Solid forms of JAK inhibitors and processes for their preparation

Abstract

The present disclosure relates to solid forms of rusotinib dihydrate and rusotinib free base, methods of preparing the same, and compositions comprising the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Nos. 63 / 352,094, filed on June 14, 2022, and 63 / 411,808, filed on September 30, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to solid forms of ruxolitinib di-hydrate and ruxolitinib free base, methods of preparing the same, and compositions comprising the same. Background Art

[0004] The Janus kinase family of protein tyrosine kinases (JAKs) belongs to non-receptor tyrosine kinases and includes family members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as leukocyte Janus kinase; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as protein tyrosine kinase 2). Pathways involving JAKs and signal transducers and activators of transcription (STATs) are involved in the signal transduction of a variety of cytokines. Cytokines are low molecular weight polypeptides or glycoproteins that stimulate biological responses in almost all cell types. In general, cytokine receptors do not have intrinsic tyrosine kinase activity, and therefore require receptor-associated kinases to propagate phosphorylation cascades. JAKs meet this function. Cytokines bind to their receptors, resulting in receptor dimerization, and this enables JAKs to phosphorylate specific tyrosine motifs within each other and cytokine receptors. STATs that recognize these phosphotyrosine motifs are recruited to the receptors, and then themselves are activated by JAK-dependent tyrosine phosphorylation events. Upon activation, STATs dissociate from the receptors, dimerize, and translocate to the nucleus, thereby binding to specific DNA sites and altering transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." Clin Diagn Lab Immunol 9(6): 1153-9).

[0005] The JAK family plays a role in the cytokine-dependent regulation of cell proliferation and function involved in immune responses. It is believed that the JAK / STAT pathway and in particular all four JAK family members play a role in the pathogenesis of asthmatic reactions, chronic obstructive pulmonary disease, bronchitis and other related inflammatory diseases of the lower respiratory tract. In addition, a variety of cytokines that conduct signals through JAK kinases have always been associated with inflammatory diseases or illnesses of the upper respiratory tract, such as those that affect the nose and sinuses (e.g., rhinitis, sinusitis), regardless of whether it is a typical allergic reaction. The JAK / STAT pathway is also involved in the inflammatory diseases / illnesses of the eyes, including but not limited to iritis, uveitis, scleritis, conjunctivitis and chronic allergic reactions.

[0006] Consistent with the foregoing, the JAK 1 / 2 inhibitor ruxolitinib ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile) has been approved in the United States as an oral agent for the treatment of myelofibrosis, polycythemia vera, acute graft-versus-host disease, and chronic graft-versus-host disease. Ruxolitinib has also been approved as a topical cream for the treatment of atopic dermatitis and has been studied in clinical trials for the treatment of vitiligo and psoriasis.

[0007] The above-mentioned approved products currently use the phosphate salt of ruxolitinib. Stable crystalline ruxolitinib phosphate is described and patented in U.S. Patent No. 8,722,693. In view of the successful use of stable crystalline ruxolitinib phosphate in approved drugs, there is no need to study other salts or solid forms of the free base. However, surprisingly, the applicant discovered the crystalline dihydrate form of ruxolitinib described herein during the scale-up work related to the manufacture of surface products using ruxolitinib phosphate. Therefore, crystalline ruxolitinib dihydrate, as well as methods for preparing and including the use of crystalline ruxolitinib dihydrate in certain pharmaceutical formulations are discussed herein.

[0008] Other solid forms of ruxolitinib, such as anhydrous crystalline ruxolitinib free base, are also discussed herein. Summary of the invention

[0009] The present disclosure provides, inter alia, a solid form, which is a ruxolitinib dihydrate having the following structure:

[0010]

[0011] The present disclosure provides a solid form which is crystalline ruxolitinib free base.

[0012] The present disclosure also provides a method for preparing a solid form of ruxolitinib dihydrate, the method comprising isolating the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component. The present disclosure also provides a method for preparing anhydrous crystalline ruxolitinib free base.

[0013] The present disclosure also provides a pharmaceutical composition in a solid form comprising ruxolitinib dihydrate. The present disclosure also provides a pharmaceutical composition comprising anhydrous crystalline ruxolitinib free base. In one aspect, the pharmaceutical composition is a topical pharmaceutical preparation. In one aspect, the pharmaceutical composition is an oral dosage form, and the oral dosage form is a sustained release dosage form. The present disclosure also provides a method for preparing a topical pharmaceutical preparation for coating the skin, the method comprising incorporating ruxolitinib dihydrate into the preparation. The present disclosure also provides a method for preparing a topical pharmaceutical preparation for coating the skin, the method comprising incorporating anhydrous crystalline ruxolitinib free base into the preparation.

[0014] The present disclosure also provides a method for preparing an oral formulation, the method comprising mixing or granulating ruxolitinib dihydrate with one or more pharmaceutically acceptable carriers. The present disclosure also provides a method for preparing an oral formulation, the method comprising mixing or granulating anhydrous crystalline ruxolitinib free base with one or more pharmaceutically acceptable carriers.

[0015] The present disclosure also provides methods of treating a disease described herein in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition or solid form of the present disclosure.

[0016] The present disclosure also provides methods of treating a skin disorder comprising applying a pharmaceutical composition or solid form described herein to an affected area of ​​a patient's skin.

[0017] The present disclosure also provides ruxolitinib dihydrate for use in any of the methods described herein. The present disclosure also provides anhydrous crystalline ruxolitinib free base for use in any of the methods described herein. The present disclosure also provides the use of ruxolitinib dihydrate for the preparation of a medicament for use in any of the methods described herein. The present disclosure also provides the use of anhydrous crystalline ruxolitinib free base for the preparation of a medicament for use in any of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is an Oak Ridge Thermal Ellipsoid Plot (ORTEP) representation of the single X-ray crystal structure of crystalline ruxolitinib dihydrate.

[0019] Figure 2 is an X-ray powder diffraction (XRPD) pattern of a representative sample of crystalline ruxolitinib dihydrate.

[0020] Figure 3 is a differential scanning calorimetry (DSC) thermogram of crystalline ruxolitinib dihydrate.

[0021] Figure 4 is a thermogravimetric analysis (TGA) thermogram of crystalline ruxolitinib dihydrate.

[0022] Figure 5 is a dynamic vapor sorption (DVS) analysis of crystalline ruxolitinib dihydrate.

[0023] Figure 6 is a comparison of the XRPD pattern of crystalline ruxolitinib dihydrate with the XRPD of crystalline ruxolitinib phosphate.

[0024] Figure 7 is and produces Figure 2 The XRPD pattern of the sample was compared to the XRPD pattern of crystalline ruxolitinib dihydrate from another batch.

[0025] Figure 8 is the XRPD pattern of crystalline ruxolitinib dihydrate after DVS.

[0026] Fig. 9 is the XRPD pattern of a representative sample of crystalline ruxolitinib dihydrate.

[0027] Fig.10 is a DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate.

[0028] Fig.11 is a TGA thermogram of a representative sample of crystalline ruxolitinib dihydrate.

[0029] Fig.12 Figure 2 is a DVS analysis of a representative sample of crystalline ruxolitinib dihydrate.

[0030] Fig.13 is the XRPD pattern of a representative sample of anhydrous crystalline ruxolitinib free base.

[0031] Fig.14 Compared to P 2 O 5 XRPD pattern of anhydrous crystalline Ruxolitinib free base produced via vacuum drying.

[0032] Fig.15 is the DSC thermogram of a representative sample of anhydrous crystalline ruxolitinib free base.

[0033] Fig.16 is the DSC thermogram of a representative sample of anhydrous crystalline ruxolitinib free base.

[0034] Fig.17is a TGA thermogram of a representative sample of anhydrous crystalline ruxolitinib free base.

[0035] Fig.18 is a TGA thermogram of a representative sample of anhydrous crystalline ruxolitinib free base.

[0036] Fig.19 Figure 2 is a DVS analysis of a representative sample of anhydrous crystalline ruxolitinib free base.

[0037] Fig. 20 is the XRPD pattern of anhydrous crystalline ruxolitinib free base after DVS compared to the starting material.

[0038] Fig.21 is the calculated XRPD pattern of Ruxolitinib dihydrate. DETAILED DESCRIPTION

[0039] Ruxolitinib dihydrate

[0040] The present disclosure provides, inter alia, a solid form which is crystalline ruxolitinib dihydrate:

[0041]

[0042] In some embodiments, the solid form is substantially isolated.

[0043] In some embodiments, the solid form is characterized by having at least one XRPD peak selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least two XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least three XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least four XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least five XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least six XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having an XRPD peak selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (± 0.2 degrees).

[0044] In some embodiments, the solid form is characterized by having an XRPD peak selected from 19.0, 22.7, and 23.1 degrees with respect to 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 10.6 and 15.4 degrees with respect to 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 11.6 and 25.7 degrees with respect to 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 6.9 and 21.8 degrees with respect to 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 12.9, 15.1, and 24.8 degrees with respect to 2-θ (± 0.2 degrees).

[0045] In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 1, Table 2, Table 3A or Table 3B with respect to 2-theta (±0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 1 with respect to 2-theta (±0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 2 with respect to 2-theta (±0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 3A with respect to 2-theta (±0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 3B with respect to 2-theta (±0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from the peaks described in Table 1, Table 2, Table 3A, or Table 3B in terms of 2-theta (± 0.2 degrees).

[0046] In some embodiments, the solid form is characterized by having characteristic peaks substantially as Figure 2 In some embodiments, the solid form is characterized by having characteristic peaks substantially as shown in Fig. 9 The XRPD pattern shown in .

[0047] In some embodiments, the solid form is characterized by single crystal x-ray diffraction having a space group of P212121 and a unit cell formula unit (Z) of 8. In some embodiments, the solid form has unit cell parameters: a is about b is about c is about α is about 90°, β is about 90°, and γ is about 90°.

[0048] In some embodiments, the solid form is characterized by an endothermic peak in a DSC thermogram with an onset temperature (±5°C) of 61°C and a maximum temperature (±5°C) of 67°C. In some embodiments, the solid form is characterized by an endothermic peak in a DSC thermogram with an onset temperature (±5°C) of 61 to 68°C and a maximum temperature (±5°C) of 67 to 72°C. In some embodiments, the solid form is characterized by an endothermic peak in a DSC thermogram with an onset temperature (±5°C) of 68°C and a maximum temperature (±5°C) of 72°C. In some embodiments, the solid form is characterized by a first endothermic peak in a DSC thermogram with an onset temperature (±5°C) of 68°C and a maximum temperature (±5°C) of 72°C and a second endothermic peak with a maximum temperature (±5°C) of 110°C.

[0049] In some embodiments, the solid form is characterized by having substantially Figure 3 In some embodiments, the solid form is characterized by having substantially Fig.10 DSC thermogram shown in .

[0050] In some embodiments, the solid form is characterized by having substantially Figure 4 In some embodiments, the solid form is characterized by having substantially Fig.11 TGA thermogram shown in .

[0051] Provided herein is a method for preparing a solid form that is a dihydrate of ruxolitinib, the method comprising contacting ruxolitinib free base with water.

[0052] Provided herein is a method for preparing a solid form that is a dihydrate of ruxolitinib, the method comprising isolating the solid form from a solution comprising a free base of ruxolitinib and an aqueous solvent component.

[0053] Isolating may comprise crystallizing the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component.

[0054] In some embodiments, crystallization comprises cooling the solution to allow crystallization of the solid form.

[0055] In some embodiments, crystallization comprises:

[0056] a) heating a solution comprising ruxolitinib free base and an aqueous solvent component; and

[0057] b) After said heating, the solution is cooled to allow crystallization of a solid form.

[0058] In some embodiments, crystallization comprises:

[0059] a) heating a solution comprising ruxolitinib free base and an aqueous solvent component;

[0060] b) cooling the solution after said heating;

[0061] c) adding seed crystals of crystalline Jakafi Jakafi dihydrate to the solution after said cooling; and

[0062] d) after said adding said seed crystals, stirring the solution to crystallize a solid form.

[0063] In some embodiments, amorphous ruxolitinib free base is used to form the solution.

[0064] In step a), the solution comprising ruxolitinib free base and the solvent mixture may be heated to a temperature of about 40° C. to about 80° C. In some embodiments, in step a), the solution comprising ruxolitinib free base and the solvent mixture is heated to a temperature of about 50° C. to about 70° C. In some embodiments, in step a), the solution comprising ruxolitinib free base and the solvent mixture is heated to a temperature of about 55° C. to about 65° C.

[0065] In step b), the solution may be cooled to a temperature of about 10° C. to about 40° C. In some embodiments, in step b), the solution is cooled to a temperature of about 15° C. to about 35° C. In some embodiments, in step b), the solution is cooled to a temperature of about 20° C. to about 30° C. In some embodiments, in step b), the solution is cooled to a temperature of about ambient temperature.

[0066] In step d), the solution may be stirred for about 1 to about 30 hours. In some embodiments, in step d), the solution is stirred for about 10 to about 20 hours. In some embodiments, in step d), the solution is stirred for about 14 to about 18 hours.

[0067] In some embodiments, the aqueous solvent component is water.

[0068] In some embodiments, the aqueous solvent component comprises a polar protic solvent and water. In some embodiments, the polar protic solvent is an alcohol. In some embodiments, the polar protic solvent is C 1-6 In some embodiments, C 1-6In some embodiments, the volume to volume ratio of polar protic solvent to water is about 1 to 0.1 to about 1 to 10. In some embodiments, the volume to volume ratio of polar protic solvent to water is about 1 to 0.5 to about 1 to 5. In some embodiments, the volume to volume ratio of polar protic solvent to water is about 1 to 1 to about 1 to 3. In some embodiments, the volume to volume ratio of polar protic solvent to water is about 1 to 2 to about 1 to 2.5.

[0069] Ruxolitinib free base can be prepared by a method comprising treating Ruxolitinib phosphate:

[0070]

[0071] Reacts with the base in the solvent component.

[0072] In some embodiments, the ruxolitinib free base is amorphous.

[0073] In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 1 to about 10 molar equivalents of base relative to ruxolitinib phosphate. In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 1 to about 5 molar equivalents of base relative to ruxolitinib phosphate. In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 1 to about 3 molar equivalents of base relative to ruxolitinib phosphate. In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 2 to about 10 molar equivalents of base relative to ruxolitinib phosphate. In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 2 to about 5 molar equivalents of base relative to ruxolitinib phosphate. In some embodiments, reacting ruxolitinib phosphate with a base comprises using about 2 to about 3 molar equivalents of base relative to ruxolitinib phosphate.

[0074] In some embodiments, reacting the ruxolitinib phosphate with a base comprises using a sufficient amount of base to produce a pH value of about 7.5 to about 8. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using a sufficient amount of base to produce a pH value of about 7 to about 8.

[0075] In some embodiments, the base is a hydroxide base. In some embodiments, the base is an alkali metal hydroxide or an alkaline earth metal hydroxide. In some embodiments, the base is an alkali metal hydroxide. In some embodiments, the base is an alkaline earth metal hydroxide. In some embodiments, the base is KOH. In some embodiments, the base is NaOH.

[0076] In some embodiments, the solvent component comprises water. In some embodiments, the solvent component comprises one or more aprotic solvents and water. In some embodiments, the solvent component comprises water, an ester solvent, a halogenated solvent, or a mixture thereof. In some embodiments, the ester solvent is ethyl acetate. In some embodiments, the halogenated solvent is dichloromethane. In some embodiments, the solvent component comprises ethyl acetate, dichloromethane, and water.

[0077] In some embodiments, the solvent mixture containing ruxolitinib phosphate is cooled to a temperature of about 0°C to about 10°C. In some embodiments, the solvent mixture containing ruxolitinib phosphate is cooled to a temperature of about 0°C to about 5°C.

[0078] Provided herein is a solid form of ruxolitinib dihydrate prepared by any one of the methods described herein.

[0079] Anhydrous crystalline ruxolitinib free base

[0080] The present disclosure also provides, inter alia, a solid form that is an anhydrous crystalline ruxolitinib free base. In some embodiments, the solid form is Form I. In some embodiments, the solid form is substantially isolated.

[0081] In some embodiments, the solid form is characterized by having at least one XRPD peak selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least two XRPD peaks selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least three XRPD peaks selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least four XRPD peaks selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least five XRPD peaks selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having at least six XRPD peaks selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having an XRPD peak selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees 2-theta (±0.2 degrees).

[0082] In some embodiments, the solid form is characterized by having an XRPD peak selected from 7.2, 13.2, and 15.8 degrees in terms of 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 19.6 and 23.9 degrees in terms of 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 11.5 and 15.4 degrees in terms of 2-θ (± 0.2 degrees). In some embodiments, the solid form is characterized by having other XRPD peaks selected from 11.6 and 19.1 degrees in terms of 2-θ (± 0.2 degrees).

[0083] In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 9A or Table 9B with respect to 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 9A with respect to 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from any one, two, three, four, five, six or more peaks described in Table 9B with respect to 2-theta (± 0.2 degrees). In some embodiments, the solid form is characterized by having XRPD peaks selected from the peaks described in Table 9A or Table 9B with respect to 2-theta (± 0.2 degrees).

[0084] In some embodiments, the solid form is characterized by having characteristic peaks substantially as Fig.13 The XRPD pattern shown in .

[0085] In some embodiments, the solid form is characterized by an endothermic peak in the DSC thermogram having an onset temperature (±5°C) of 83°C and a maximum temperature (±5°C) of 93°C. In some embodiments, the solid form is characterized by an endothermic peak in the DSC thermogram having an onset temperature (±5°C) of 81°C and a maximum temperature (±5°C) of 91°C. In some embodiments, the solid form is characterized by having substantially Fig.15 or Fig.16 DSC thermogram shown in .

[0086] In some embodiments, the solid form is characterized by having substantially Fig.17 or Fig.18 TGA thermogram shown in .

[0087] Provided herein are methods for preparing anhydrous crystalline ruxolitinib free base. In some embodiments, the method for preparing anhydrous crystalline ruxolitinib free base comprises drying ruxolitinib dihydrate.

[0088] Drying may comprise drying the crystalline ruxolitinib dihydrate in a vacuum oven from about room temperature to about 60°C. In some embodiments, drying is performed at about room temperature, 35°C, 40°C, 45°C, 50°C, 55°C, or 60°C. In some embodiments, drying is performed for about 1 day to about 10 days. In some embodiments, drying is performed for about 1 day to about 5 days. In some embodiments, drying is performed for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, drying comprises drying the crystalline ruxolitinib dihydrate in a jar containing a desiccant at about room temperature. In some embodiments, the desiccant is P 2 O 5In some embodiments, drying is performed for about 4 to 10 days. In some embodiments, drying is performed for about 4 to 5 days.

[0089] Provided herein is anhydrous crystalline ruxolitinib prepared by any one of the methods described herein.

[0090] Generally, in the context of temperature amounts or reagent equivalents used in the synthetic processes described herein, the term "about" means ± 10%. In some embodiments, the term "about" means ± 5%.

[0091] Solid forms can be detected, identified and characterized by well-known techniques such as, but not limited to, X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), single crystal X-ray diffraction measurement, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution rate further help identify the form and help determine stability and solvent / water content.

[0092] The XRPD pattern of reflection (peak) is generally considered to represent a specific crystalline form. As is well known, the relative intensity of the XRPD peak can vary widely, depending in particular on sample preparation techniques, crystal size distribution, the various filters used, sample installation procedures and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or setting. As used herein, "peak" refers to any peak or other special features that will be recognized by those skilled in the art that are not attributed to background noise. Peak assignment values ​​(such as those reported herein) can vary ± about 0.2 ° (2-θ). As used herein in the context of XRPD, the terms "substantially" and "about" are meant to encompass all of the above-mentioned variations.

[0093] In the same manner, temperature readings in conjunction with DSC, TGA or other thermal experiments may vary by about ±5°C, depending on the instrument, specific settings, sample preparation, etc. Therefore, crystalline forms reported herein as having a DSC thermogram "substantially" as shown in any Figure, or the term "about", should be understood to accommodate such variations.

[0094] In some embodiments, solid forms as described herein can be substantially separated. "Substantially separated" means that the solid form is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in a compound or intermediate. Substantially separating can include a composition containing at least about 50 % by weight, at least about 60 % by weight, at least about 70 % by weight, at least about 80 % by weight, at least about 90 % by weight, at least about 95 % by weight, at least about 97 % by weight, or at least about 99 % by weight of a compound or intermediate.

[0095] In some embodiments, ruxolitinib dihydrate is crystalline.

[0096] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are understood in the art and typically refer to a temperature that is approximately the temperature of the room in which the reaction is carried out (e.g., reaction temperature), for example a temperature of about 20°C to about 30°C.

[0097] The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy or spectrophotometry (eg, UV-visible); or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), or other related techniques.

[0098] As used herein, the terms "reacting" and "contacting" are used as known in the art and generally refer to bringing together chemical reagents in a manner that allows them to interact at the molecular level to achieve a chemical or physical transformation. In some embodiments, the reaction involves two reagents, wherein one or more equivalents of the second reagent are used relative to the first reagent. The reaction steps of the methods described herein can be carried out for a certain period of time and under conditions suitable for preparing the identified product.

[0099] The reaction of the methods described herein can be carried out in a suitable solvent. Suitable solvents may not react substantially with starting materials (reactants), intermediates or products at a temperature (e.g., a temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent) for the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the specific reaction steps, a suitable solvent can be selected for the specific reaction steps. In some embodiments, the reaction can be carried out in the absence of a solvent, such as when at least one of the reagents is a liquid or a gas.

[0100] Suitable solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, 1,1,1-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof, and the like.

[0101] Suitable solvents may include ether solvents such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, mixtures thereof, and the like.

[0102] Suitable protic solvents may include, for example, but are not limited to, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol or 3-pentanol, neopentyl alcohol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, mixtures thereof, and the like.

[0103] Suitable aprotic solvents may include, for example, but are not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, mixtures thereof, and the like.

[0104] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane (eg, n-heptane), ethylbenzene, m-, o- or p-xylene, octane, indane, nonane, naphthalene, mixtures thereof, and the like.

[0105] The reactions described herein can be carried out at a suitable temperature. The reaction temperature will depend on, for example, the melting and boiling points of the reagents and solvents (if present); the thermodynamics of the reaction (e.g., a violently exothermic reaction may require a low temperature); and the kinetics of the reaction (e.g., a high activation barrier may require a high temperature). "Elevated body temperature" refers to a temperature above room temperature (room temperature may include a temperature of about 20°C to about 30°C).

[0106] The reactions of the methods described herein can be carried out in air or under an inert atmosphere. In general, reactions involving reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan.

[0107] Exemplary bases include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, and potassium hydroxide), alkaline earth metal hydroxides (e.g., calcium hydroxide), and alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, and potassium carbonate). Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein: alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and tert-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl substituted amides.

[0108] Following preparation of the solid forms of the present disclosure (and intermediates used to prepare the solid forms), concentration, filtration, extraction, solid phase extraction, recrystallization, chromatography, and the like may be used to isolate one or more desired products.

[0109] Drug preparations and dosage forms

[0110] Typically, in the context of the amount of an excipient or active ingredient in the compositions, formulations, and dosage forms described herein, the term "about" means ± 10%. In some embodiments, the term "about" means ± 5%.

[0111] When used as a drug, the compounds or solid forms described herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and on the area to be treated. Administration can be surface (including transdermal, transepidermal, transocular and to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose, or may be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers; aqueous, powder or oily bases; thickeners, etc. may be necessary or required. Coated condoms, gloves, etc. may also be useful.

[0112] Also provided herein is a pharmaceutical composition comprising a solid form as described herein. The pharmaceutical composition contains a combination of one or more of the solid forms described herein as active ingredients and one or more pharmaceutically acceptable carriers (excipients). In the preparation of the composition, the active ingredient is usually mixed with an excipient, diluted with an excipient or surrounded in such a carrier in the form of a capsule, saccharide, paper or other container. When an excipient acts as a diluent, it can be a solid, semisolid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the following forms: tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0113] When preparing a formulation, the active compound may be ground to provide an appropriate particle size prior to combining with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0114] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The composition may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

[0115] As used herein, "based on free base" refers to the weight of ruxolitinib calculated based on the weight of ruxolitinib free base in the total composition or dosage form. For example, 10 mg of ruxolitinib dihydrate based on free base means 11.18 mg of ruxolitinib dihydrate, which is equivalent to 10 mg of ruxolitinib free base.

[0116] In some embodiments, the composition comprises about 5 mg to about 50 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 5 mg to about 25 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 10 mg to about 50 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 10 mg to about 40 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 10 mg to about 30 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 5 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 10 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 15 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 20 mg of ruxolitinib dihydrate in terms of free base. In some embodiments, the composition comprises about 25 mg of ruxolitinib dihydrate in free base. In some embodiments, the composition comprises about 30 mg of ruxolitinib dihydrate in free base. In some embodiments, the composition comprises about 40 mg of ruxolitinib dihydrate in free base. In some embodiments, the composition comprises about 50 mg of ruxolitinib dihydrate in free base. In some embodiments, each of the foregoing compositions is an oral dosage form. In some embodiments, each of the foregoing compositions is a sustained release oral dosage form. In some embodiments, each of the foregoing dosage forms is a tablet. In some embodiments, each of the foregoing dosage forms is a capsule. In some embodiments, each of the foregoing compositions is a topical preparation.

[0117] In some embodiments, the composition comprises about 5 mg to about 50 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 5 mg to about 25 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 10 mg to about 50 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 10 mg to about 40 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 10 mg to about 30 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 5 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 10 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 15 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 20 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 25 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 30 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 40 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises about 50 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, each of the foregoing compositions is an oral dosage form. In some embodiments, each of the foregoing compositions is a sustained release oral dosage form. In some embodiments, each of the foregoing dosage forms is a tablet. In some embodiments, each of the foregoing dosage forms is a capsule. In some embodiments, each of the foregoing compositions is a topical preparation.

[0118] In some embodiments, the present disclosure provides an oral dosage form comprising ruxolitinib dihydrate. In some embodiments, the oral dosage form comprises ruxolitinib dihydrate, wherein the ruxolitinib dihydrate is less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight %, less than about 0.07 weight %, less than about 0.0 6 weight %, less than about 0.05 weight %, less than about 0.04 weight %, less than about 0.03 weight %, less than about 0.02 weight %, less than about 0.01 weight %, less than about 0.009 weight %, less than about 0.008 weight %, less than about 0.007 weight %, less than about 0.006 weight %, less than about 0.005 weight %, less than about 0.004 weight %, less than about 0.003 weight %, less than about 0.002 weight %, or less than about 0.001 weight %. In some embodiments, the oral dosage form comprises ruxolitinib dihydrate at a concentration of less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight %, less than about 0.07 weight %, less than about 0.06 weight %, of the dosage form. %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0119] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the active ingredient. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0120] Tablets or pills can be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action. For example, a tablet or pill can include an inner dose and an outer dose component, the latter being in the form of a film on the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to be delivered intact to the duodenum or delayed when released. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0121] Liquid forms in which the compounds and compositions described herein may be incorporated for administration orally or by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions using edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0122] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. As described above, liquid or solid compositions may contain suitable pharmaceutically acceptable excipients. In some embodiments, the composition is applied by topical administration. In some embodiments, the composition is applied to the skin by topical administration. In some embodiments, the composition is applied by oral or nasal respiratory routes to obtain local or systemic effects. The composition can be atomized by using an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be attached to a mask or intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0123] The amount of the compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration (such as prevention or treatment), the state of the patient, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending clinician, depending on factors such as the severity of the disease, the age, weight and general condition of the patient.

[0124] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be aseptically filtered. The aqueous solution may be packaged for use as is, or lyophilized, and the lyophilized preparation may be combined with a sterile aqueous carrier prior to administration. The pH value of the compound formulation will generally be between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of certain excipients, carriers or stabilizers described herein will result in the formation of pharmaceutically acceptable salts.

[0125] The therapeutic dose of the solid form described herein may vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the solid form in the pharmaceutical composition may vary according to many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound of the present invention may be provided in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dosage range is about 0.01 mg to about 100 mg per kilogram of body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health status of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be inferred from a dose-response curve obtained from an in vitro or animal model test system.

[0126] In some embodiments, the pharmaceutical composition is an oral dosage form.

[0127] In some embodiments, the oral dosage form is an immediate release dosage form. In some embodiments, ruxolitinib dihydrate is present in an amount of about 5 to about 25 mg as a free base. In some embodiments, ruxolitinib dihydrate is present in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 25 mg of ruxolitinib dihydrate as a free base. In some embodiments, anhydrous crystalline ruxolitinib free base is present in an amount of about 5 to about 25 mg. In some embodiments, anhydrous crystalline ruxolitinib free base is present in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, or about 25 mg.

[0128] Sustained release dosage form

[0129] In some embodiments, the pharmaceutical composition is an oral dosage form.

[0130] In some embodiments, the oral dosage form is a sustained release dosage form comprising a solid form described herein.

[0131] In some embodiments, the sustained release form comprises ruxolitinib dihydrate as an active ingredient. In some embodiments, ruxolitinib dihydrate is present in an amount of about 10 to about 50 mg based on the free base. In some embodiments, ruxolitinib dihydrate is present in an amount of about 10 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 37.5 mg, about 40 mg, about 45 mg, or about 50 mg based on the free base. In some embodiments, ruxolitinib dihydrate is present in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg of ruxolitinib dihydrate based on the free base.

[0132] In some embodiments, the sustained release form comprises anhydrous crystalline ruxolitinib free base as an active ingredient. In some embodiments, anhydrous crystalline ruxolitinib free base is present in an amount of about 10 to about 50 mg. In some embodiments, anhydrous crystalline ruxolitinib free base is present in an amount of about 10 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 37.5 mg, about 40 mg, about 45 mg, or about 50 mg. In some embodiments, anhydrous crystalline ruxolitinib free base is present in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg.

[0133] In some embodiments, the oral, sustained release dosage form comprises ruxolitinib dihydrate at a level of less than about 0.9 wt %, less than about 0.8 wt %, less than about 0.7 wt %, less than about 0.6 wt %, less than about 0.5 wt %, less than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.08 wt %, less than about 0.07 wt %, less than about 0.08 wt %, less than about 0.0 ... 0.06 weight %, less than about 0.05 weight %, less than about 0.04 weight %, less than about 0.03 weight %, less than about 0.02 weight %, less than about 0.01 weight %, less than about 0.009 weight %, less than about 0.008 weight %, less than about 0.007 weight %, less than about 0.006 weight %, less than about 0.005 weight %, less than about 0.004 weight %, less than about 0.003 weight %, less than about 0.002 weight %, or less than about 0.001 weight %. In some embodiments, the oral, sustained release dosage form comprises ruxolitinib dihydrate at a concentration of less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight %, less than about 0.07 weight %, less than about 0.0 6 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0134] Dosage form can include sustained release matrix forming agent.In some embodiments, dosage form includes the sustained release matrix forming agent of about 10 % by weight to about 30 % by weight.In some embodiments, sustained release matrix forming agent is one or more cellulose ethers.In some embodiments, sustained release matrix forming agent is hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose) (this is a kind of high viscosity polymer).In some embodiments, dosage form includes one or more hydroxypropyl methylcellulose of about 10 % by weight to about 30 % by weight.In some embodiments, preparation has one or more hydroxypropyl methylcellulose of about 20 % by weight.Exemplary hydroxypropyl methylcellulose includes Methocel K15M, Methocel K4M and Methocel K100LV.

[0135] The sustained release dosage form described herein may also include one or more fillers, glidants, disintegrants, binding agents or lubricants as inactive ingredients. The filler can be present in the formulation in an amount of 0 wt % to about 85 wt %. In some embodiments, the formulation has a filler of about 50 wt % to about 80 wt %, about 55 wt % to about 75 wt % or about 60 wt % to about 70 wt %. The non-limiting examples of fillers include lactose monohydrate, microcrystalline cellulose, starch 1500 and anhydrous lactose or a combination thereof. In some embodiments, the filler comprises microcrystalline cellulose, lactose monohydrate or both.

[0136] Lubricants can be present in dosage forms described herein in an amount of 0 wt % to about 5 wt %. Non-limiting examples of lubricants include magnesium stearate, stearic acid (stearyl), hydrogenated oil, polyethylene glycol, sodium stearyl fumarate and glyceryl behenate. In some embodiments, the formulation includes magnesium stearate, stearic acid or both.

[0137] Glidants can be present in the dosage forms described herein in an amount of 0 to about 5% by weight. Non-limiting examples of glidants include talc, colloidal silicon dioxide, and corn starch. In some embodiments, the glidant is colloidal silicon dioxide.

[0138] Disintegrants can be present in the dosage forms described herein in an amount of 0% to about 10% by weight. Non-limiting examples of disintegrants include crosslinked sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, starch, cellulose, and low-substituted hydroxypropyl cellulose. Crosslinked sodium carboxymethylcellulose is a preferred disintegrant.

[0139] The coating agent may be present in an amount of 0 wt % to about 5 wt %.Non-limiting illustrative examples of coating agents include hypromellose or polyvinyl alcohol based coatings plus titanium dioxide, talc and optional colorants available in several commercially available complete coating systems.

[0140] Examples of sustained release dosage forms include tablets, caplets, capsules, etc. containing any of the sustained release formulations described herein. The dosage form may also include a pharmaceutically acceptable coating, pigment, or dye.

[0141] The dosage form contains a sustained release formulation that releases ruxolitinib relatively slowly after administration, characterized by specific pharmacokinetic parameters that are different from those of an immediate release formulation. The sustained release dosage form can minimize potentially harmful spikes in drug plasma concentrations associated with immediate release formulations, and can help provide continuous, stable, and therapeutically effective drug plasma levels. The dosage form can be administered to a human patient as needed to obtain a therapeutic effect for the disease being treated, for example, once a day.

[0142] Topical and cream preparations

[0143] In some embodiments, the pharmaceutical composition is a topical pharmaceutical formulation.In some embodiments described herein, the topical pharmaceutical formulation is suitable for application to the skin.

[0144] In some embodiments, the topical formulation comprises about 0.5% to about 1.5% by weight of ruxolitinib dihydrate of the topical formulation in terms of free base. In some embodiments, the topical formulation comprises about 1.5% by weight of ruxolitinib dihydrate of the topical formulation in terms of free base. In some embodiments, the topical formulation comprises about 1.0% by weight of ruxolitinib dihydrate of the topical formulation in terms of free base. In some embodiments, the topical formulation comprises about 0.75% by weight of ruxolitinib dihydrate of the topical formulation in terms of free base. In some embodiments, the topical formulation comprises about 0.5% by weight of ruxolitinib dihydrate of the topical formulation in terms of free base.

[0145] In some embodiments, the topical formulation comprises anhydrous crystalline ruxolitinib free base at about 0.5% to about 1.5% by weight of the topical formulation. In some embodiments, the topical formulation comprises anhydrous crystalline ruxolitinib free base at about 1.5% by weight of the topical formulation. In some embodiments, the topical formulation comprises anhydrous crystalline ruxolitinib free base at about 1.0% by weight of the topical formulation. In some embodiments, the topical formulation comprises anhydrous crystalline ruxolitinib free base at about 0.75% by weight of the topical formulation. In some embodiments, the topical formulation comprises anhydrous crystalline ruxolitinib free base at about 0.5% by weight of the topical formulation.

[0146] In some embodiments, the topical formulation is prepared by dissolving ruxolitinib dihydrate in a solvent component. In some embodiments, the solvent component comprises water. When ruxolitinib dihydrate is completely dissolved in the solvent component, it is generally understood to be present in the formulation as ruxolitinib free base, with loss of crystalline structure after dissolution.

[0147] In some embodiments, the topical formulation is prepared by dissolving anhydrous crystalline ruxolitinib free base in a solvent component. In some embodiments, the solvent component comprises water. When the anhydrous crystalline ruxolitinib free base is completely dissolved in the solvent component, it is generally understood to be present in the formulation as ruxolitinib free base, with loss of crystalline structure after dissolution.

[0148] In some embodiments, the topical formulation comprises about 0.5% to about 1.5% by weight of ruxolitinib in terms of free base of the topical formulation. In some embodiments, the topical formulation comprises about 1.5% by weight of ruxolitinib in terms of free base of the topical formulation. In some embodiments, the topical formulation comprises about 1.0% by weight of ruxolitinib in terms of free base of the topical formulation. In some embodiments, the topical formulation comprises about 0.75% by weight of ruxolitinib in terms of free base of the topical formulation. In some embodiments, the topical formulation comprises about 0.5% by weight of ruxolitinib in terms of free base of the topical formulation.

[0149] In some embodiments, the topical formulation comprises ruxolitinib dihydrate at less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.07%, less than about 0.0 6%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02%, less than about 0.01%, less than about 0.009%, less than about 0.008%, less than about 0.007%, less than about 0.006%, less than about 0.005%, less than about 0.004%, less than about 0.003%, less than about 0.002% or less than about 0.001% are present in the formulation.

[0150] In some embodiments, the topical formulation comprises ruxolitinib dihydrate at a level of less than about 0.9 wt %, less than about 0.8 wt %, less than about 0.7 wt %, less than about 0.6 wt %, less than about 0.5 wt %, less than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.08 wt %, less than about 0.07 wt %, less than about 0.0 6 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0151] In some embodiments, the topical formulation comprises (a) ruxolitinib free base in an amount from about 0.5% to about 1.5% by weight of the formulation; and (b) ruxolitinib dihydrate, wherein the ruxolitinib dihydrate is less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.09%, less than about 0.08% by weight of the formulation as a free base. %, less than about 0.07 wt %, less than about 0.06 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0152] In some embodiments, the topical pharmaceutical formulation is prepared in large batch sizes. In some embodiments, the topical pharmaceutical formulation is prepared in batch sizes of 1000 kg or more.

[0153] In some embodiments, the present disclosure provides a topical pharmaceutical formulation comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) ruxolitinib dihydrate, wherein the ruxolitinib dihydrate is less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight %, based on the free base of the formulation. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 1.5% by weight of the formulation based on the free base. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5% by weight of the formulation based on the free base. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinib phosphate. In some embodiments, the formulation is prepared in large batch sizes. In some embodiments, the batch size is 1000 kg or more.

[0154] In some embodiments, the present disclosure provides a topical pharmaceutical formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the formulation comprises less than about 0.9 wt %, less than about 0.8 wt %, less than about 0.7 wt %, less than about 0.6 wt %, less than about 0.5 wt %, less than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.08 wt %, less than about 0.07 wt %, less than about 0.08 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.08 ... In some embodiments, the present invention provides a pharmaceutical composition comprising at least about 0.06% by weight, less than about 0.05% by weight, less than about 0.04% by weight, less than about 0.03% by weight, less than about 0.02% by weight, less than about 0.01% by weight, less than about 0.009% by weight, less than about 0.008% by weight, less than about 0.007% by weight, less than about 0.006% by weight, less than about 0.005% by weight, less than about 0.004% by weight, less than about 0.003% by weight, less than about 0.002% by weight, or less than about 0.001% by weight of ruxolitinib dihydrate, wherein the formulation is prepared in a large batch size. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% by weight to about 1.5% by weight of the formulation based on the free base. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5% by weight of the formulation based on the free base. In some embodiments, ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinib phosphate. In some embodiments, the batch size is 1000 kg or more.

[0155] In some embodiments, provided herein is a method for releasing a batch of topical pharmaceutical formulations described herein, the method comprising (i) testing a sample of the topical pharmaceutical formulation for the absence of crystalline ruxolitinib dihydrate; and if the sample passes the test in step (i), then: (ii) releasing the batch for public use. In some embodiments, the test comprises observing a sample of the formulation under an optical microscope to detect the absence or presence of crystals. In some embodiments, the test comprises observing a sample of the formulation under an optical microscope to detect the absence or presence of crystals, wherein the sample passes the test when no crystals are detected.

[0156] In some embodiments, the topical formulation is a cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion.

[0157] In some embodiments, the topical formulation is prepared by incorporating ruxolitinib dihydrate into the formulation. In some embodiments, the topical formulation is prepared by dissolving ruxolitinib dihydrate in a solvent component.

[0158] In some embodiments, a cream formulation is prepared by incorporating ruxolitinib dihydrate in an oil-in-water emulsion.

[0159] In some embodiments, the emulsion comprises about 0.5% to about 1.5% by weight of ruxolitinib dihydrate of the emulsion as free base. In some embodiments, the emulsion comprises about 1.5% by weight of ruxolitinib dihydrate of the emulsion as free base. In some embodiments, the emulsion comprises about 1.0% by weight of ruxolitinib dihydrate of the emulsion as free base. In some embodiments, the emulsion comprises about 0.75% by weight of ruxolitinib dihydrate of the emulsion as free base. In some embodiments, the emulsion comprises about 0.5% by weight of ruxolitinib dihydrate of the emulsion as free base.

[0160] In some embodiments, the emulsion comprises about 0.5% to about 1.5% by weight of ruxolitinib, calculated as the free base, of the emulsion. In some embodiments, the emulsion comprises about 1.5% by weight of ruxolitinib, calculated as the free base, of the emulsion. In some embodiments, the emulsion comprises about 1.0% by weight of ruxolitinib, calculated as the free base, of the emulsion. In some embodiments, the emulsion comprises about 0.75% by weight of ruxolitinib, calculated as the free base, of the emulsion. In some embodiments, the emulsion comprises about 0.5% by weight of ruxolitinib, calculated as the free base, of the emulsion.

[0161] As used herein, in the context of an emulsion or a topical formulation prepared by incorporating ruxolitinib dihydrate in an emulsion, "percentage of ruxolitinib as free base" or "as free base" means that the % w / w is calculated based on the weight of ruxolitinib free base in the total emulsion. For example, for 100 grams of a 1.5% (w / w) formulation, 1.68 grams of ruxolitinib dihydrate would need to be incorporated in the emulsion or topical formulation to obtain 1.5 grams of ruxolitinib free base.

[0162] In some embodiments, the cream is a dissolving cream.

[0163] In some embodiments, the cream has a pH of about 2.8 to about 3.6. In the context of pH, "about" means ± 0.5 (preferably ± 0.3 or more preferably ± 0.2).

[0164] In some embodiments, the cream formulation is any one of the cream formulations disclosed in U.S. Patent Publication No. 2015 / 0250790, which is incorporated herein by reference in its entirety, except that ruxolitinib dihydrate or anhydrous crystalline ruxolitinib free base as described herein is used.

[0165] In some embodiments, the cream is an oil-in-water emulsion as described in US2015 / 0250790, which is incorporated herein by reference in its entirety. Specifically, Examples 3-6 of US2015 / 0250790 (and in particular Tables 3 to 5 and the accompanying text) are incorporated herein by reference.

[0166] In some embodiments, the oil component is present in an amount from about 10% to about 40% by weight of the emulsion.

[0167] In some embodiments, the oil component is present in an amount from about 10% to about 24% by weight of the emulsion.

[0168] In some embodiments, the oil component is present in an amount from about 15% to about 24% by weight of the emulsion.

[0169] In some embodiments, the oil component is present in an amount from about 18% to about 24% by weight of the emulsion.

[0170] In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of petrolatum, fatty alcohols, mineral oil, triglycerides, and silicone oil.

[0171] In some embodiments, the oil component comprises one or more substances independently selected from the group consisting of white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone.

[0172] In some embodiments, the oil component comprises a sealant component.

[0173] In some embodiments, the sealant component is present in an amount from about 2% to about 15% by weight of the emulsion.

[0174] In some embodiments, the sealant component is present in an amount from about 5% to about 10% by weight of the emulsion.

[0175] In some embodiments, the sealant component comprises one or more substances selected from the group consisting of fatty acids (e.g., lanolin acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyols (e.g., propylene glycol), silicones (e.g., dimethicone, sterols (e.g., cholesterol), vegetable or animal fats (e.g., cocoa butter), vegetable waxes (e.g., carnauba wax), and wax esters (e.g., beeswax).

[0176] In some embodiments, the sealant component comprises one or more substances selected from the group consisting of lanolin fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

[0177] In some embodiments, the sealant component comprises petrolatum.

[0178] In some embodiments, the sealant component comprises white petrolatum.

[0179] In some embodiments, the oil component comprises a hardener component.

[0180] In some embodiments, the hardener component is present in an amount from about 2% to about 8% by weight of the emulsion.

[0181] In some embodiments, the hardener component is present in an amount from about 3% to about 6% by weight of the emulsion.

[0182] In some embodiments, the hardener component is present in an amount from about 4% to about 7% by weight of the emulsion.

[0183] In some embodiments, the hardener component comprises one or more substances independently selected from fatty alcohols.

[0184] In some embodiments, the hardener component comprises one or more independently selected from C 12-20 Substances containing fatty alcohols.

[0185] In some embodiments, the hardener component comprises one or more independently selected from C 16-18 Substances containing fatty alcohols.

[0186] In some embodiments, the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

[0187] In some embodiments, the oil component comprises an emollient component.

[0188] In some embodiments, the emollient component is present in an amount from about 5% to about 15% by weight of the emulsion.

[0189] In some embodiments, the emollient component is present in an amount from about 7% to about 13% by weight of the emulsion.

[0190] In some embodiments, the emollient component comprises one or more materials independently selected from mineral oil and triglycerides.

[0191] In some embodiments, the emollient component comprises one or more materials independently selected from light mineral oil and medium chain triglycerides.

[0192] In some embodiments, the emollient component comprises one or more materials independently selected from light mineral oil, medium chain triglycerides, and dimethicone.

[0193] In some embodiments, water is present in an amount from about 35% to about 65% by weight of the emulsion.

[0194] In some embodiments, water is present in an amount from about 40% to about 60% by weight of the emulsion.

[0195] In some embodiments, water is present in an amount from about 45% to about 55% by weight of the emulsion.

[0196] In some embodiments, the emulsifier component is present in an amount from about 1% to about 9% by weight of the emulsion.

[0197] In some embodiments, the emulsifier component is present in an amount from about 2% to about 6% by weight of the emulsion.

[0198] In some embodiments, the emulsifier component is present in an amount from about 3% to about 5% by weight of the emulsion.

[0199] In some embodiments, the emulsifier component is present in an amount from about 4% to about 7% by weight of the emulsion.

[0200] In some embodiments, the emulsion comprises an emulsifier component and a hardener component, wherein the combined amount of the emulsifier component and the hardener component is at least about 8% by weight of the emulsion.

[0201] In some embodiments, the emulsifier component comprises one or more substances independently selected from fatty acid glycerides and sorbitan fatty acid esters.

[0202] In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0203] In some embodiments, the emulsion further comprises a stabilizer component.

[0204] In some embodiments, the stabilizer component is present in an amount from about 0.05% to about 5% by weight of the emulsion.

[0205] In some embodiments, the stabilizer component is present in an amount from about 0.1% to about 2% by weight of the emulsion.

[0206] In some embodiments, the stabilizer component is present in an amount from about 0.3% to about 0.5% by weight of the emulsion.

[0207] In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.

[0208] In some embodiments, the stabilizer component comprises xanthan gum.

[0209] In some embodiments, the emulsion further comprises a solvent component.

[0210] In some embodiments, the solvent component is present in an amount from about 10% to about 35% by weight of the emulsion.

[0211] In some embodiments, the solvent component is present in an amount from about 15% to about 30% by weight of the emulsion.

[0212] In some embodiments, the solvent component is present in an amount from about 20% to about 25% by weight of the emulsion.

[0213] In some embodiments, the solvent component comprises one or more materials independently selected from alkylene glycols and polyalkylene glycols.

[0214] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0215] In some embodiments, the emulsion comprises:

[0216] from about 35% to about 65% by weight of the emulsion water;

[0217] from about 10% to about 40% by weight of the emulsion as an oil component;

[0218] from about 1% to about 9% by weight of the emulsion of an emulsifier component;

[0219] from about 10% to about 35% by weight of the emulsion as a solvent component;

[0220] from about 0.05% to about 5% by weight of the emulsion of a stabilizer component; and

[0221] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0222] In some embodiments, the emulsion comprises:

[0223] from about 35% to about 65% by weight of the emulsion water;

[0224] from about 10% to about 24% by weight of the emulsion as an oil component;

[0225] from about 1% to about 9% by weight of the emulsion of an emulsifier component;

[0226] from about 10% to about 35% by weight of the emulsion as a solvent component;

[0227] from about 0.05% to about 5% by weight of the emulsion of a stabilizer component; and

[0228] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0229] In some embodiments, the emulsion comprises:

[0230] from about 40% to about 60% by weight of the emulsion water;

[0231] from about 15% to about 30% by weight of the emulsion as an oil component;

[0232] from about 2% to about 6% by weight of the emulsion of an emulsifier component;

[0233] from about 15% to about 30% by weight of the emulsion as a solvent component;

[0234] from about 0.1% to about 2% by weight of the emulsion of a stabilizer component; and

[0235] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0236] In some embodiments, the emulsion comprises:

[0237] from about 40% to about 60% by weight of the emulsion water;

[0238] from about 15% to about 30% by weight of the emulsion as an oil component;

[0239] from about 2% to about 6% by weight of the emulsion of an emulsifier component;

[0240] from about 15% to about 24% by weight of the emulsion as a solvent component;

[0241] from about 0.1% to about 2% by weight of the emulsion of a stabilizer component; and

[0242] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0243] In some embodiments, the emulsion comprises:

[0244] from about 45% to about 55% by weight of the emulsion water;

[0245] from about 15% to about 24% by weight of the emulsion as an oil component;

[0246] from about 3% to about 5% by weight of the emulsion of an emulsifier component;

[0247] from about 20% to about 25% by weight of the emulsion as a solvent component;

[0248] from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and

[0249] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0250] In some embodiments, the emulsion comprises:

[0251] from about 45% to about 55% by weight of the emulsion water;

[0252] from about 15% to about 24% by weight of the emulsion as an oil component;

[0253] from about 4% to about 7% by weight of the emulsion of an emulsifier component;

[0254] from about 20% to about 25% by weight of the emulsion as a solvent component;

[0255] from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component; and

[0256] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0257] In some embodiments:

[0258] The oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oil, triglycerides and dimethicone;

[0259] the emulsifier component comprises one or more substances independently selected from fatty acid glycerides and sorbitan fatty acid esters;

[0260] The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols; and

[0261] The stabilizer component comprises one or more substances independently selected from polysaccharides.

[0262] In some embodiments:

[0263] The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone;

[0264] the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;

[0265] The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol; and

[0266] The stabilizer component comprises xanthan gum.

[0267] In some embodiments, the emulsion comprises:

[0268] from about 35% to about 65% by weight of the emulsion water;

[0269] from about 2% to about 15% by weight of the emulsion of a blocking agent component;

[0270] from about 2% to about 8% by weight of the emulsion of a hardener component;

[0271] from about 5% to about 15% by weight of the emulsion of an emollient component;

[0272] from about 1% to about 9% by weight of the emulsion of an emulsifier component;

[0273] from about 0.05% to about 5% by weight of the emulsion of a stabilizer component;

[0274] from about 10% to about 35% by weight of the emulsion of a solvent component; and

[0275] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0276] In some embodiments, the emulsion comprises:

[0277] from about 40% to about 60% by weight of the emulsion water;

[0278] from about 5% to about 10% by weight of the emulsion of a blocking agent component;

[0279] from about 2% to about 8% by weight of the emulsion of a hardener component;

[0280] from about 7% to about 12% by weight of the emulsion of an emollient component;

[0281] from about 2% to about 6% by weight of the emulsion of an emulsifier component;

[0282] from about 0.1% to about 2% by weight of the emulsion of a stabilizer;

[0283] from about 15% to about 30% by weight of the emulsion of a solvent component; and

[0284] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0285] In some embodiments, the emulsion comprises:

[0286] from about 45% to about 55% by weight of the emulsion water;

[0287] from about 5% to about 10% by weight of the emulsion of a blocking agent component;

[0288] from about 3% to about 6% by weight of the emulsion of a hardener component;

[0289] from about 7% to about 13% by weight of the emulsion of an emollient component;

[0290] from about 3% to about 5% by weight of the emulsion of an emulsifier component;

[0291] from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component;

[0292] from about 20% to about 25% by weight of the emulsion of a solvent component; and

[0293] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0294] In some embodiments, the emulsion comprises:

[0295] from about 45% to about 55% by weight of the emulsion water;

[0296] from about 5% to about 10% by weight of the emulsion of a blocking agent component;

[0297] from about 4% to about 7% by weight of the emulsion of a hardener component;

[0298] from about 7% to about 13% by weight of the emulsion of an emollient component;

[0299] from about 4% to about 7% by weight of the emulsion of an emulsifier component;

[0300] from about 0.3% to about 0.5% by weight of the emulsion of a stabilizer component;

[0301] from about 20% to about 25% by weight of the emulsion of a solvent component; and

[0302] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0303] In some embodiments, the emulsion comprises:

[0304] from about 45% to about 55% by weight of the emulsion water;

[0305] about 7% by weight of the emulsion of a sealant component;

[0306] from about 4.5% to about 5% by weight of the emulsion of a hardener component;

[0307] about 10% by weight of the emulsion of an emollient component;

[0308] from about 4% to about 4.5% by weight of the emulsion of an emulsifier component;

[0309] about 0.4% by weight of the emulsion of a stabilizer component;

[0310] about 22% by weight of the emulsion as a solvent component; and

[0311] The emulsion contains about 0.5% to 1.5% by weight of ruxolitinib based on the free base.

[0312] In some embodiments, the combined amount of the hardener component and the emulsifier component is at least about 8% by weight of the emulsion.

[0313] In some embodiments:

[0314] The sealant component includes petrolatum;

[0315] The hardener component comprises one or more substances independently selected from one or more fatty alcohols;

[0316] The emollient component comprises one or more materials independently selected from mineral oil and triglycerides;

[0317] The emulsifier component comprises one or more substances independently selected from fatty acid glycerides and sorbitan fatty acid esters;

[0318] The stabilizer component comprises one or more substances independently selected from polysaccharides; and

[0319] The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0320] In some embodiments:

[0321] The sealant component contains white petrolatum;

[0322] The hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol;

[0323] the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides and dimethicone;

[0324] the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;

[0325] The stabilizer component comprises xanthan gum; and

[0326] The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0327] In some embodiments, the emulsion further comprises an antimicrobial preservative component.

[0328] In some embodiments, the antimicrobial preservative component is present in an amount from about 0.05% to about 3% by weight of the emulsion.

[0329] In some embodiments, the antimicrobial preservative component is present in an amount from about 0.1% to about 1% by weight of the emulsion.

[0330] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkyl parabens and phenoxyethanol.

[0331] In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.

[0332] In some embodiments, the emulsion further comprises a chelating agent component.

[0333] In some embodiments, the chelator component comprises edetate disodium.

[0334] As used herein, the term "emulsifier component" refers in one aspect to a substance or mixture of substances that maintains a suspension of elements or particles within a fluid medium. In some embodiments, the emulsifier component allows the oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component refers to one or more nonionic surfactants.

[0335] As used herein, the term "occlusive agent component" refers to a hydrophobic agent or a mixture of hydrophobic agents that forms an occlusive film on the skin, thereby reducing transepidermal water loss (TEWL) by preventing evaporation of water from the stratum corneum.

[0336] As used herein, the term "hardening agent component" refers to a substance or mixture of substances that increases the viscosity and / or thickness of a cream or improves the rheology of a cream.

[0337] As used herein, the term "emollient component" refers to an agent that softens or soothes the skin or soothes an irritated internal surface.

[0338] As used herein, the term "stabilizer component" refers to a substance or mixture of substances that improves the stability of a cream and / or the compatibility of components in a cream. In some embodiments, the stabilizer component prevents emulsion aggregation and stabilizes droplets in an oil-in-water emulsion.

[0339] As used herein, the term "solvent component" is a liquid substance or a mixture of liquid substances that can dissolve ruxolitinib dihydrate in the cream. In some embodiments, the solvent component is a liquid substance or a mixture of liquid substances in which ruxolitinib or a pharmaceutically acceptable salt thereof has a reasonable solubility. For example, the solubility of ruxolitinib free base is reported in Table 21 of US2015 / 0250790, which is incorporated herein by reference in its entirety. The solubility information of ruxolitinib dihydrate is shown in Tables 2 and 3 below.

[0340] As used herein, the phrase "antimicrobial preservative component" is a substance or mixture of substances that inhibits the growth of microorganisms in the cream.

[0341] As used herein, the phrase "chelator component" refers to a compound or mixture of compounds that has the ability to strongly bind to metal ions.

[0342] As used herein, "percent by weight of the emulsion" means that the percentage concentration of a component in the emulsion is on a weight / weight basis. For example, 1% w / w of component A = [(mass of component A) / (total mass of the emulsion)] x 100.

[0343] As used herein, the term "component" may mean one substance or a mixture of substances.

[0344] As used herein, the term "fatty acid" refers to a saturated or unsaturated aliphatic acid. In some embodiments, the fatty acid is in the form of a mixture of different fatty acids. In some embodiments, the fatty acid has an average of about eight to about thirty carbons. In some embodiments, the fatty acid has an average of about 12 to 20, 14-20 or 16-18 carbons. Suitable fatty acids include but are not limited to cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid, cetearyl stearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid and arachidonic acid or a mixture thereof.

[0345] As used herein, the term "fatty alcohol" refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is in the form of a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, octanol, caprylyl alcohol, oleyl alcohol, linoleyl alcohol, arachidonic acid, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, squalane alcohol, and linoleyl alcohol or mixtures thereof.

[0346] As used herein, the term "polyalkylene glycol", used alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units or a copolymer of different oxyalkylene monomer units, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "oxyalkylene", used alone or in combination with other terms, refers to a group of formula -O-alkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.

[0347] As used herein, the term "sorbitan fatty acid esters" includes products derived from sorbitan or sorbitol and fatty acids and optionally poly(ethylene glycol) units, including sorbitan esters and polyethoxylated sorbitan esters. In some embodiments, the sorbitan fatty acid ester is a polyethoxylated sorbitan ester.

[0348] As used herein, the term "sorbitan ester" refers to a compound or mixture of compounds resulting from the esterification of sorbitol and at least one fatty acid. Fatty acids can be used to derive sorbitan esters, including but not limited to those described herein. Suitable sorbitan esters include but are not limited to Span TM The sorbitan esters of the present invention are described in the Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate) and 85 (sorbitan trioleate). Other suitable sorbitan esters include those listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, which reference is incorporated herein by reference in its entirety.

[0349] As used herein, the term "polyethoxylated sorbitan ester" refers to a compound or mixture thereof obtained by ethoxylation of sorbitan esters. The polyoxyethylene portion of the compound may be located between the fatty acid ester and the sorbitan portion. As used herein, the term "sorbitan ester" refers to a compound or mixture of compounds obtained by esterification of sorbitol and at least one fatty acid. Fatty acids that can be used to derive polyethoxylated sorbitan esters include, but are not limited to, those fatty acids described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 200 ethylene oxide units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 100 ethylene oxide units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 80 ethylene oxide units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 40 ethylene oxide units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 20 ethylene oxide units. Suitable polyethoxylated sorbitan esters include, but are not limited to, Tween TMThe Tween series (available from Uniqema) includes Tween 20 (POE (20) sorbitan monolaurate), 21 (POE (4) sorbitan monolaurate), 40 (POE (20) sorbitan monopalmitate), 60 (POE (20) sorbitan monostearate), 60K (POE (20) sorbitan monostearate), 61 (POE (4) sorbitan monostearate), 65 (POE (20) sorbitan tristearate), 80 (POE (20) sorbitan monooleate), 80K (POE (20) sorbitan monooleate), 81 (POE (5) sorbitan monooleate) and 85 (POE (20) sorbitan trioleate). As used herein, the abbreviation "POE" refers to polyoxyethylene. The number following the POE abbreviation refers to the number of ethylene oxide repeating units in the compound. Other suitable polyethoxylated sorbitan esters include polyoxyethylene sorbitan fatty acid esters listed in RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, which reference is incorporated herein by reference in its entirety. In some embodiments, the polyethoxylated sorbitan ester is polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

[0350] As used herein, the term "fatty acid glyceride" refers to a monoglyceride, diglyceride or triglyceride of a fatty acid. The fatty acid glyceride may be optionally substituted with a sulfonic acid group, or a pharmaceutically acceptable salt thereof. Suitable fatty acids for deriving the glyceride of fatty acids include, but are not limited to, those fatty acids described herein. In some embodiments, the fatty acid glyceride is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the fatty acid glyceride is stearic acid glyceride.

[0351] As used herein, the term "triglyceride" refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium chain triglyceride.

[0352] As used herein, the term "alkylene glycol" refers to a radical of the formula -O-alkylene-, wherein the alkylene radical has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propylene glycol).

[0353] As used herein, the term "polyethylene glycol" refers to a 2 -CH 2-Polymers of ethylene glycol monomer units. Suitable polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with low carbon alkyl groups (e.g., methyl groups). Derivatives of polyethylene glycol with esterifiable carboxyl groups are also suitable. Polyethylene glycols that can be used in the present disclosure may be polymers of any chain length or molecular weight, and may include branched chains. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number after the dash in the name refers to the average molecular weight of the polymer.

[0354] method

[0355] Ruxolitinib inhibits JAK1 and JAK2 and is selective for JAK1 over JAK3. One aspect of the present disclosure is a method of treating a JAK-related disease or condition in an individual (e.g., a patient) by administering a therapeutically effective amount or dose of a solid form, a pharmaceutical formulation, or a pharmaceutical composition of the present disclosure to an individual in need of such treatment. JAK-related diseases may include those characterized by the expression of mutant JAK2, such as those having at least one mutation in the pseudokinase domain (e.g., JAK2V617F).

[0356] Provided herein is a method of treating a disease in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition described herein, wherein the disease is myelofibrosis, polycythemia vera, acute graft-versus-host disease, or chronic graft-versus-host disease.

[0357] Examples of JAK-related diseases include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis or myeloid metaplasia with myelofibrosis (MMM), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), etc. In some embodiments, myeloproliferative diseases are myelofibrosis. In some embodiments, myelofibrosis is primary myelofibrosis, myelofibrosis after polycythemia vera, or myelofibrosis after essential thrombocythemia. In some embodiments, myeloproliferative diseases are polycythemia vera. In some embodiments, myeloproliferative diseases are essential thrombocythemia.

[0358] In other embodiments, the JAK-associated disease is a cancer, including those characterized by solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma, etc.), blood cancers (e.g., lymphomas, leukemias such as acute lymphoblastic leukemia or multiple myeloma), and skin cancers (such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma). Exemplary cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides.

[0359] Examples of JAK-related diseases include diseases involving the immune system, including, for example, organ transplant rejection (e.g., allogeneic transplant rejection and graft-versus-host disease). In some embodiments, the JAK-related disease is graft-versus-host disease. In some embodiments, the JAK-related disease is acute graft-versus-host disease. In some embodiments, the JAK-related disease is chronic graft-versus-host disease.

[0360] Other examples of JAK-related diseases include allergic disorders such as asthma, food allergies and rhinitis. Other examples of JAK-related diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papillomavirus (HPV) and Coronavirus (e.g. SARS-COV-2).

[0361] Other JAK-related diseases include inflammation and inflammatory diseases. Exemplary inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, or related diseases), inflammatory diseases of the respiratory tract (e.g., upper respiratory tract including the nose and sinuses, such as rhinitis or sinusitis, or lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, etc.), inflammatory myopathy (such as myocarditis), and other inflammatory diseases. Other inflammatory diseases that can be treated with the compounds of the present disclosure include systemic inflammatory response syndrome (SIRS) and septic shock.

[0362] Other examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorders, and the like.

[0363] JAK inhibitors described herein may also be used to treat ischemia-reperfusion injury or diseases or conditions associated with inflammatory ischemic events (such as stroke or cardiac arrest). JAK inhibitors described herein may also be used to treat anorexia, cachexia or fatigue, such as those produced by or associated with cancer. JAK inhibitors described herein may also be used to treat restenosis, scleroderma or fibrosis. JAK inhibitors described herein may also be used to treat conditions associated with hypoxia or astrogliosis, such as diabetic retinopathy, cancer or neurodegeneration. See, for example, Dudley, AC et al. Biochem. J. 2005, 390 (Pt 2): 427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Electronic publication on March 2, 2004.

[0364] The JAK inhibitors described herein may also be used to treat gout and increased prostate size due to, for example, benign prostatic hypertrophy or benign prostatic hyperplasia.

[0365] Other examples of JAK-related diseases include skin diseases. In some embodiments, provided herein are methods for treating skin disorders in patients in need, the methods comprising administering to the patient a pharmaceutical composition described herein. In some embodiments, provided herein are methods for treating skin disorders in patients in need, the methods comprising administering to the affected skin area of ​​the patient a topical pharmaceutical formulation described herein. In some embodiments, provided herein is a method for treating skin disorders, the methods comprising applying a pharmaceutical composition described herein to a skin area of ​​a patient in need.

[0366] In some embodiments, the skin disorder is an autoimmune skin disease. In some embodiments, the skin disorder is atopic dermatitis. In some embodiments, the skin disorder is vitiligo. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder, such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). In some embodiments, the skin disease is lichen planus. In some embodiments, the skin disease is prurigo nodularis. In some embodiments, the skin disease is hidradenitis suppurativa. In some embodiments, the skin disease is psoriasis. In some embodiments, the skin disease is psoriasis vulgaris or plaque psoriasis. In some embodiments, the skin disease is rash, skin irritation or skin sensitization. In some embodiments, the skin disease is contact dermatitis or allergic contact dermatitis. In some embodiments, the skin disease is bullous pemphigoid.

[0367] The present disclosure also provides a method for treating the skin side effects of other drugs by applying the compounds of the present disclosure. For example, many medicaments produce undesirable allergic reactions, and undesirable allergic reactions can be manifested as acne-like rashes or related dermatitis. Exemplary medicaments with such undesirable side effects include anticancer drugs, such as gefitinib, cetuximab, erlotinib, etc. The preparations of the present disclosure can be combined (e.g., simultaneously or sequentially) with medicaments with undesirable skin side effects systemically or by topical administration (e.g., localized to the vicinity of dermatitis). In some embodiments, the preparations of the present disclosure can be topically administered together with one or more other drugs, wherein other drugs cause contact dermatitis, allergic contact sensitization or similar skin disorders when surface-coated in the absence of the preparations of the present disclosure. Therefore, the preparations of the present disclosure include a surface preparation of another medicament that also includes dermatitis, skin disorders or related side effects.

[0368] In some embodiments, contacting a JAK with a solid form of the disclosure comprises administering a compound of the disclosure to an individual or patient (such as a human) having a JAK, as well as, for example, introducing a compound of the disclosure into a sample containing cells or containing a purified preparation of a JAK.

[0369] As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. In some embodiments, the patient is a human patient.

[0370] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting the disease, disorder or condition in an individual experiencing or displaying the pathology or symptoms of the disease, disorder or condition; and (2) ameliorating the disease; e.g., ameliorating the disease, disorder or condition in an individual experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0371] In some embodiments, the compounds and compositions described herein can prevent diseases, disorders or conditions. Preventing / prevention of a disease, disorder or condition refers to administering a compound or composition described herein to an individual who may be susceptible to the disease, disorder or condition but has not yet experienced or shown the pathology or symptoms of the disease.

[0372] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits in a tissue, system, animal, individual or human the biological or medical response sought by a researcher, veterinarian, medical doctor or other clinician, including one or more of the following:

[0373] (1) inhibiting the disease; for example, inhibiting the disease, disorder or condition in an individual who experiences or exhibits the pathology or symptoms of the disease, disorder or condition (i.e., inhibiting the pathology and / or symptoms from developing further); and

[0374] (2) ameliorating the disease; e.g., ameliorating the disease, disorder or condition in an individual experiencing or displaying the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms).

[0375] Combination therapy

[0376] One or more other agents (such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, and Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors (such as those described in WO 2006 / 056399) or other agents) can be used in combination with the compositions described herein to treat JAK-related diseases, disorders or conditions. One or more other agents can be administered to the patient simultaneously or sequentially.

[0377] Exemplary chemotherapeutic agents include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0378] Exemplary steroids include corticosteroids, such as dexamethasone or prednisone.

[0379] Exemplary Bcr-Abl inhibitors include compounds of the classes and species disclosed in US Pat. No. 5,521,184, WO 04 / 005281, and US Pat. No. 7,745,437, and pharmaceutically acceptable salts thereof.

[0380] Exemplary suitable Flt-3 inhibitors include compounds disclosed in WO 03 / 037347, WO 03 / 099771 and WO 04 / 046120, and pharmaceutically acceptable salts thereof.

[0381] Exemplary suitable RAF inhibitors include compounds disclosed in WO 00 / 09495 and WO 05 / 028444 and pharmaceutically acceptable salts thereof.

[0382] Exemplary suitable FAK inhibitors include compounds disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595 and WO 01 / 014402, and pharmaceutically acceptable salts thereof.

[0383] In some embodiments, the compositions described herein can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

[0384] In some embodiments, a corticosteroid, such as dexamethasone, is administered to a patient in combination with a composition described herein, wherein the dexamethasone is administered intermittently rather than continuously.

[0385] Pill Box

[0386] The present disclosure also includes pharmaceutical kits that can be used, for example, to treat or prevent JAK-related diseases or disorders (such as cancer), comprising one or more containers containing a compound or composition. Such kits may also include (if necessary) one or more of various conventional pharmaceutical kit components, such as containers containing one or more pharmaceutically acceptable carriers, other containers as will be readily apparent to those skilled in the art, and the like. Instructions in the form of inserts or labels may also be included in the kit, indicating the amounts of the components to be administered, administration guidelines, and / or guidelines for mixing the components.

[0387] Other Implementations

[0388] Embodiment 1: A solid form, which is crystalline ruxolitinib dihydrate:

[0389]

[0390] Embodiment 2: A solid form as described in Embodiment 1, wherein the solid form is substantially isolated.

[0391] Embodiment 3: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least one XRPD peak selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0392] Embodiment 4: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least two XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0393] Embodiment 5: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least three XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0394] Embodiment 6: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least four XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0395] Embodiment 7: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least five XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0396] Embodiment 8: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having at least six XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0397] Embodiment 9: A solid form as described in Embodiment 1 or 2, wherein the solid form is characterized by having an XRPD peak selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8 and 25.7 degrees in terms of 2-θ (±0.2 degrees).

[0398] Embodiment 10: The solid form of Embodiment 1 or 2, wherein the solid form is characterized by having an XRPD peak selected from 19.0, 22.7, and 23.1 degrees in 2-theta (±0.2 degrees).

[0399] Embodiment 11: A solid form as described in Embodiment 10, wherein the solid form is characterized by having additional XRPD peaks selected from 10.6 and 15.4 degrees in terms of 2-theta (±0.2 degrees).

[0400] Embodiment 12: A solid form as described in Embodiment 11, wherein the solid form is characterized by having additional XRPD peaks selected from 11.6 and 25.7 degrees in terms of 2-theta (±0.2 degrees).

[0401] Embodiment 13: A solid form as described in Embodiment 12, wherein the solid form is characterized by having additional XRPD peaks selected from 6.9 and 21.8 degrees in terms of 2-theta (±0.2 degrees).

[0402] Embodiment 14: A solid form as described in Embodiment 13, wherein the solid form is characterized by having additional XRPD peaks selected from 12.9, 15.1 and 24.8 degrees in terms of 2-theta (±0.2 degrees).

[0403] Embodiment 15: A solid form as described in any one of Embodiments 1-14, wherein the solid form is characterized by having characteristic peaks substantially as Figure 2 The XRPD pattern shown in .

[0404] Embodiment 16: A solid form as described in any one of Embodiments 1-14, wherein the solid form is characterized by having characteristic peaks substantially as Fig. 9 The XRPD pattern shown in .

[0405] Embodiment 17: A solid form as described in any of Embodiments 1-16, wherein the solid form is characterized by single crystal x-ray diffraction having a space group of P212121 and a unit cell formula unit (Z) of 8.

[0406] Embodiment 18: A solid form as described in Embodiment 17, wherein the solid form has a unit cell parameter: a is about b is about c is about α is about 90°, β is about 90° and γ is about 90°.

[0407] Embodiment 19: A solid form as described in any of Embodiments 1-18, wherein the solid form is characterized by an endothermic peak in a DSC thermogram having an onset temperature (±5°C) of 61°C and a maximum temperature (±5°C) of 67°C.

[0408] Embodiment 20: A solid form as described in any of embodiments 1-18, wherein the solid form is characterized by a first endothermic peak with an onset temperature (±5°C) of 68°C and a maximum temperature (±5°C) of 72°C in the DSC thermogram, and a second endothermic peak with a maximum temperature (±5°C) of 110°C.

[0409] Embodiment 21: A solid form as described in any of Embodiments 1-18, wherein the solid form is characterized by having substantially Figure 3 DSC thermogram shown in .

[0410] Embodiment 22: A solid form as described in any of Embodiments 1-18, wherein the solid form is characterized by having substantially Fig.10 DSC thermogram shown in .

[0411] Embodiment 23: A solid form as described in any of Embodiments 1-22, wherein the solid form is characterized by having substantially Figure 4 TGA thermogram shown in .

[0412] Embodiment 24: A solid form as described in any of Embodiments 1-22, wherein the solid form is characterized by having substantially Fig.11 TGA thermogram shown in .

[0413] Embodiment 25: A solid form, which is anhydrous crystalline ruxolitinib free base.

[0414] Embodiment 26. The solid form of Embodiment 25, wherein the solid form is substantially isolated.

[0415] Embodiment 27: A solid form as described in Embodiment 25 or 26, wherein the solid form is characterized by having at least one XRPD peak selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0 and 23.9 degrees in terms of 2-θ (±0.2 degrees).

[0416] Embodiment 28: A solid form as described in Embodiment 25 or 26, wherein the solid form is characterized by having an XRPD peak selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0 and 23.9 degrees in terms of 2-θ (±0.2 degrees).

[0417] Embodiment 29: A solid form of Embodiment 25 or 26, wherein the solid form is characterized as having an XRPD peak selected from 7.2, 13.2, and 15.8 degrees in 2-theta (±0.2 degrees).

[0418] Embodiment 30: A solid form as described in Embodiment 29, wherein the solid form is characterized by having additional XRPD peaks selected from 19.6 and 23.9 degrees in terms of 2-theta (±0.2 degrees).

[0419] Embodiment 31: A solid form as described in Embodiment 30, wherein the solid form is characterized by having additional XRPD peaks selected from 11.5 and 15.4 degrees in terms of 2-theta (±0.2 degrees).

[0420] Embodiment 32: A solid form as described in Embodiment 31, wherein the solid form is characterized by having additional XRPD peaks selected from 11.6 and 19.1 degrees in terms of 2-theta (±0.2 degrees).

[0421] Embodiment 33: A solid form as described in any one of Embodiments 25-32, wherein the solid form is characterized by having characteristic peaks substantially as Fig.13 The XRPD pattern shown in .

[0422] Embodiment 34: A solid form as described in any of Embodiments 25-33, wherein the solid form is characterized by an endothermic peak in a DSC thermogram having an onset temperature (±5°C) of 83°C and a maximum temperature (±5°C) of 93°C.

[0423] Embodiment 35: A solid form as described in any of Embodiments 25-33, wherein the solid form is characterized by an endothermic peak in the DSC thermogram having an onset temperature (±5°C) of 81°C and a maximum temperature (±5°C) of 91°C.

[0424] Embodiment 36: A solid form as described in any of Embodiments 25-33, wherein the solid form is characterized by having substantially Fig.15 or Fig.16 DSC thermogram shown in .

[0425] Embodiment 37: A solid form as described in any of Embodiments 25-36, wherein the solid form is characterized by having substantially Fig.17 or Fig.18 TGA thermogram shown in .

[0426] Embodiment 38: A method for preparing a solid form, wherein the solid form is ruxolitinib dihydrate:

[0427]

[0428] The method comprises contacting ruxolitinib free base with water.

[0429] Embodiment 39: A method for preparing a solid form, wherein the solid form is ruxolitinib dihydrate:

[0430]

[0431] The method comprises isolating the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component.

[0432] Embodiment 40: The method of Embodiment 39, wherein the isolating comprises crystallizing the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component.

[0433] Embodiment 41: A method as described in Embodiment 40, wherein the crystallization comprises cooling the solution to allow the solid form to crystallize.

[0434] Embodiment 42: A method according to embodiment 40, wherein the crystallization comprises:

[0435] a) heating the solution comprising ruxolitinib free base and an aqueous solvent component; and

[0436] b) after said heating, cooling said solution to allow crystallization of said solid form.

[0437] Embodiment 43: A method according to embodiment 40, wherein the crystallization comprises:

[0438] a) heating the solution comprising ruxolitinib free base and an aqueous solvent component;

[0439] b) cooling the solution after said heating;

[0440] c) adding seed crystals of crystalline Jakafi Jakafi dihydrate to the solution after said cooling; and

[0441] d) after said adding said seed crystals, stirring said solution to crystallize said solid form.

[0442] Embodiment 44: The method of any one of Embodiments 39-43, wherein the solution is formed using amorphous ruxolitinib free base.

[0443] Embodiment 45: The method of any one of Embodiments 42-44, wherein in step a), the solution comprising ruxolitinib free base and solvent mixture is heated to a temperature of about 40°C to about 80°C.

[0444] Embodiment 46: The method of any one of Embodiments 42-44, wherein in step a), the solution comprising ruxolitinib free base and solvent mixture is heated to a temperature of about 50°C to about 70°C.

[0445] Embodiment 47: The method of any one of Embodiments 42-44, wherein in step a), the solution comprising ruxolitinib free base and solvent mixture is heated to a temperature of about 55°C to about 65°C.

[0446] Embodiment 48: The method of any one of Embodiments 42-47, wherein in step b), the solution is cooled to a temperature of about 10°C to about 40°C.

[0447] Embodiment 49: The method of any one of Embodiments 42-47, wherein in step b), the solution is cooled to a temperature of about 15°C to about 35°C.

[0448] Embodiment 50: The method of any one of Embodiments 42-47, wherein in step b), the solution is cooled to a temperature of about 20°C to about 30°C.

[0449] Embodiment 51: The method of any one of Embodiments 42-47, wherein in step b), the solution is cooled to a temperature of about ambient temperature.

[0450] Embodiment 52: The method of any one of Embodiments 43-51, wherein in step d), the solution is stirred for about 1 to about 30 hours.

[0451] Embodiment 53: The method of any one of Embodiments 43-51, wherein in step d), the solution is stirred for about 10 to about 20 hours.

[0452] Embodiment 54: The method of any one of Embodiments 43-51, wherein in step d), the solution is stirred for about 14 to about 18 hours.

[0453] Embodiment 55: A method as described in any of Embodiments 39-54, wherein the aqueous solvent component is water.

[0454] Embodiment 56: A method as described in any of Embodiments 39-54, wherein the aqueous solvent component comprises a polar protic solvent and water.

[0455] Embodiment 57: A method as described in Embodiment 56, wherein the polar protic solvent is an alcohol.

[0456] Embodiment 58: A method as described in Embodiment 56, wherein the polar protic solvent is C1-6 alcohol.

[0457] Embodiment 59: A method as described in Embodiment 58, wherein the C 1-6 The alcohol was isopropyl alcohol.

[0458] Embodiment 60: A method as described in any of Embodiments 56-59, wherein the volume to volume ratio of the polar protic solvent to the water is about 1 to 0.1 to about 1 to 10.

[0459] Embodiment 61: The method of any one of Embodiments 56-59, wherein the volume to volume ratio of polar protic solvent to water is about 1 to 0.5 to about 1 to 5.

[0460] Embodiment 62: The method of any one of Embodiments 56-59, wherein the volume to volume ratio of polar protic solvent to water is about 1 to 1 to about 1 to 3.

[0461] Embodiment 63: The method of any one of Embodiments 56-59, wherein the volume to volume ratio of polar protic solvent to water is about 1 to 2 to about 1 to 2.5.

[0462] Embodiment 64: The method of any one of embodiments 38-63, wherein the ruxolitinib free base is prepared by a method comprising:

[0463]

[0464] Reacts with the base in the solvent component.

[0465] Embodiment 65: A method as described in Embodiment 64, wherein the ruxolitinib free base is amorphous.

[0466] Embodiment 66: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 1 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate.

[0467] Embodiment 67: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 1 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate.

[0468] Embodiment 68: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 1 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate.

[0469] Embodiment 69: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 2 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate.

[0470] Embodiment 70: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 2 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate.

[0471] Embodiment 71: The method of embodiment 64 or 65, wherein the reacting the ruxolitinib phosphate with a base comprises using about 2 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate.

[0472] Embodiment 72: The method of any one of Embodiments 64-71, wherein said reacting the ruxolitinib phosphate with a base comprises using an amount of said base sufficient to produce a pH value of about 7.5 to about 8.

[0473] Embodiment 73: The method of any one of Embodiments 64-71, wherein said reacting the ruxolitinib phosphate with a base comprises using an amount of said base sufficient to produce a pH value of about 7 to about 8.

[0474] Embodiment 74: A method as described in any of Embodiments 64-73, wherein the base is a hydroxide base.

[0475] Embodiment 75: A method as described in any of Embodiments 64-73, wherein the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

[0476] Embodiment 76: A method as described in any of Embodiments 64-73, wherein the base is KOH.

[0477] Embodiment 77: A method as described in any of Embodiments 64-73, wherein the base is NaOH.

[0478] Embodiment 78: The method of any one of Embodiments 64-77, wherein the solvent component comprises water.

[0479] Embodiment 79: The method of any one of Embodiments 64-77, wherein the solvent component comprises one or more aprotic solvents and water.

[0480] Embodiment 80: A method as described in any of Embodiments 64-77, wherein the solvent component comprises water, an ester solvent, a halogenated solvent, or a mixture thereof.

[0481] Embodiment 81: A method as described in Embodiment 80, wherein the ester solvent is ethyl acetate.

[0482] Embodiment 82: A method as described in Embodiment 80, wherein the halogenated solvent is dichloromethane.

[0483] Embodiment 83: A method as described in Embodiment 80, wherein the solvent component comprises ethyl acetate, dichloromethane and water.

[0484] Embodiment 84: The method of any one of Embodiments 64-83, wherein the solvent component containing the ruxolitinib phosphate salt is cooled to a temperature of about 0°C to about 10°C.

[0485] Embodiment 85: The method of any one of Embodiments 64-83, wherein the solvent component containing the ruxolitinib phosphate salt is cooled to a temperature of about 0°C to about 5°C.

[0486] Embodiment 86: A method for preparing a solid form, which is an anhydrous crystalline ruxolitinib free base, comprising drying crystalline ruxolitinib dihydrate.

[0487] Embodiment 87: The method of embodiment 86, wherein the drying comprises drying the crystalline ruxolitinib dihydrate in a can containing a desiccant at about room temperature.

[0488] Embodiment 88: A method as described in embodiment 87, wherein the desiccant is P 2 O 5 .

[0489] Embodiment 89: A solid form, which is ruxolitinib dihydrate, and the ruxolitinib dihydrate is prepared by the method as described in any one of embodiments 38-85.

[0490] Embodiment 90: A solid form, which is anhydrous crystalline ruxolitinib, and the anhydrous crystalline ruxolitinib is prepared by the method as described in any one of embodiments 86-88.

[0491] Embodiment 91: A pharmaceutical composition comprising the solid form of any one of Embodiments 1-37, 89 and 90.

[0492] Embodiment 92: The pharmaceutical composition as described in Embodiment 91 is an oral dosage form.

[0493] Embodiment 93: A pharmaceutical composition according to Embodiment 92, wherein the oral dosage form is an immediate release dosage form.

[0494] Embodiment 94: The pharmaceutical composition of Embodiment 93, wherein the ruxolitinib dihydrate is present in an amount of about 5 to about 25 mg calculated as the free base.

[0495] Embodiment 95: A pharmaceutical composition as described in Embodiment 93, wherein the ruxolitinib dihydrate is present in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg of ruxolitinib dihydrate as a free base.

[0496] Embodiment 96: A pharmaceutical composition as described in Embodiment 93, wherein the oral dosage form is a sustained release dosage form.

[0497] Embodiment 97: The pharmaceutical composition of Embodiment 96, wherein the ruxolitinib dihydrate is present in an amount of about 10 to about 50 mg calculated as the free base.

[0498] Embodiment 98: A pharmaceutical composition as described in Embodiment 96, wherein the ruxolitinib dihydrate is present in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg or about 50 mg of ruxolitinib dihydrate calculated as the free base.

[0499] Embodiment 99: A pharmaceutical composition as described in Embodiment 91, wherein the composition is a topical preparation.

[0500] Embodiment 100: A pharmaceutical composition as described in Embodiment 99, wherein the topical formulation is a cream formulation.

[0501] Embodiment 101: The pharmaceutical composition of embodiment 100, wherein the cream formulation comprises an oil-in-water emulsion.

[0502] Embodiment 102: The pharmaceutical composition according to Embodiment 101, wherein the cream formulation is prepared by incorporating ruxolitinib dihydrate into the oil-in-water emulsion.

[0503] Embodiment 103: A topical pharmaceutical formulation comprising ruxolitinib free base and a solvent component, wherein the formulation is prepared by dissolving the solid form according to any one of Embodiments 1-37, 89 and 90 in the solvent component.

[0504] Embodiment 104: The topical pharmaceutical formulation of any one of Embodiments 99-103, wherein the ruxolitinib free base is present in an amount of about 0.5% to about 1.5% by weight of the ruxolitinib free base of the formulation.

[0505] Embodiment 105: The topical pharmaceutical formulation of embodiment 104, wherein the ruxolitinib free base is present in an amount of about 1.5% by weight of the ruxolitinib free base of the formulation.

[0506] Embodiment 106: A topical pharmaceutical formulation as described in any of Embodiments 103-105, wherein the topical pharmaceutical formulation comprises ruxolitinib dihydrate, and the ruxolitinib dihydrate is less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight %, ...9 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.8 weight %, less than about The invention also provides an amount less than about 0.07 wt %, less than about 0.06 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0507] Embodiment 107: A topical pharmaceutical formulation comprising (a) ruxolitinib free base in an amount of about 0.5 wt % to about 1.5 wt % of the formulation; and (b) ruxolitinib dihydrate, wherein the ruxolitinib dihydrate is less than about 0.9 wt %, less than about 0.8 wt %, less than about 0.7 wt %, less than about 0.6 wt %, less than about 0.5 wt %, less than about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.1 wt %, less than about 0.09 wt %, less than about 0.08 wt %, less than about 0.09 ...8 wt %, less than about 0.09 wt %, less than about 0.08 wt %, less than about 0.08 wt %, less than about 0.08 wt %, less than about 0.08 wt %, less than about The present invention is present in an amount of about 0.08 wt %, less than about 0.07 wt %, less than about 0.06 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0508] Embodiment 108: The topical drug formulation of any one of embodiments 99-107, wherein the topical drug formulation is prepared in large batch sizes.

[0509] Embodiment 109: The topical pharmaceutical formulation of any one of Embodiments 103-107, wherein the topical pharmaceutical formulation is prepared in a batch size of 1000 kg or more.

[0510] Embodiment 110: A topical pharmaceutical preparation comprising (a) ruxolitinib or a pharmaceutically acceptable salt thereof, and (b) ruxolitinib dihydrate, wherein the ruxolitinib dihydrate accounts for less than about 0.9 weight %, less than about 0.8 weight %, less than about 0.7 weight %, less than about 0.6 weight %, less than about 0.5 weight %, less than about 0.4 weight %, less than about 0.3 weight %, less than about 0.2 weight %, less than about 0.1 weight %, less than about 0.09 weight %, less than about 0.08 weight % of the preparation as a free base. %, less than about 0.07 wt %, less than about 0.06 wt %, less than about 0.05 wt %, less than about 0.04 wt %, less than about 0.03 wt %, less than about 0.02 wt %, less than about 0.01 wt %, less than about 0.009 wt %, less than about 0.008 wt %, less than about 0.007 wt %, less than about 0.006 wt %, less than about 0.005 wt %, less than about 0.004 wt %, less than about 0.003 wt %, less than about 0.002 wt %, or less than about 0.001 wt %.

[0511] Embodiment 111: The topical drug formulation of embodiment 110, wherein the topical drug formulation is prepared in large batch sizes.

[0512] Embodiment 112: The topical pharmaceutical preparation of embodiment 110, wherein the topical pharmaceutical preparation is prepared in a batch size of 1000 kg or more.

[0513] Embodiment 113: A topical pharmaceutical formulation as described in any one of Embodiments 110-112, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 1.5% by weight of the formulation as a free base.

[0514] Embodiment 114: The topical pharmaceutical formulation of embodiment 9113, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is present in an amount of about 1.5% by weight of the formulation as a free base.

[0515] Embodiment 115: The topical pharmaceutical formulation according to any one of Embodiments 110 to 114, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is ruxolitinib phosphate.

[0516] Embodiment 116: A topical pharmaceutical formulation comprising ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the formulation comprises less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.07%, less than about 0. 0.06%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02%, less than about 0.01%, less than about 0.009%, less than about 0.008%, less than about 0.007%, less than about 0.006%, less than about 0.005%, less than about 0.004%, less than about 0.003%, less than about 0.002% or less than about 0.001% by weight of ruxolitinib dihydrate, wherein the formulation is prepared in a large batch size.

[0517] Embodiment 117: The topical pharmaceutical formulation of Embodiment 116, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is present in an amount of about 0.5 wt % to about 1.5 wt % of the formulation as a free base.

[0518] Embodiment 118: The topical pharmaceutical formulation of Embodiment 117, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is present in an amount of about 1.5% by weight of the formulation as a free base.

[0519] Embodiment 119: The topical pharmaceutical formulation of any one of Embodiments 116-118, wherein the ruxolitinib or the pharmaceutically acceptable salt thereof is ruxolitinib phosphate.

[0520] Embodiment 120: A topical pharmaceutical formulation as described in any of Embodiments 116-119, wherein the batch size is 1000 kg or more.

[0521] Embodiment 121: A method for releasing a batch of a topical pharmaceutical formulation as described in any of Embodiments 116-120, the method comprising (i) testing a sample of the topical pharmaceutical formulation for the absence of crystalline ruxolitinib dihydrate; and if the sample passes the test in step (i), then: (ii) releasing the batch for public use.

[0522] Embodiment 122: The method of embodiment 121, wherein the testing comprises observing a sample of the formulation under an optical microscope to detect the absence or presence of crystals, wherein the sample passes the test when no crystals are detected.

[0523] Embodiment 123: A method of treating a disease in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition as described in any of Embodiments 91-115, wherein the disease is myelofibrosis, polycythemia vera, acute graft-versus-host disease, or chronic graft-versus-host disease.

[0524] Embodiment 124: A method of treating a skin disorder in a patient in need thereof, the method comprising administering to the patient the pharmaceutical composition of any one of Embodiments 91-115.

[0525] Embodiment 125: A method of treating a skin condition in a patient in need thereof, the method comprising applying to the affected skin area of ​​the patient the topical pharmaceutical formulation of any one of Embodiments 99-115.

[0526] Embodiment 126: The method of any one of Embodiments 124-125, wherein the skin disorder is an autoimmune skin disease.

[0527] Embodiment 127: The method of any one of Embodiments 124-125, wherein the skin disorder is atopic dermatitis.

[0528] Embodiment 128: The method of any one of Embodiments 124-125, wherein the skin disorder is lichen planus.

[0529] Embodiment 129: The method of any one of Embodiments 124-125, wherein the skin disorder is hidradenitis suppurativa.

[0530] Embodiment 130: The method of any one of Embodiments 124-125, wherein the skin disorder is psoriasis.

[0531] Embodiment 131: The method of any one of Embodiments 124-125, wherein the skin disorder is plaque psoriasis.

[0532] Embodiment 132: The method of any one of Embodiments 124-125, wherein the skin disorder is a rash, skin irritation, or skin sensitization.

[0533] Embodiment 133: The method of any one of Embodiments 124-125, wherein the skin disorder is contact dermatitis or allergic contact dermatitis.

[0534] Embodiment 134: The method of any one of Embodiments 124-125, wherein the skin disorder is bullous pemphigoid.

[0535] Embodiment 135: The method of any one of Embodiments 124-134, wherein the patient is a human patient.

[0536] It should be further understood that certain features of the present disclosure described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for simplicity, various features of the present disclosure described in the context of a single embodiment may also be provided individually or in any suitable sub-combination.

[0537] The present disclosure will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present disclosure in any way. Those skilled in the art will readily recognize multiple non-critical parameters that can be changed or modified to obtain substantially the same results.

[0538] Example

[0539] The crystalline dihydrate form of ruxolitinib was found during the scale-up work up to 3200 kg of surface product with 1.5% (w / w) of ruxolitinib phosphate in terms of free base (prepared by methods similar to those described in Example 16 on a smaller scale) and was isolated by diluting the product with water, filtering, washing with water and drying. Two methods have been used to prepare crystalline ruxolitinib dihydrate. The first method is to produce crystalline ruxolitinib dihydrate from isolated amorphous ruxolitinib free base (Example 1, Scheme 1). In this method, the crystalline ruxolitinib phosphate is neutralized with a base (such as an aqueous potassium hydroxide (KOH) solution). The resulting ruxolitinib free base is then extracted into an organic solvent (EtOAc or DCM) or an organic solvent system (EtOAc and DCM). After distillation to remove one or more solvents, ruxolitinib free base in the form of an amorphous solid is obtained. Amorphous ruxolitinib free base is then crystallized in a mixed solvent system, such as isopropyl alcohol (IPA) and water, to produce crystalline ruxolitinib dihydrate.

[0540] The second method for preparing crystalline ruxolitinib dihydrate uses ruxolitinib free base generated in situ to crystallize in aqueous isopropanol solution (Example 2, Flow 2). In this method, ruxolitinib free base does not need to be separated. Alternatively, the solvent of the solution of ruxolitinib free base in DCM or ethyl acetate (EtOAc) or a mixture of EtOAc and DCM is replaced with isopropanol (IPA). After adding water and seeding with separated ruxolitinib dihydrate crystals using the previous method, crystalline ruxolitinib dihydrate is produced.

[0541] The preparation and isolation of ruxolitinib phosphate can be found in WO2008 / 157208, which is incorporated herein by reference in its entirety. The preparation and isolation of compound 3 L-tartrate dihydrate, compound 2 chloride hydrochloride, and ruxolitinib free base can also be found in U.S. Patent Publication No. 20220056035, which is incorporated herein by reference in its entirety.

[0542] Example 1. Preparation of crystalline ruxolitinib dihydrate from isolated amorphous ruxolitinib free base

[0543] Process 1:

[0544]

[0545] Step 1: Neutralization of ruxolitinib phosphate and isolation of amorphous ruxolitinib free base.

[0546] A suspension of crystalline ruxolitinib phosphate (116.14 g, 287.2 mmol) in ethyl acetate (EtOAc, 400 mL), water (350 mL) and dichloromethane (DCM, 1500 mL) was cooled to 0-5 ° C in an ice bath and then gradually charged with an aqueous solution of 3M potassium hydroxide (KOH, 200 mL, 600 mmol). After neutralization (pH 7.5-8.0), the initial suspension became a solution with two phases. The two phases were separated and the organic phase was washed with water (500 mL) and washed with magnesium sulfate (MgSO 4 ) and dried. After filtering to remove the desiccant, the organic solution was concentrated to dryness under reduced pressure. The resulting amber syrup was further dried under vacuum to provide ruxolitinib free base in the form of an off-white to light yellow amorphous powder, which was used in the subsequent crystallization process without further purification. For amorphous ruxolitinib free base: 1 H NMR (DMSO-d 6 ,400MHz)δ12.10(br.s,1H),8.78(s,1H),8.67(s,1H),8.36(s,1H),7.58(dd,1H,J=2.3,3.4Hz),6.97(dd,1H,J=1.5,3.6Hz),4.50(t C 17 H 18 N 6 (MW, 306.37), LCMS (EI) m / e 307 (M ++H).

[0547] Step 2: Amorphous ruxolitinib free base is crystallized in aqueous isopropanol to produce crystalline ruxolitinib dihydrate.

[0548] Water (214 mL) was gradually added to a solution of amorphous ruxolitinib free base (9.32 g, 28.1 mmol) in isopropanol (IPA, 86 mL) from step 1 at ambient temperature. The resulting mixture was warmed to 55-65 ° C to produce a transparent solution. The resulting solution was then cooled to ambient temperature, and then crystalline ruxolitinib dihydrate seeds (20.9 mg) were introduced into the solution. The crystallization mixture was then stirred at ambient temperature for 16 hours and the solid was gradually crystallized from the solution. The solid was collected by filtration, washed with cold water (50 mL), and dried to constant weight under vacuum, providing (R) -3- (4- (7H- pyrrolo [2,3-d] pyrimidine -4- bases) -1H- pyrazol -1- bases) -3- cyclopentyl propionitrile dihydrate (9.03 g, 9.62 g theoretical value, 93.9%) in the form of white to off-white crystalline powder. For crystalline Ruxolitinib dihydrate: chemical purity according to HPLC>99.9%; chiral purity according to chiral HPLC>99.9%; water content according to KF is 10.30%; 1 H NMR (500 MHz, DMSO-d 6 )δ12.09(s,1H),8.79(s,1H),8.69(s,1H),8.38(s,1H),7.59(dd,J=3.7,2.0Hz,1H) ,6.99(dd,J=3.7,1.4Hz,1H),4.54(td,J=9.7,4.0Hz,1H),3.28(dd,J=17.1,9.7Hz, 1H),3.19(dd,J=17.1,4.0Hz,1H),2.49–2.37(m,1H),1.85–1.78(m,1H),1.66–1.58 (m,1H),1.57–1.49(m,2H),1.48–1.39(m,1H),1.37–1.26(m,2H),1.25–1.16(m,1H); 13 C NMR (DMSO-d 6 ,126MHz)δ152.60,151.42,150.39,139.71,131.47,127.17,121.03,118 .63,113.29,100.24,62.98,44.80,29.57,29.53,25.41,24.80,22.99; C 17 H 22 N 6 O 2(MW, 342.40 (for ruxolitinib dihydrate)) and C 17 H 18 N 6 (MW, 306.37 (for ruxolitinib free base)), LCMS (EI) m / e 307 (M + +H (for ruxolitinib free base)).

[0549] Alternative Step 2: Preparation of crystalline Ruxolitinib dihydrate without seeding.

[0550] A 40 mL scintillation vial with a stirring bar was charged with (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (ruxolitinib free base, 1.13 g, 3.61 mmol) and IPA (7.15 mL, 93 mmol) at ambient temperature. The mixture was warmed in a 60 °C water bath to partially dissolve the foam. Water (16.0 mL, 888 mmol) was then introduced and the resulting mixture was warmed in a 60 °C water bath until completely dissolved. The solution was then cooled to ambient temperature (18.2 °C) and stirred at ambient temperature. After stirring for 6 hours at ambient temperature, the solution became turbid. An additional amount of water (1.85 mL, 103 mmol) was charged and the resulting mixture was stirred at ambient temperature for an additional 17 hours. The solids were collected by filtration and the wet cake was dried under house vacuum by pulling air through the filter cake. The desired product (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile dihydrate (ruxolitinib dihydrate, 0.913 g, 1.236 g theoretical value, 74% yield) was obtained as an off-white to light pink crystalline powder, which was identical to the crystalline ruxolitinib dihydrate prepared in the seeded state in every similar aspect including XRPD and DSC.

[0551] Example 2. Preparation of crystalline ruxolitinib dihydrate from in situ generated ruxolitinib free base

[0552] Process 2

[0553]

[0554] Step 1: Preparation of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propenylidene)-N-methylmethanaminium chloride hydrochloride.

[0555] A solution of oxalyl chloride (21.88 g, 15.1 mL, 169 mmol, 2.25 equivalents) in anhydrous acetonitrile (65 mL) was cooled to 0-5 ° C in an ice bath. Anhydrous DMF (70.8 g, 75.0 mL, 969 mmol, 12.9 equivalents) was added dropwise to the solution to form the corresponding Vilsmeier reagent. During the addition of DMF, the internal temperature was controlled to below 10 ° C. The ice batch was removed and the reaction mixture was gradually warmed to ambient temperature over 40 minutes. Methyl-7H-pyrrolo[2,3-d]pyrimidine (Compound 1, 10.0 g, 75.1 mmol) was once loaded into the Vilsmeier reagent generated in situ in solid form at ambient temperature, and the resulting slurry was stirred at ambient temperature for 5-10 minutes to ensure complete mixing, and then warmed to 85-90 ° C. The reaction mixture was stirred at 85-90 ° C for one hour, and then gradually cooled to ambient temperature. Fill with anhydrous acetone (CH 3 COCH 3 , 100 mL) and the resulting slurry was stirred at ambient temperature for two hours, followed by stirring at 0-5 ° C for two hours. The solid was collected by filtration, washed with a one-to-one mixture of acetone and MTBE (2 x 100 mL), and dried under vacuum to constant weight to provide the desired product (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propenylene)-N-methylmethanaminium chloride hydrochloride (Compound 2 chloride hydrochloride, 22.0 g, 23.72 g theoretical value, 98.9% according to HPLC area %, 97.6 wt%, 92.7% yield) as a yellow to brown crystalline solid, which contained <1% DMF and acetonitrile and 1-2% water and was used in subsequent reactions without further purification. For Compound 2 chloride hydrochloride: 1 H NMR (500 MHz, DMSO-d 6 )δ13.65(s,1H),8.99(s,1H),8.48(s,2H),7.99–7.94(m,1H),6.84(dd,J=3.6,1.6Hz,1H),3.48(s,6H),2.82(s,6H)ppm; 13 C NMR (DMSO-d 6 ,125MHz) δ163.8,151.3,147.6,145.0,132.1,117.5,102.9,91.6,48.9,42.1ppm; C 13 H 19 Cl 2 N 5(MW, 279.77 (for compound 2 chloride hydrochloride) and 244.32 (for compound 2 without anion)) LCMS (EI) m / e 244.2 (M + , base peak). Note that Compound 2 chloride hydrochloride is identical to the crystalline Form I of Compound 2b in WO 2022 / 040180.

[0556] Step 2: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (ruxolitinib free base).

[0557] A solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propenylidene)-N-methylmethanaminium chloride hydrochloride (Compound 2 chloride hydrochloride, 10.0 g, 31.6 mmol) in water (10.0 mL) was treated with a 30% aqueous solution of NaOH to a pH of 7-8 at 0-5°C. To the resulting aqueous solution was added charcoal (2.0 g) and the mixture was stirred at ambient temperature for 2-4 hours. The charcoal was removed by filtration through a pad of celite and the wet charcoal cake was washed with water (15 mL). The resulting aqueous solution containing (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)propenylene)-N-methylmethanaminium chloride (Compound 2 chloride) was then treated with ethanol (30 mL) and (R)-3-cyclopentyl-3-hydrazinopropionitrile L-tartrate dihydrate (Compound 3 L-tartrate dihydrate, 11.21 g, 33.0 mmol, 1.04 equiv) at ambient temperature. The resulting mixture was then stirred at ambient temperature for 16 hours. When the reaction was complete, the reaction mixture was filtered to remove the solid (L-tartaric acid). The filter cake was washed with ethanol (2 x 10 mL). The filtrate and wash solutions were combined and the combined solution was concentrated under reduced pressure at 40-50 °C to remove most of the ethanol. H was then added to the residue. 2 O (30mL) and dichloromethane (DCM, 50mL) and the mixture was treated with 30% aqueous sodium hydroxide (NaOH) to adjust the pH to about 10. The two layers were separated and the aqueous layer was extracted with DCM (30mL). The combined organic extracts were filtered through a celite bed and the celite bed was washed with DCM (10mL). The solution of ruxolitinib free base in DCM was then used directly in subsequent process steps to produce crystalline ruxolitinib dihydrate.

[0558] Step 3: Preparation of crystalline (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile dihydrate (crystalline ruxolitinib dihydrate).

[0559] The solution of Ruxolitinib free base in DCM is concentrated under reduced pressure to remove most of DCM. Then isopropanol (IPA, 50mL) is loaded into the residue and the resulting solution is further concentrated under reduced pressure. Additional IPA (50mL) is loaded into the concentrated solution to convert the solvent completely into IPA. Then the resulting solution of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (Ruxolitinib free base) in IPA is cooled to ambient temperature, and then water (208mL) is gradually loaded into the IPA solution under stirring at ambient temperature. After the water addition is completed, the resulting mixture is warmed to 55-65°C to produce a clear solution. The resulting solution is then cooled to ambient temperature, and then crystallized Ruxolitinib dihydrate seeds (32mg) (separated from the method described above) are introduced into the solution. The crystallization mixture is then stirred at ambient temperature for 16 hours and the solid is gradually crystallized from the solution. The solid was collected by filtration, washed with a mixture of IPA and water (20% IPA in water, 25 mL), and dried under vacuum to constant weight to provide ruxolitinib dihydrate (6.76 g, 10.82 g theoretical, 62.5%) as a white to off-white crystalline powder, which was identical in every similar respect to the material obtained in Example 1.

[0560] Physicochemical properties of crystalline ruxolitinib dihydrate

[0561] The structure of Ruxolitinib dihydrate was determined by single crystal x-ray analysis. See Example 3. The physicochemical properties of crystalline Ruxolitinib dihydrate were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic vapor sorption (DVS). See Examples 4-7.

[0562] Example 3. Single crystal X-ray analysis of ruxolitinib dihydrate.

[0563] Will have 0.260×0.190×0.120mm 3 Colorless bulk crystals of approximately 1.3 × 10 mm in size were mounted in random orientation on a polymer ring. Preliminary examination and data collection were performed on a Bruker AXS D8 Quest diffractometer equipped with a copper anode micro-source sealed X-ray tube (Cu Kα ) and PhotonIII_C14 charge integrating and photon counting pixel array detectors.

[0564] The unit cell constants and orientation matrix for data collection were obtained from least squares refinement using set angles for 9104 reflections in the range 3.4603° <θ < 78.3810°. Data were collected at room temperature with a maximum diffraction angle (2θ) of 159.822°.

[0565] The crystal system is orthorhombic and the space group is P212121. The unit cell parameters and calculated volumes are: α=90°, β=90°, γ=90°, The formula weight is 342.40 g mol -1 and Z = 8, yielding 1.271 g cm -3 The calculation density of .

[0566] The single crystal structure of Ruxolitinib dihydrate was determined. The structure of Ruxolitinib dihydrate was determined to be a hydrated crystalline form, such as Figure 1 As shown in , it consists of two ruxolitinib molecules and four water molecules in the asymmetric unit.

[0567] Example 4A. X-ray powder diffraction (XRPD) analysis of crystalline ruxolitinib dihydrate.

[0568] X-ray powder diffraction (XRPD) was obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was: (1) X-ray radiation from copper and LYNXEYE with a slit of 0.6 mm TM detector; (2) 40 kV, 25 mA X-ray power; and (3) sample powder dispersed on a zero background sample holder. The general measurement conditions of XRPD are: start angle 3 degrees; stop angle 30 degrees; sampling 0.015 degrees; and scanning speed 2 degrees / min.

[0569] XRPD analysis is a means of determining crystallinity. Here, XRPD analysis of a sample of Ruxolitinib dihydrate showed that it was a crystalline solid ( Figure 2 ). The XRPD pattern is consistent with the XRPD pattern calculated from the single crystal structure. Table 1 provides the corresponding Figure 2 XRPD peak data. Figure 6 A comparison of the XRPD pattern of ruxolitinib dihydrate with the XRPD pattern of ruxolitinib phosphate is shown. Another batch of ruxolitinib dihydrate also showed that the product was crystalline, see Tables 2 and Figure 7 .

[0570] Table 1: XRPD data of a representative sample of crystalline Ruxolitinib dihydrate

[0571]

[0572]

[0573] Table 2: XRPD data of another representative sample of crystalline Ruxolitinib dihydrate

[0574]

[0575]

[0576] Example 4B. XRPD Characterization of Other Representative Samples of Ruxolitinib Dihydrate (Method A)

[0577] Additional representative samples of ruxolitinib dihydrate were analyzed.

[0578] Transmission geometry

[0579] The incident beam of Cu radiation produced by Optix long fine focusing source is used to collect X RPD pattern. Cu Kα X-ray is focused through sample and arrives on detector using elliptical gradient multilayer mirror. Before analysis, silicon sample (NIST SRM 640f) is analyzed to verify that the observed position of Si 111 peak is consistent with the position confirmed by NIST. The sample of sample is sandwiched between 3-μm thick film and analyzed with transmission geometry. The background produced by air is minimized using beam interceptor (beam-stop) short anti-scatter extension and anti-scatter blade. Use Soller slit (Soller slit) for incident and diffracted beam to minimize the widening from axis divergence. Use scanning position sensitive detector (X'Ce lerator) and data collector software 5.5 version positioned at 240mm distance sample to collect diffraction pattern.

[0580] In most cases, peaks within a range of up to about 30° 2θ were selected. Each peak was rounded to the nearest 0.1° or 0.01° 2θ using a rounding algorithm, depending on the instrument used to collect the data and / or the inherent peak resolution. The positions of the peaks along the x-axis (° 2θ) in the figures and tables are determined using dedicated software and rounded to one or two significant digits after the decimal point based on the above criteria. Based on the recommendations outlined in the USP discussion of variability in x-ray powder diffraction, the peak position variability is within ± 0.2° 2θ. The accuracy and precision associated with any specific measurement reported herein has not been determined. In addition, measurements by third parties on independently prepared samples on different instruments may result in variability greater than ± 0.2° 2θ. For the d-spacing tabulations, the wavelength used to calculate the d-spacing is (Cu-K α1Wavelength). The variability associated with the d-spacing assessment is calculated for each d-spacing as recommended by USP and is provided in the corresponding data tables.

[0581] According to USP guidelines, variable hydrates and solvates may exhibit peak differences greater than 0.2° 2Θ and therefore a peak difference of 0.2° 2Θ is not applicable for these materials.

[0582] For samples with only one XRPD pattern and no other means to assess whether the sample provides a good approximation of the powder average, the peak table contains data identified only as "major peaks". These peaks are a subset of the entire observed peak list. Major peaks are selected from the observed peaks by identifying non-overlapping, low-angle peaks that preferably have high intensity.

[0583] If multiple diffraction patterns are available, an assessment of particle statistics (PS) and / or optimal orientation (PO) is possible. Reproducibility among XRPD patterns of multiple samples analyzed on a single diffractometer indicates that particle statistics are adequate. The consistency of relative intensity between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern can be compared with an XRPD pattern calculated based on a single crystal structure (if available). Two-dimensional scattering patterns using an area detector can also be used to assess PS / PO. If the effects of PS and PO are determined to be negligible, the XRPD pattern represents the average powder intensity of the sample and the main peak can be identified as a "representative peak". In general, the more data collected to determine representative peaks, the more confident a peak is that it may belong to the category of those peaks.

[0584] "Characteristic peaks", where they exist, are a subset of representative peaks and are used to distinguish one crystalline polymorph from another (a polymorph is a crystalline form having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound that are within ±0.2° 2θ relative to all other known crystalline polymorphs of the compound. Not all crystalline polymorphs of a compound must have at least one characteristic peak. Fig. 9 The XRPD pattern of crystalline ruxolitinib dihydrate is shown, with the observed peaks shown in Table 3A and the major peaks shown in Table 3B.

[0585] Table 3A. Observed Peaks of Ruxolitinib Dihydrate

[0586]

[0587]

[0588] Table 3B. Representative peaks of Ruxolitinib dihydrate

[0589]

[0590] Example 5. Differential Scanning Calorimetry (DSC) Analysis of Crystalline Ruxolitinib Dihydrate.

[0591] DSC was obtained from a TA Instruments Differential Scanning Calorimeter Discovery DSC 2500 with autosampler. The DSC instrument conditions were as follows: 20-300°C, 10°C / min; Tzero aluminum sample pan and lid; and nitrogen flow, 50 mL / min.

[0592] Figure 3 The DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in . The DSC thermogram reveals an endothermic event with an onset temperature of 60.5°C and a peak temperature of 66.7°C, which corresponds to the dehydration process. In another DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate, there is an endothermic event with an onset temperature of 59.5°C. In another DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate, there is an endothermic event with a peak temperature of 69.1°C.

[0593] The materials were subjected to individual DSC thermogram analysis. In this experiment, DSC (Method B) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Tau hysteresis adjustment was performed with indium, tin, and zinc. Temperature and enthalpy were adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustment was then verified with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in an airtightly sealed aluminum DSC pan, the weight was accurately recorded, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as a sample pan was placed on the reference side of the cell. The pan cover was pierced before sample analysis. The sample was analyzed at 10°C / min from -30°C to 250°C.

[0594] Fig.10 The DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in . A broad endothermic event with an onset temperature of 68°C and a peak temperature of 72°C and a secondary endotherm with a peak maximum at 110°C was observed.

[0595] Example 6A. Thermogravimetric analysis (TGA) of crystalline ruxolitinib dihydrate.

[0596] TGA was obtained from a TA Instruments thermogravimetric analyzer Discovery TGA 5500 with autosampler. General experimental conditions for TGA were: ramp from 25°C to 300°C, 10°C / min; nitrogen purge gas flow, 25 mL / min; platinum sample holder.

[0597] Figure 4 The TGA thermogram of a representative sample of crystalline Ruxolitinib dihydrate is shown in . A weight loss of 10.4% was observed below 100°C, which was attributed to dehydration. Above 200°C the resulting anhydrous free base decomposed.

[0598] A representative sample of crystalline Ruxolitinib dihydrate lost all hydrate from 30°C to 80°C to become an amorphous solid. After adding one drop of water, the amorphous solid remained an amorphous solid. One day later, after adding two drops of water, the amorphous solid became a crystalline dihydrate.

[0599] Example 6B. Another Thermogravimetric Analysis of Crystalline Ruxolitinib Dihydrate

[0600] The material was subjected to another TGA thermogram analysis. Thermogravimetric analysis (Method C) was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were made using indium, tin, zinc, and phenyl salicylate, and then verified with indium. Balance was verified with calcium oxalate. The sample was placed in an aluminum pan. The pan was hermetically sealed, the lid was pierced, and the pan was inserted into the TG furnace. A weighed aluminum pan configured as a sample pan was placed on a reference platform. The furnace was heated under nitrogen. The sample was analyzed at 10°C / min from ambient temperature to 350°C. Thermogravimetric analysis typically undergoes a period of equilibrium at the beginning of each analysis, indicated by brackets on the thermogram. For accuracy, the starting temperature for the relevant weight loss calculation was selected as a point outside this region (usually above 35°C).

[0601] Fig.11 A TGA thermogram of a representative sample of crystalline Ruxolitinib dihydrate is shown in . TGA analysis indicated a 1.7% weight loss up to 90° C., followed by another 8.2% weight loss up to 178° C. A 10.5% (9.9% observed) weight loss would be consistent with the dihydrate.

[0602] Example 7A. Dynamic vapor sorption (DVS) analysis of crystalline ruxolitinib dihydrate.

[0603] DVS experiments were performed on a VTI-SA+ gas phase adsorption analyzer from TA Instruments. A representative sample of crystalline ruxolitinib dihydrate was first dried at 60 °C under N 2 The mixture was pre-dried at 0% RH for 1 h. The humidity was then cycled from 5% RH to 95% RH (adsorption) and back to 5% RH (desorption) at a constant temperature of 25°C, using 5% RH intervals. The equilibrium criterion was 0.010 wt% in 5 minutes, and the maximum equilibrium time for each step was 180 minutes.

[0604] In a pre-drying step at 60 °C, a representative sample of crystalline ruxolitinib dihydrate was dehydrated to form amorphous ruxolitinib free base. It then re-adsorbed up to 9.6% of water at 95% RH and remained relatively stable at 5% RH. XRPD analysis indicated that the solid obtained after DVS was crystalline ruxolitinib dihydrate, see Figure 8 and Table 4. Figure 5 The results of the DVS experiment performed on this representative sample of crystalline ruxolitinib dihydrate are shown in FIG.

[0605] Table 4. XRPD data of crystalline Ruxolitinib dihydrate after DVS

[0606]

[0607]

[0608] Example 7B. Other DVS analyses

[0609] Additional DVS for crystalline Ruxolitinib dihydrate was collected on a surface measurement system DVS Intrinsic instrument (Method D). The samples were not dried prior to analysis. Adsorption and desorption data were collected from 5% to 95% RH in 10% RH increments under a nitrogen purge. The equilibrium standard for analysis was 0.001 dm / dt weight change in 5 minutes, with a minimum step time of 30 minutes and a maximum equilibrium time of 180 minutes, with a data recording interval of 3 minutes. The data was not corrected for the initial water content of the sample.

[0610] DVS showed that during the DVS analysis, ruxolitinib dihydrate gained 0.23% weight from 5% to 95% relative humidity and lost 0.20% after desorption ( Fig.12 and Table 5).

[0611] Table 5. DVS data of Ruxolitinib dihydrate

[0612] Target sample Adsorption quality sample Desorption quality RH(%) RH(%) change(%) RH(%) change(%) Hysteresis 5.0 4.8 0.0013 5.6 0.0334 15.0 15.1 0.0412 17.1 0.0940 0.0528 25.0 25.0 0.0707 25.8 0.1168 0.0461 35.0 35.0 0.0904 35.9 0.1302 0.0399 45.0 45.1 0.1069 46.0 0.1447 0.0378 55.0 55.1 0.1214 56.0 0.1572 0.0357 65.0 65.1 0.1359 66.0 0.1706 0.0347 75.0 74.9 0.1561 76.6 0.1872 0.0311 85.0 84.8 0.1882 87.6 0.2115 0.0233 95.0 94.0 0.2343 94.0 0.2343

[0613] Example 8. Hot stage microscopy analysis of crystalline Ruxolitinib dihydrate

[0614] A representative sample of crystalline Ruxolitinib dihydrate was heated at a rate of 5°C / min starting from a temperature of 25°C. The crystals showed no significant changes at temperatures equal to and below 60°C. From 62°C to 70°C the crystals became darker in color, which corresponds to the dehydration process. Melting was observed at about 75°C and was complete at 80°C. No crystallization was observed after cooling to 25°C.

[0615] Example 9. Water solubility of Ruxolitinib dihydrate

[0616] The solubility of representative samples of crystalline Ruxolitinib dihydrate was measured in different aqueous solutions at 20-25°C (Table 6). The results are summarized in Table 6.

[0617] Table 6: Aqueous solubility data of Ruxolitinib dihydrate

[0618]

[0619]

[0620] *Borate buffer prepared from boric acid and potassium chloride. Buffer pH adjusted with sodium hydroxide.

[0621] Example 10. Solubility of crystalline ruxolitinib dihydrate in organic solvents

[0622] The solubility of representative samples of crystalline ruxolitinib dihydrate was measured in different organic solvents (Table 7). The results are summarized in Table 7. In polar solvents, ruxolitinib dihydrate loses crystal water. The resulting ruxolitinib free base is easily soluble in organic solvents.

[0623] Table 7: Solubility data of Ruxolitinib dihydrate in organic solvents

[0624] Solvents Solubility (mg / mL) Methanol (MeOH) >500 Ethanol (EtOH) >500 Isopropyl alcohol (IPA) >500 acetone >500 Ethyl acetate >200

[0625] Example 11. Characterization of single crystals of Ruxolitinib dihydrate

[0626] preparation:

[0627] Single crystals of Ruxolitinib dihydrate were prepared as follows. 98.4 mg of amorphous Ruxolitinib was loaded into a vial and contacted with 1 ml of ethyl acetate. The resulting solution was dried over magnesium sulfate. The sample was seeded with crystalline Ruxolitinib dihydrate, followed by the addition of 1 ml of heptane to cause oiling. The sample was contacted with 0.02 ml of water to dissolve the seed material. The sample was seeded again and 2 ml of heptane was added. The sample was stored at room temperature for 8 days to nucleate the hexagonal tablets.

[0628] Data Collection:

[0629] Will have 0.56×0.36×0.08mm 3 Colorless plates of approximate dimensions of were mounted on polymer rings in random orientation. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu Kα ) and Dectris Pilatus3R 200K hybrid pixel array detector.

[0630] The orientation matrix for unit cell constants and data collection was obtained from least squares refinement using set angles of 12431 reflections in the range 4.7310° <θ < 75.4160°. RYS A LIS P RO The space group is determined to be P2 1 2 1 2 1 (International Form No. 19).

[0631] Table 8 below provides the crystal data and data collection parameters.

[0632] Table 8. Crystallographic data and data collection parameters for Ruxolitinib dihydrate.

[0633]

[0634]

[0635] Calculated X-ray Powder Diffraction (XRPD) pattern:

[0636] The calculated XRPD pattern was generated for Cu radiation using mercury and atomic coordinates, space group and unit cell parameters from the single crystal structure. Fig.21 .

[0637] Example 12. Relative humidity test of Ruxolitinib dihydrate

[0638] Ruxolitinib dihydrate was maintained at selected relative humidity to help determine the range of physical stability (see table below). The dihydrate was transferred to vials, which were then opened and placed in a tank containing a saturated saline solution for the specified period of time:

[0639] Humidity at 25°C Salt in RH tank 11%RH Lithium chloride 33%RH Magnesium chloride 53%RH Magnesium Nitrate 58%RH Sodium bromide 69%RH Potassium iodide 98%RH Potassium sulfate

[0640] The dihydrate form was observed to be physically stable above 11% RH, converting to the anhydrous crystalline free base form (Form I) at an undetermined value below 11% RH during the time tested. The XRPD peak positions were consistent between the XRPD patterns and did not represent a variable system.

[0641]

[0642] Example 13. Water slurry experiment

[0643] Limited water activity slurries were prepared using Ruxolitinib dihydrate (see table below). Water activity (a) was investigated by competitive water activity grinding experiments (slurries) in various aqueous solvent mixtures. w ) on the hydration state of the dihydrate. The resulting solid phase was characterized by XRPD. The experiment determined that at various aw The water activity is also related to the relative humidity, because RH% = a w x 100. Therefore, the stability of the anhydrous / hydrate system in the slurry experiment can be directly correlated to the solid state stability. The literature shows that the slurry technique provides an accurate method for rapidly predicting the physically stable form in the anhydrous / hydrate system under controlled water activity. The method is particularly valuable when the relatively slow transformation kinetics in the solid state prevent true equilibrium from being reached within a reasonable time frame, because the solvent-mediated transformation accelerates the transformation process.

[0644] The crystalline dihydrate form was observed from all conditions tested.

[0645]

[0646] Example 14. Dehydration of Ruxolitinib Dihydrate

[0647] Dehydration of ruxolitinib dihydrate resulted in the isolation of anhydrous crystalline ruxolitinib free base (Form I) (see table below). Form I is described in more detail in Example 15.

[0648]

[0649] Example 15. Anhydrous crystalline ruxolitinib free base

[0650] Dehydration of ruxolitinib dihydrate as described in Example 14 resulted in the isolation of anhydrous crystalline ruxolitinib free base (Form I). 2 O 5 Drying yielded a mostly crystalline product and the XRPD pattern of Form I was successfully indexed using Method A for XRPD (see Fig.13 and Tables 9A and 9B).

[0651] Table 9A. Observed Peaks of Anhydrous Crystalline Ruxolitinib Free Base (Form I)

[0652]

[0653]

[0654] Table 9B. Main Peaks of Anhydrous Crystalline Ruxolitinib Free Base (Form I)

[0655]

[0656] Differences in the XRPD patterns of Form I were observed with respect to crystallinity. Crystallinity is affected by the desolvation method. When dehydration is performed at a slower rate (such as at P) than vacuum drying or heating,2 O 5 When stored on Fig.14 ).

[0657] Two Form I samples were thermally analyzed by DSC Method B and TGA Method C. The thermal data were consistent with an anhydrous solid. TGA indicated a 0.07% weight loss ( Fig.17 ), and DSC showed a single endothermic event with an onset temperature of 83 °C ( Fig.15 ). The event was broad, with the signal returning to baseline around 140° C. No evidence of crystallization was observed after the postulated melt at 83° C.

[0658] The second Form I sample exhibited a greater weight loss in the TGA, with a 0.4% weight loss until 98°C, with no significant additional weight loss observed until after 260°C ( Fig.18 A single endothermic event with an onset temperature of 81°C was observed by DSC ( Fig.16 ). An exothermic trend was observed prior to the onset of the endotherm at 81° C. and may be related to the increased crystallinity of the Form I sample prior to melting at 81° C. The second sample of Form I was observed to contain a small amount of diffuse scattering when compared to the first sample and would indicate that the material may contain defects or a small amount of amorphous content.

[0659] DVS data generated via DVS Method D were collected and Form I was determined to be hygroscopic ( Fig.19 ). Minimal water absorption was observed from 5% to 55% RH, and a 0.26% weight gain was observed. A 10.6% weight gain was observed from 55% to 95% RH (corresponding to 2 moles of water and confirmed as a dihydrate by variable humidity XRPD and RH stress studies). Hysteresis was observed after desorption. Only 1% weight loss was observed from 95% to 15% RH, followed by another 4.8% loss from 15% to 5% RH. The post-DVS sample was observed to be Form I, but with less crystallinity than the starting material ( Fig. 20 ).

[0660] Table 10. DVS data

[0661]

[0662]

[0663] Example 16. Cream formulation produced using Ruxolitinib dihydrate as a starting material

[0664] An oil-in-water cream formulation was prepared using 0.5, 1.0 and 1.5% by weight (free base equivalent) of ruxolitinib dihydrate of the formulation. The three strengths of the formulation were identical except that the amount of purified water was adjusted based on the amount of active ingredient. All excipients used in the formulation were pharmacopeia grade (i.e., USP / NF or BP) or approved for use in topical products. Quantitative formulations for representative 400 kg batches of 0.5, 1.0 and 1.5% cream formulations of ruxolitinib dihydrate are also provided in Tables 11, 12 and 13, respectively.

[0665] Table 11

[0666]

[0667]

[0668] Table 12

[0669]

[0670] Table 13

[0671]

[0672]

[0673] The oil-in-water cream formulation was synthesized at 400 kg scale according to the following procedure. Typically, an overhead mixer with high and low shear mixing blades is suitable for the process.

[0674] program

[0675] 1. Prepare the paraben phase by mixing methylparaben and propylparaben with a portion of propylene glycol (see percentages in Tables 11 to 13).

[0676] 2. Next, prepare the xanthan gum phase by mixing xanthan gum with propylene glycol (see percentages in Tables 11 to 13).

[0677] 3. Then prepare the oil phase by mixing light mineral oil, glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone and medium chain triglycerides. Heat the phase to 70-80°C to melt and form a homogeneous mixture.

[0678] 4. Next prepare the aqueous phase by mixing purified water, polyethylene glycol and disodium EDTA. Heat the phase to 70-80°C.

[0679] 5. Combine the aqueous phase from step 4, the paraben phase from step 1, and ruxolitinib dihydrate to form a mixture.

[0680] 6. The xanthan gum phase from step 2 is then added to the mixture from step 5.

[0681] 7. The oil phase from step 3 was then combined with the mixture from step 6 under high shear mixing to form an emulsion.

[0682] 8. Phenoxyethanol was then added to the emulsion from step 7. Mixing was continued and the product was then cooled under low shear mixing.

[0683] Example 17. Sustained Release Formulation of Ruxolitinib Dihydrate

[0684] A 25 mg sustained release formulation of Ruxolitinib dihydrate was prepared according to the following method. The formulation components are provided in Table 14. The percentages are by weight.

[0685] Table 14

[0686]

[0687] method

[0688] Step 1. Add microcrystalline cellulose, ruxolitinib phosphate, lactose monohydrate and hypromellose into a suitable blender and mix.

[0689] Step 2. Transfer the mixture from step 1 to a suitable granulator and mix.

[0690] Step 3. Add purified water while mixing. Alternatively, dry granulate the mixture.

[0691] Step 4. Screen the particles from step 3.

[0692] Step 5. Transfer the granules from step 4 to a suitable dryer and dry until the LOD does not exceed 3%.

[0693] Step 6. Screen the particles from step 5.

[0694] Step 7. Mix colloidal silicon dioxide with the granules from step 6 in a suitable blender.

[0695] Step 8. Combine stearic acid and magnesium stearate with the blend in step 7 and blend.

[0696] Step 9. Compress the final blend from Step 8 on a suitable rotary tablet press.

[0697] From the foregoing description, various modifications of the present disclosure, except those described herein, will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications and publications, is incorporated herein by reference in its entirety.

Claims

1. A solid form, which is crystalline ruxolitinib dihydrate: wherein the solid form is substantially isolated.

2. The solid form of claim 1, wherein the solid form is characterized by having at least one XRPD peak selected from the group consisting of 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (±0.2 degrees).

3. The solid form of claim 1, wherein the solid form is characterized by having at least five XRPD peaks selected from 6.9, 10.6, 11.6, 12.9, 15.1, 15.4, 19.0, 21.8, 22.7, 23.1, 24.8, and 25.7 degrees 2-theta (±0.2 degrees).

4. The solid form of any one of claims 1-3, wherein the solid form is characterized by an XRPD pattern having characteristic peaks substantially as shown in Figure 2.

5. The solid form of any one of claims 1-4, wherein the solid form is characterized by single crystal x-ray diffraction having a space group of P212121 and a unit cell formula unit (Z) of 8.

6. A solid form as described in claim 5, wherein the solid form has a unit cell parameter: a is about b is about c is about α is about 90°, β is about 90° and γ is about 90°.

7. The solid form of any one of claims 1-6, wherein the solid form is characterized by an endothermic peak in a DSC thermogram having an onset temperature (±5°C) of 61°C and a maximum temperature (±5°C) of 67°C.

8. The solid form of any one of claims 1-6, wherein the solid form is characterized by having a DSC thermogram substantially as shown in Figure 3.

9. The solid form of any one of claims 1-8, wherein the solid form is characterized by having a TGA thermogram substantially as shown in Figure 4.

10. A solid form which is anhydrous crystalline ruxolitinib free base.

11. The solid form of claim 10, wherein the solid form is substantially isolated.

12. The solid form of claim 10 or 11, wherein the solid form is characterized by having at least one XRPD peak selected from 7.2, 11.5, 11.6, 13.2, 14.0, 15.4, 15.7, 18.2, 19.1, 19.6, 22.0, and 23.9 degrees in 2-theta (±0.2 degrees).

13. The solid form of any one of claims 10-12, wherein the solid form is characterized by an XRPD pattern having characteristic peaks substantially as shown in Figure 13.

14. The solid form of any one of claims 10-13, wherein the solid form is characterized by an endothermic peak in a DSC thermogram having an onset temperature (±5°C) of 83°C and a maximum temperature (±5°C) of 93°C.

15. The solid form of any one of claims 10-13, wherein the solid form is characterized by having a DSC thermogram substantially as shown in Figure 15 or Figure 16.

16. The solid form of any one of claims 10-15, wherein the solid form is characterized by having a TGA thermogram substantially as shown in Figure 17 or Figure 18.

17. A method for preparing a solid form according to any one of claims 1 to 9, wherein the solid form is ruxolitinib dihydrate: The method comprises isolating the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component.

18. The method of claim 17, wherein the aqueous solvent component comprises a polar protic solvent and water, wherein the polar protic solvent is isopropanol.

19. The method of any one of claims 17 or 18, wherein the ruxolitinib free base is prepared by a process comprising: Reaction with a base in a solvent component, wherein: The reacting ruxolitinib phosphate with a base comprises using about 2 to about 3 molar equivalents of the base relative to ruxolitinib phosphate, The base is a hydroxide base; and The solvent component comprises water, an ester solvent, a halogenated solvent or a mixture thereof, wherein the ester solvent is ethyl acetate; and wherein the halogenated solvent is dichloromethane.

20. A method of preparing the solid form of any one of claims 10-16, the method comprising drying crystalline ruxolitinib dihydrate.

21. The method of claim 20, wherein the drying comprises drying the crystalline Jakafi Jakafi dihydrate in a can containing a desiccant at about room temperature.

22. A pharmaceutical composition comprising the solid form of any one of claims 1-16.

23. The pharmaceutical composition of claim 22, which is an oral dosage form.

24. The pharmaceutical composition of claim 23, wherein the oral dosage form is an immediate release dosage form.

25. The pharmaceutical composition of any one of claims 22-24, wherein the solid form is ruxolitinib dihydrate, and the ruxolitinib dihydrate is present in an amount of about 5 to about 25 mg calculated as free base.

26. The pharmaceutical composition of claim 23, wherein the oral dosage form is a sustained release dosage form.

27. The pharmaceutical composition of any one of claims 22, 23 and 26, wherein the solid form is ruxolitinib dihydrate, and the ruxolitinib dihydrate is present in an amount of about 10 to about 50 mg calculated as free base.

28. The pharmaceutical composition of claim 22, wherein the composition is a topical formulation.

29. The pharmaceutical composition of claim 28, wherein the topical formulation is a cream formulation.

30. The pharmaceutical composition of claim 29, wherein the cream formulation comprises an oil-in-water emulsion.

31. The pharmaceutical composition of claim 30, wherein the cream formulation is prepared by incorporating ruxolitinib dihydrate into the oil-in-water emulsion.

32. A method for releasing a batch of a topical pharmaceutical formulation as described in any one of claims 28-31, the method comprising (i) testing a sample of the topical pharmaceutical formulation for the absence of crystalline ruxolitinib dihydrate; and if the sample passes the test in step (i), then: (ii) releasing the batch for public use.

33. The method of claim 32, wherein the testing comprises observing a sample of the formulation under an optical microscope to detect the absence or presence of crystals, wherein the sample passes the test when no crystals are detected.

34. A method of treating a disease in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition as described in any one of claims 22-31, wherein the disease is myelofibrosis, polycythemia vera, acute graft-versus-host disease, or chronic graft-versus-host disease.

35. A method of treating a skin disorder in a human patient in need thereof, the method comprising administering to the patient the pharmaceutical composition of any one of claims 22-31.

36. A method of treating a skin condition in a human patient in need thereof, the method comprising applying to the affected skin area of ​​the patient the topical pharmaceutical formulation of any one of claims 28-31.

37. The method of any one of claims 35 or 36, wherein the skin disorder is an autoimmune skin disease.

38. The method of claim 37, wherein the skin disorder is: atopic dermatitis; or lichen planus; or Hidradenitis suppurativa; or psoriasis; or Rash, skin irritation, or skin sensitization; or contact dermatitis or allergic contact dermatitis; or bullous pemphigoid.

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