. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 16, characterized by an XRPD pattern having no peak at 13.6 to 13.8° 2θ ± 0.2° 2θ. 18. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 17, characterized by an XRPD pattern having no peaks at 19.9 to 20.2°2θ±0.2°2θ. 19. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 18, characterized by an XRPD pattern having no peaks at 22.9 to 23.4°2θ±0.2°2θ. 20. The crystalline delgocitinib form DL1 according to any one of paragraphs 10 to 19, which is a hydrate, optionally a monohydrate. 21. Crystalline delgocitinib designated as Form DL3, characterized by data selected from an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8°2θ±0.2°2θ, or an XRPD pattern substantially as depicted in FIG. 3. 22. The crystalline delgocitinib form DL3 of paragraph 21, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 14.1, 22.3, 24.4, and 25.3 °2θ ± 0.2 °2θ. 23. The crystalline delgocitinib form DL3 according to paragraph 21 or 22, characterized by an XRPD pattern having peaks at 9.1, 14.1, 18.6, 21.6, 22.3, 24.4, 25.3, 26.6 and 28.8 °2θ±0.2 °2θ. 24. The crystalline delgocitinib form DL3 according to any one of paragraphs 21 to 23, characterized by an XRPD pattern having no peaks at 2.8 to 3.8°2θ±0.2°2θ. 25. The crystalline delgocitinib form DL3 according to any one of paragraphs 21 to 24, characterized by an XRPD pattern having no peaks at 5.2 to 7.7°2θ±0.2°2θ. 26. The crystalline delgocitinib form DL3 according to any one of paragraphs 21 to 25, characterized by an XRPD pattern having no peaks at 12.0 to 12.6° 2θ ± 0.2° 2θ. 27. The crystalline delgocitinib form DL3 according to any one of paragraphs 21 to 26, which is an anhydrous form. 28. (i) an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ; or (ii) Crystalline delgocitinib designated as Form DL10, characterized by data selected from: an XRPD pattern substantially as depicted in Figure 11. 29. The crystalline delgocitinib form DL10 of paragraph 28, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ, no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.6, 21.4, and 26.4 °2θ ± 0.2 °2θ. 30. The crystalline delgocitinib form DL10 of paragraph 28 or 29, characterized by an XRPD pattern having peaks at 9.1, 13.1, 18.4, 19.6, 21.4, 25.1, 26.4, and 28.6 °2θ ± 0.2 °2θ and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ. 31. The crystalline delgocitinib form DL10 according to any one of paragraphs 28 to 30, further characterized by an XRPD pattern having no peaks between 3.5 and 7.0°2θ±0.2°2θ. 32. Crystalline delgocitinib designated as Form DL10, characterized by an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 degrees 2θ ± 0.2 degrees 2θ, and optionally no peaks between 3.5 and 7.0 degrees 2θ ± 0.2 degrees 2θ. 33. The crystalline delgocitinib form DL10 of any one of paragraphs 28 to 32, characterized by having no peak at 8.0 to 8.6° 2θ ± 0.2° 2θ. 34. The crystalline delgocitinib form DL10 of any one of paragraphs 28 to 33, characterized by having no peak at 11.2 to 12.4°2θ±0.2°2θ. 35. The crystalline delgocitinib form DL10 according to any one of paragraphs 28 to 34, which is an anhydrous form. 36. One or more of the following: (i) an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ; or (ii) Crystalline delgocitinib designated as Form DL11, characterized by data selected from: an XRPD pattern substantially as depicted in Figure 12. 37. The crystalline delgocitinib form DL11 of paragraph 36, characterized by an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ, no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 11.0, 21.0, and 29.1 °2θ ± 0.2 °2θ. 38. The crystalline delgocitinib form DL11 of paragraph 36 or 37, characterized by an XRPD pattern having peaks at 11.0, 12.4, 14.6, 18.1, 21.0, 21.9, 26.9, and 29.1 degrees 2θ ± 0.2 degrees 2θ, and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 degrees 2θ ± 0.2 degrees 2θ. 39. The crystalline delgocitinib form DL11 of any one of paragraphs 36 to 38, further characterized by an XRPD pattern having no peaks at 3.5 to 5.2 degrees 2θ±0.2 degrees 2θ. 40. Crystalline delgocitinib designated as Form DL11, characterized by an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, and 26.9 degrees 2θ ± 0.2 degrees 2θ, and optionally no peak between 3.5 and 5.2 degrees 2θ ± 0.2 degrees 2θ. 41. The crystalline delgocitinib form DL11 of any one of paragraphs 36 to 40, characterized by having no peak at 6.5 to 7.7°2θ±0.2°2θ. 42. The crystalline delgocitinib form DL11 of any one of paragraphs 36 to 41, characterized by having no peak at 8.2 to 10.1 degrees 2θ±0.2 degrees 2θ. 43. The crystalline form of delgocitinib form DL11 according to any one of paragraphs 36 to 42, which is an anhydrous form. 44. The crystalline product of any one of items 1 to 43, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other crystalline form of delgocitinib. 45. The crystalline product of any one of paragraphs 1 to 44, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous delgocitinib. 46. ​​A pharmaceutical composition comprising the crystalline product according to any one of items 1 to 45. 47. Use of the crystalline product according to any one of paragraphs 1 to 45 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation. 48. A pharmaceutical formulation comprising the crystalline product according to any one of items 1 to 45 or the pharmaceutical composition according to item 46, and at least one pharmaceutically acceptable excipient. 49. A method for preparing the pharmaceutical formulation of item 48, comprising combining the crystalline product of any one of items 1 to 45 or the pharmaceutical composition of item 46 with at least one pharmaceutically acceptable excipient. 50. The crystalline product according to any one of items 1 to 45, the pharmaceutical composition according to item 46, or the pharmaceutical formulation according to item 48, for use as a pharmaceutical. 51. The crystalline product according to any one of items 1 to 45, the pharmaceutical composition according to item 46, or the pharmaceutical formulation according to item 48 for use in the treatment of atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema and atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; particularly atopic dermatitis. 52. A method for treating atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema or atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; particularly a method for treating atopic dermatitis, comprising administering a therapeutically effective amount of the crystalline product according to any one of items 1 to 45, the pharmaceutical composition according to item 46, or the pharmaceutical formulation according to item 48 to a subject in need of treatment. 53. The crystalline product according to any one of items 1 to 45, the pharmaceutical composition according to item 46, or the pharmaceutical formulation according to item 48 for the manufacture of a pharmaceutical for the treatment of atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema and atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; and in particular atopic dermatitis. 54. Use of the crystalline product according to any one of paragraphs 1 to 45 in the preparation of another solid form of delgocitinib or a salt of delgocitinib or a solid form thereof.

Claims

1. 2. A crystalline delgocitinib designated as Form DL2, characterized by data selected from an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ±0.2 °2θ, or an XRPD pattern substantially as shown in FIG.

2.

2. 2. The crystalline delgocitinib form DL2 of claim 1, characterized by an XRPD pattern having peaks at 4.5, 8.8, 14.5, 18.2, 28.5, and 29.3 °2θ±0.2 °2θ, and further having one, two, or three additional peaks selected from 19.3, 22.2, and 25.5 °2θ±0.2 °2θ.

3. 3. The crystalline delgocitinib form DL2 of claim 1 or 2, characterized by an XRPD pattern with peaks at 4.5, 8.8, 14.5, 18.2, 19.3, 22.2, 25.5, 28.5, and 29.3 degrees 2θ±0.2 degrees 2θ.

4. The crystalline delgocitinib form DL2 of any one of claims 1 to 4 or 8, which is in an anhydrous form.

5. 1. A crystalline delgocitinib designated as Form DL1, characterized by data selected from an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ±0.2 degrees 2θ, or an XRPD pattern substantially as shown in FIG. 1 .

6. 6. The crystalline delgocitinib form DL1 of claim 5, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.5, 12.6, 14.3, 16.8, and 18.1 degrees 2θ±0.2 degrees 2θ, and further having one, two, or three additional peaks selected from 9.0, 19.1, and 27.4 degrees 2θ±0.2 degrees 2θ.

7. 7. The crystalline delgocitinib form DL1 of claim 5 or 6, characterized by an XRPD pattern with peaks at 9.0, 9.5, 12.6, 14.3, 16.8, 18.1, 19.1, and 27.4 °2θ±0.2 °2θ.

8. The crystalline delgocitinib form DL1 according to any one of claims 5 to 7, which is a hydrate, optionally a monohydrate.

9. 3. A crystalline delgocitinib designated as Form DL3, characterized by data selected from an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ±0.2 °2θ, or an XRPD pattern substantially as shown in FIG.

10. 10. The crystalline delgocitinib form DL3 of claim 9, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 18.6, 21.6, 26.6, and 28.8 °2θ ± 0.2 °2θ, and further having one, two, three, or four additional peaks selected from 14.1, 22.3, 24.4, and 25.3 °2θ ± 0.2 °2θ.

11. 11. The crystalline delgocitinib form DL3 of claim 9 or 10, characterized by an XRPD pattern with peaks at 9.1, 14.1, 18.6, 21.6, 22.3, 24.4, 25.3, 26.6, and 28.8 °2θ±0.2 °2θ.

12. The crystalline delgocitinib form DL3 of any one of claims 9 to 11, which is in anhydrous form.

13. (i) an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ; or (ii) an XRPD pattern substantially as shown in Figure 11; 1. A crystalline delgocitinib designated as Form DL10, characterized by data selected from:

14. 14. The crystalline delgocitinib form DL10 of claim 13, characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.1, 13.1, 18.4, 25.1, and 28.6 °2θ ± 0.2 °2θ, no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 19.6, 21.4, and 26.4 °2θ ± 0.2 °2θ.

15. 15. The crystalline delgocitinib form DL10 of claim 13 or 14, characterized by an XRPD pattern having peaks at 9.1, 13.1, 18.4, 19.6, 21.4, 25.1, 26.4, and 28.6 °2θ ± 0.2 °2θ and no peaks at 4.5, 10.2, 11.4, 11.8, 12.7, 18.0, 20.3, 21.8, and 23.6 °2θ ± 0.2 °2θ.

16. The crystalline delgocitinib form DL10 of any one of claims 13 to 15, which is in an anhydrous form.

17. One or more of the following: (i) an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ; or (ii) an XRPD pattern substantially as shown in Figure 12; 1. A crystalline delgocitinib designated as Form DL11, characterized by data selected from:

18. 18. The crystalline delgocitinib form DL11 of claim 17, characterized by an XRPD pattern having peaks at 12.4, 14.6, 18.1, 21.9, 26.9 °2θ ± 0.2 °2θ, no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ, and further having one, two, or three additional peaks selected from 11.0, 21.0, and 29.1 °2θ ± 0.2 °2θ.

19. 19. The crystalline delgocitinib form DL11 of claim 17 or 18, characterized by an XRPD pattern having peaks at 11.0, 12.4, 14.6, 18.1, 21.0, 21.9, 26.9, and 29.1 °2θ ± 0.2 °2θ and no peaks at 4.5, 8.8, 10.2, 11.4, 11.8, 15.6, 16.5, 19.3, 20.3, 23.8, and 26.0 °2θ ± 0.2 °2θ.

20. The crystalline form of delgocitinib form DL11 of any one of claims 17 to 19, which is in an anhydrous form.

21. The crystalline product of any one of claims 1 to 20, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other crystalline form of delgocitinib.

22. 22. The crystalline product of any one of claims 1-21, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous delgocitinib.

23. A pharmaceutical composition comprising the crystalline product of any one of claims 1 to 22.

24. Use of the crystalline product according to any one of claims 1 to 22 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation.

25. A pharmaceutical formulation comprising the crystalline product of any one of claims 1 to 22 or the pharmaceutical composition of claim 23, and at least one pharmaceutically acceptable excipient.

26. 26. A process for preparing the pharmaceutical formulation of claim 25, comprising combining the crystalline product of any one of claims 1 to 22, or the pharmaceutical composition of claim 23, with at least one pharmaceutically acceptable excipient.

27. A crystalline product according to any one of claims 1 to 22, a pharmaceutical composition according to claim 23 or a pharmaceutical formulation according to claim 25 for use as a medicament.

28. 26. A crystalline product according to any one of claims 1 to 22, a pharmaceutical composition according to claim 23 or a pharmaceutical formulation according to claim 25 for use in the treatment of atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema and atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; in particular atopic dermatitis.

29. 26. A method for treating atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema or atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; in particular atopic dermatitis, comprising administering to a subject in need of said treatment a therapeutically effective amount of the crystalline product of any one of claims 1 to 22, the pharmaceutical composition of claim 23, or the pharmaceutical formulation of claim 25.

30. 26. The crystalline product of any one of claims 1 to 22, the pharmaceutical composition of claim 23 or the pharmaceutical formulation of claim 25 for the manufacture of a medicament for the treatment of atopic dermatitis, including moderate to severe atopic dermatitis; eczema, including moderate to severe chronic hand eczema and atopic eczema; discoid lupus erythematosus; alopecia areata; or psoriasis; in particular atopic dermatitis.

31. Use of the crystalline product of any one of claims 1 to 22 in the preparation of another solid form of delgocitinib or a salt of delgocitinib or a solid form thereof.

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