Solid Forms of JAK Inhibitors and Processes for Preparing the Same

Abstract

The present disclosure relates to solid forms of loxicotinib dihydrate and loxicotinib free base, processes for preparing the same, and compositions containing the same.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 352,094, filed on June 14, 2022, and U.S. Provisional Application No. 63 / 411,808, filed on September 30, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to solid forms of loxicodib hydrochloride dihydrate and loxicodib free base, processes for preparing the same, and compositions containing the same.

Background Art

[0003] The Janus kinase family of protein tyrosine kinases (JAK) belongs to the non-receptor type of tyrosine kinases and includes family members of JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK, and Janus kinase-3), and TYK2 (also known as protein-tyrosine kinase 2). The pathways involving JAK and signal transducer and activator of transcription (STAT) are involved in the signal transduction of a wide range of cytokines. Cytokines are low molecular weight polypeptides or glycoproteins that stimulate biological responses in substantially all cell types. Generally, cytokine receptors do not have intrinsic tyrosine kinase activity and thus require receptor-associated kinases to propagate the phosphorylation cascade. JAK performs this function. Cytokines bind to these receptors, causing receptor dimerization, which enables JAK to phosphorylate not only each other but also specific tyrosine motifs within the cytokine receptor. STATs that recognize these phosphotyrosine motifs are recruited to the receptor and are then themselves activated by JAK-dependent tyrosine phosphorylation events. Once activated, STATs dissociate from the receptor, dimerize, translocate to the nucleus, bind to specific DNA sites, and alter transcription (Scott, M. J., C. J. Godshall, et al. (2002) "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6):1153-9).

[0004] The JAK family plays a role in the cytokine-dependent regulation of the proliferation and function of cells involved in the immune response. The JAK / STAT pathway, particularly all four members of the JAK family, is thought to play a role in the etiology of asthmatic reactions, chronic obstructive pulmonary disease, bronchitis, and other related lower airway inflammatory diseases. Furthermore, multiple cytokines that signal through JAK kinases are associated with upper airway inflammatory diseases or conditions that affect the nose and paranasal sinuses (e.g., rhinitis, sinusitis), whether classical allergic reactions or not. The JAK / STAT pathway is also suggested to play a role in inflammatory diseases / conditions of the eye (including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, and chronic allergic responses).

[0005] Consistent with the foregoing, the JAK1 / 2 inhibitor ruxolitinib ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile) has been approved in the United States as an oral drug 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 is being investigated in clinical trials for the treatment of vitiligo and psoriasis.

[0006] The aforementioned approved products currently use the phosphate salt of ruxolitinib. Stable crystalline ruxolitinib phosphate is described in U.S. Patent No. 8,722,693 and is patented. Given the success of using stable crystalline ruxolitinib phosphate in approved drugs, there was no need to investigate other salts or solid forms of the free base. However, surprisingly, the present inventors discovered the crystalline dihydrate form of ruxolitinib described herein during scale-up operations related to the manufacture of topical products using ruxolitinib phosphate. Accordingly, the crystalline ruxolitinib dihydrate is discussed herein together with methods for making and using the crystalline ruxolitinib dihydrate contained in certain pharmaceutical formulations.

[0007] Other solid forms of ruxolitinib, such as anhydrous crystalline ruxolitinib free base, are also discussed herein.

Summary of the Invention

[0008] The present disclosure provides, inter alia, a solid form that is ruxolitinib dihydrate having the following structure.

Chemical formula

[0009] The present disclosure provides a solid form that is crystalline ruxolitinib free base.

[0010] The present disclosure further provides a process for preparing a solid form of ruxolitinib dihydrate, the process comprising isolating the solid form from a solution comprising ruxolitinib free base and an aqueous solvent component. The present disclosure further provides a process for preparing anhydrous crystalline ruxolitinib free base.

[0011] The present disclosure also provides a pharmaceutical composition comprising a solid form of 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 formulation. In one aspect, the pharmaceutical composition is an oral dosage form that is a sustained release oral dosage form.

[0012] The present disclosure further provides a process for preparing a topical pharmaceutical formulation for skin application, the process comprising incorporating ruxolitinib dihydrate into the formulation. The present disclosure further provides a process for preparing a topical pharmaceutical formulation for skin application, the process comprising incorporating anhydrous crystalline ruxolitinib free base into the formulation.

[0013] The present disclosure further provides a process for preparing an oral formulation, the process comprising mixing or granulating ruxolitinib dihydrate with one or more pharmaceutically acceptable carriers. The present disclosure further provides a process for preparing an oral formulation, the process comprising mixing or granulating anhydrous crystalline ruxolitinib free base with one or more pharmaceutically acceptable carriers.

[0014] The present disclosure further provides a method 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.

[0015] The present disclosure further provides a method of treating a skin disorder, the method comprising applying to the affected area of the patient's skin a pharmaceutical composition or solid form described herein.

[0016] 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.

[0017] The present disclosure further provides the use of ruxolitinib dihydrate for the preparation of a drug for use in any of the methods described herein. The present disclosure further provides the use of anhydrous crystalline ruxolitinib free base for the preparation of a drug for use in any of the methods described herein.

Brief Description of the Drawings

[0018]

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Mode for Carrying Out the Invention

[0019] Ruxolitinib dihydrate The present disclosure provides, inter alia, solid forms that are crystalline ruxolitinib dihydrates as follows.

Chemical Formula

[0020] In some embodiments, the solid form is substantially isolated.

[0021] In some embodiments, the solid form is characterized by having at least one XRPD peak in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having at least two XRPD peaks in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having at least three XRPD peaks in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having at least four XRPD peaks in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having at least five XRPD peaks in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having at least six XRPD peaks in terms of 2θ (±0.2 degrees) 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 some embodiments, the solid form is characterized by having XRPD peaks in terms of 2θ (±0.2 degrees) 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.

[0022] In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from 19.0, 22.7, and 23.1 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 10.6, and 15.4 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 11.6, and 25.7 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 6.9, and 21.8 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 12.9, 15.1, and 24.8 degrees.

[0023] In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 1, 2, 3A, or 3B. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 1. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 2. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 3A. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 3B. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from the peaks listed in Table 1, 2, 3A, or 3B.

[0024] In some embodiments, the solid form is characterized by having an XRPD pattern with characteristic peaks substantially as shown in Figure 2. In some embodiments, the solid form is characterized by having an XRPD pattern with characteristic peaks substantially as shown in Figure 9.

[0025] In some embodiments, the solid form is characterized by having single crystal X-ray diffraction with space group P212121 and lattice composition unit (Z) 8. In some embodiments, the solid form has the following unit cell parameters: a is about 9.97 Å, b is about 15.18 Å, c is about 23.64 Å, α is about 90°, β is about 90°, and γ is about 90°.

[0026] In some embodiments, the solid form is characterized by having an endothermic peak in the DSC thermogram with onset temperature (±5 °C) of 61 °C and peak temperature (±5 °C) of 67 °C. In some embodiments, the solid form is characterized by having an endothermic peak in the DSC thermogram with onset temperature (±5 °C) of 61 - 68 °C and peak temperature (±5 °C) of 67 - 72 °C. In some embodiments, the solid form is characterized by having an endothermic peak in the DSC thermogram with onset temperature (±5 °C) of 68 °C and peak temperature (±5 °C) of 72 °C. In some embodiments, the solid form is characterized by having a first endothermic peak in the DSC thermogram with onset temperature (±5 °C) of 68 °C and peak temperature (±5 °C) of 72 °C, and a second endothermic peak with peak temperature (±5 °C) of 110 °C.

[0027] In some embodiments, the solid form is characterized by having a DSC thermogram substantially as depicted in Figure 3. In some embodiments, the solid form is characterized by having a DSC thermogram substantially as depicted in Figure 10.

[0028] In some embodiments, the solid form is characterized by having a TGA thermogram substantially as depicted in FIG. 4. In some embodiments, the solid form is characterized by having a TGA thermogram substantially as depicted in FIG. 11.

[0029] Disclosed herein is a process for preparing a solid form that is lucitanib dihydrate, the process comprising contacting the lucitanib free base with water.

[0030] Disclosed herein is a process for preparing a solid form that is lucitanib dihydrate, the process comprising isolating the solid form from a solution comprising the lucitanib free base and an aqueous solvent component.

[0031] Isolating may include crystallizing the solid form from a solution comprising the lucitanib free base and an aqueous solvent component.

[0032] In some embodiments, crystallizing includes cooling the solution to crystallize the solid form.

[0033] In some embodiments, crystallizing a) heating a solution comprising the lucitanib free base and an aqueous solvent component; and b) after said heating, cooling the solution to crystallize the solid form.

[0034] In some embodiments, crystallizing a) heating a solution comprising the lucitanib free base and an aqueous solvent component; and b) after said heating, cooling the solution; and c) after said cooling, adding seeds of crystalline lucitanib dihydrate to the solution; and d) after said addition of seeds, stirring the solution to crystallize the solid form.

[0035] In some embodiments, the solution is formed using amorphous loxoribine free base.

[0036] In step a), the solution containing loxoribine free base and the solvent mixture can be heated to a temperature of about 40°C to about 80°C. In some embodiments, in step a), the solution containing loxoribine 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 containing loxoribine free base and the solvent mixture is heated to a temperature of about 55°C to about 65°C.

[0037] In step b), the solution can 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 approximately ambient temperature.

[0038] In step d), the solution can 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.

[0039] In some embodiments, the aqueous solvent component is water.

[0040] 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 alcohol. In some embodiments, C 1-6The alcohol is isopropanol. In some embodiments, the volume:volume ratio of the polar protic solvent to water is from about 1:0.1 to about 1:10. In some embodiments, the volume:volume ratio of the polar protic solvent to water is from about 1:0.5 to about 1:5. In some embodiments, the volume:volume ratio of the polar protic solvent to water is from about 1:1 to about 1:3. In some embodiments, the volume:volume ratio of the polar protic solvent to water is from about 1:2 to about 1:2.5.

[0041] The ruxolitinib free base is ruxolitinib phosphate: [Chemical formula] It can be prepared by a process comprising reacting with a base in a solvent component.

[0042] In some embodiments, the ruxolitinib free base is amorphous.

[0043] In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 1 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 1 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 1 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 2 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 2 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate. In some embodiments, reacting the ruxolitinib phosphate with a base comprises using from about 2 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate.

[0044] In some embodiments, reacting the lucitanib phosphate with a base comprises using an amount of base sufficient to produce a pH of from about 7.5 to about 8. In some embodiments, reacting the lucitanib phosphate with a base comprises using an amount of base sufficient to produce a pH of from about 7 to about 8.

[0045] 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.

[0046] 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.

[0047] In some embodiments, the lucitanib phosphate in the solvent mixture is cooled to a temperature of from about 0 °C to about 10 °C. In some embodiments, the lucitanib phosphate in the solvent mixture is cooled to a temperature of from about 0 °C to about 5 °C.

[0048] Provided herein is a solid form of lucitanib dihydrate prepared by any of the processes described herein.

[0049] Anhydrous crystalline lucitanib free base The present disclosure also provides, inter alia, a solid form that is the anhydrous crystalline free base of ruxolitinib. In some embodiments, the solid form is Form I. In some embodiments, the solid form is substantially isolated.

[0050] In some embodiments, the solid form is characterized by having at least one XRPD peak, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having at least two XRPD peaks, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having at least three XRPD peaks, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having at least four XRPD peaks, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having at least five XRPD peaks, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having at least six XRPD peaks, converted to 2θ (±0.2 degrees), 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 some embodiments, the solid form is characterized by having an XRPD peak, converted to 2θ (±0.2 degrees), 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.

[0051] In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from 7.2, 13.2, and 15.8 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 19.6, and 23.9 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 11.5, and 15.4 degrees. In some embodiments, the solid form is characterized by having additional XRPD peaks at 2θ (±0.2 degrees) selected from 11.6, and 19.1 degrees.

[0052] In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 9A or 9B. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 9A. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from any 1, 2, 3, 4, 5, 6 or more peaks listed in Table 9B. In some embodiments, the solid form is characterized by having XRPD peaks at 2θ (±0.2 degrees) selected from the peaks listed in Table 9A or 9B.

[0053] In some embodiments, the solid form is characterized by having an XRPD pattern with characteristic peaks substantially as shown in Figure 13.

[0054] In some embodiments, the solid form is characterized by having an endothermic peak with an onset temperature (±5 °C) of 83 °C and a peak temperature (±5 °C) of 93 °C in a DSC thermogram. In some embodiments, the solid form is characterized by having an endothermic peak with an onset temperature (±5 °C) of 81 °C and a peak temperature (±5 °C) of 91 °C in a DSC thermogram. In some embodiments, the solid form is characterized by having a DSC thermogram substantially as depicted in FIG. 15 or FIG. 16.

[0055] In some embodiments, the solid form is characterized by having a TGA thermogram substantially as depicted in FIG. 17 or FIG. 18.

[0056] Provided herein is a process for preparing anhydrous crystalline loxoribine free base. In some embodiments, the process for preparing anhydrous crystalline loxoribine free base comprises drying loxoribine dihydrate.

[0057] Drying may include drying crystalline loxoribine dihydrate in a vacuum oven at approximately room temperature to about 60 °C. In some embodiments, drying is performed at approximately 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 includes drying crystalline loxoribine dihydrate at approximately room temperature in a jar containing a desiccant. In some embodiments, the desiccant is P2O5. In some embodiments, drying is performed for about 4 days to 10 days. In some embodiments, drying is performed for about 4 days to 5 days.

[0058] Provided herein is anhydrous crystalline loxoribine prepared by any of the processes described herein.

[0059] Generally, the term "about" in the context of the temperature or the equivalent amount of a reagent used in the synthetic processes described herein means ±10%. In some embodiments, the term "about" means ±5%.

[0060] Solid forms can be detected, identified, and characterized by well-known techniques such as, but not limited to, powder X-ray diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), single crystal X-ray diffraction, 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 not only further assist in the identification of the form, but also help in determining stability and solvent / water content.

[0061] The XRPD pattern of the reflection (peak) is typically regarded as representative of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending, inter alia, on the sample preparation technique, the crystal size distribution, the various filters used, the sample mounting procedure, and the particular instrument employed. In some cases, depending on the type or setting of the instrument, new peaks may be observed or existing peaks may disappear. As used herein, the term "peak" refers to any peak or other distinctive feature that would be recognized by one of ordinary skill in the art as not being due to background noise. The peak assignments as reported herein can vary by plus or minus about 0.2° (2θ). The terms "substantially" and "about" as used herein in the context of XRPD mean encompassing all of the aforementioned variables.

[0062] Similarly, temperature readings for DSC, TGA, or other thermal experiments can vary by approximately ±5 °C depending on the equipment, specific settings, sample preparation, etc. Accordingly, the crystalline forms reported in this specification having a DSC thermogram "substantially" as shown in any of the drawings, or the term "about", are understood to account for such variations.

[0063] In some embodiments, the solid forms described herein can be substantially isolated. "Substantially isolated" means that the solid form is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition rich in the compound or intermediate. Substantial isolation can include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compound or intermediate.

[0064] In some embodiments, ruxolitinib dihydrate is crystalline.

[0065] As used herein, the expressions "ambient temperature" and "room temperature" and "rt" are understood in the art and generally refer to a reaction temperature close to the temperature of the room, for example, where the reaction is taking place, for example, a temperature of about 20 °C to about 30 °C.

[0066] The processes described herein can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, or spectrophotometry (e.g., UV-visible light), etc., or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), or other related techniques.

[0067] As used herein, the terms "react" and "contact" are used as known in the art and generally refer to bringing chemical reagents together in such a way that their interactions at the molecular level enable the achievement of chemical or physical transformations. In some embodiments, the reaction involves two reagents, where more than one equivalent of the second reagent is used relative to the first reagent. The reaction steps of the processes described herein can be carried out at times and under conditions suitable for the preparation of the specified product.

[0068] The reactions of the processes described herein can be carried out in a suitable solvent. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, e.g., in the range from the freezing temperature to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected. 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.

[0069] Suitable solvents can include, for example, 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, and mixtures thereof.

[0070] Suitable solvents may include, for example, 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, t-butyl methyl ether, and mixtures thereof.

[0071] Suitable protic solvents include, by way of non-limiting example, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neopentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, and mixtures thereof.

[0072] Suitable aprotic solvents include, by way of non-limiting example, 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-methylpyrrolidinone (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, and mixtures thereof.

[0073] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane (e.g., n - heptane), ethylbenzene, m -, o -, or p - xylene, octane, indane, nonane, naphthalene, mixtures thereof, and the like.

[0074] The reactions of the processes described herein can be carried out at a suitable temperature. The reaction temperature depends, for example, on the melting and boiling points of the reagents and solvents (if present), the thermodynamics of the reaction (e.g., a highly exothermic reaction may need to be carried out at a reduced temperature), and the kinetics of the reaction (e.g., a high activation energy barrier may require a high temperature). "High temperature" refers to a temperature above room temperature (room temperature can include temperatures from about 20 °C to about 30 °C).

[0075] The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air can be carried out using air - sensitive synthetic techniques well - known to those skilled in the art.

[0076] 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, where alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t - butyloxide, 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, i - propyl, n - butyl, t - butyl, trimethylsilyl, and cyclohexyl - substituted amides.

[0077] Depending on the preparation of the solid forms (and intermediates for making the solid forms) of the present disclosure, the desired product(s) can be isolated using concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, etc.

[0078] Pharmaceutical formulations and dosage forms Generally, the term “about” in the context of the amounts of excipients or active ingredients in the compositions, formulations, and dosage forms described herein means ±10%. In some embodiments, the term “about” means ±5%.

[0079] When used as a pharmaceutical, the compounds or solid forms described herein can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether a local treatment is desired or a systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and delivery to mucous membranes including nasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, etc. may be essential or desirable. Coated condoms, gloves, etc. may also be useful in some cases.

[0080] Similarly, this specification provides pharmaceutical compositions comprising the solid forms described herein. The pharmaceutical compositions contain, as an active ingredient, one or more of the solid forms described herein, in combination with one or more pharmaceutically acceptable carriers (excipients). When preparing the compositions, typically the active ingredient is mixed with the excipient and diluted by the excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0081] When preparing the formulation, the active compound can be milled to provide an appropriate particle size before being combined with the other components. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0082] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl benzoate and propyl hydroxybenzoate, sweetening agents, and flavoring agents. The compositions can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient.

[0083] As used herein, "free base basis" means that the weight of nilotinib is calculated based on the weight of nilotinib free base in the total composition or dosage form. For example, 10 mg of nilotinib dihydrate on a free base basis means 11.18 mg of nilotinib dihydrate, which is equivalent to 10 mg of nilotinib free base.

[0084] In some embodiments, the composition comprises from about 5 mg to about 50 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises from about 5 mg to about 25 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises from about 10 mg to about 50 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises from about 10 mg to about 40 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises from about 10 mg to about 30 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 5 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 10 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 15 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 20 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 25 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 30 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 40 mg of nilotinib dihydrate on a free base basis. In some embodiments, the composition comprises about 50 mg of nilotinib dihydrate on a free base basis. 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 formulation.

[0085] In some embodiments, the composition comprises from about 5 mg to about 50 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises from about 5 mg to about 25 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises from about 10 mg to about 50 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises from about 10 mg to about 40 mg of anhydrous crystalline ruxolitinib free base. In some embodiments, the composition comprises from 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 formulation.

[0086] In some embodiments, the present disclosure provides an oral dosage form comprising ruxolitinib dihydrate. In some embodiments, the oral dosage form comprises ruxolitinib dihydrate in an amount 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 0.06 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% of total ruxolitinib, based on the free base, in the dosage form. In some embodiments, the oral dosage form comprises ruxolitinib dihydrate in an amount 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 0.06 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% of the dosage form.

[0087] To prepare solid compositions such as tablets, the major active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the active ingredient. When referring to these preformulation compositions as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, whereby the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0088] Tablets or pills can be coated or otherwise formulated to provide a dosage form that offers the advantage of long - acting effects. For example, tablets or pills can contain components for internal and external dosages, where the latter is in the form of an envelope covering the former. The two components can be separated by an enteric - soluble layer that functions to prevent decomposition in the stomach and allows the internal component to reach the duodenum intact or with a delayed release. A number of polymeric acids, as well as various materials including mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate, can be utilized as such enteric - soluble layers or coatings.

[0089] Liquid forms in which the compounds and compositions described herein can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0090] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions can contain the suitable pharmaceutically acceptable excipients described above. In some embodiments, the composition is administered by topical administration. In some embodiments, the composition is administered to the skin by topical administration. In some embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic effects. The composition can be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive - pressure breathing apparatus. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0091] The amount of the compound or composition to be administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. For therapeutic use, 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 depends on the judgment of the attending physician based on the pathological condition being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0092] The composition to be administered to a patient can be in the form of the above-mentioned pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or may be aseptically filtered. The aqueous solutions can be packaged for use as such or can be lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation will typically be from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It will be understood that pharmaceutical salt formulations can be obtained by the use of certain excipients, carriers, or stabilizers described herein.

[0093] The therapeutic doses in solid form described herein can vary, for example, according to the particular use for which the treatment is carried out, 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 can vary depending on several factors including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the selected compound, the formulation of the excipients, and the route of its administration. The effective dose can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

[0094] In some embodiments, the pharmaceutical composition is an oral dosage form.

[0095] In some embodiments, the oral dosage form is an immediate-release dosage form. In some embodiments, the ruxolitinib dihydrate is present in an amount of about 5 to about 25 mg on a free base basis. In some embodiments, 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 on a free base basis. In some embodiments, the anhydrous crystalline ruxolitinib free base is present in an amount of about 5 to about 25 mg. In some embodiments, the 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.

[0096] Sustained-release dosage form In some embodiments, the pharmaceutical composition is an oral dosage form.

[0097] In some embodiments, the oral dosage form is a sustained-release dosage form that includes a solid form described herein.

[0098] In some embodiments, the sustained-release form includes ruxolitinib dihydrate as an active ingredient. In some embodiments, the ruxolitinib dihydrate is present in an amount of about 10 to about 50 mg on a free base basis. In some embodiments, the 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 on a free base basis. In some embodiments, 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 on a free base basis.

[0099] In some embodiments, the sustained release form comprises anhydrous crystalline ruxolitinib free base as the active ingredient. In some embodiments, the anhydrous crystalline ruxolitinib free base is present in an amount of about 10 to about 50 mg. In some embodiments, the 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, the 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.

[0100] In some embodiments, the oral sustained release dosage form contains 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 0.06 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% of nilotinib dihydrate, based on the free base, in the dosage form. In some embodiments, the oral sustained release dosage form contains 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 0.06 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% of nilotinib dihydrate in the dosage form.

[0101] The dosage form may include a sustained-release matrix former. In some embodiments, the dosage form includes from about 10% to about 30% by weight of a sustained-release matrix former. In some embodiments, the sustained-release matrix former is one or more cellulose ethers. In some embodiments, the sustained-release matrix former is hydroxypropyl methylcellulose (HPMC, hypromellose), which is a high-viscosity polymer. In some embodiments, the dosage form includes from about 10% to about 30% by weight of one or more hydroxypropyl methylcelluloses. In some embodiments, the formulation has from about 20% by weight of one or more hydroxypropyl methylcelluloses. Exemplary hydroxypropyl methylcelluloses include Methocel K15M, Methocel K4M, and Methocel K100LV.

[0102] The sustained-release dosage forms described herein may further include, as inert ingredients, one or more fillers, glidants, disintegrants, binders, or lubricants. The filler may be present in the formulation in an amount of from 0% to about 85% by weight. In some embodiments, the formulation has from about 50% to about 80%, from about 55% to about 75%, or from about 60% to about 70% by weight of a filler. Non-limiting examples of fillers include lactose monohydrate, microcrystalline cellulose, starch 1500, and lactose free anhydrous, or combinations thereof. In some embodiments, the filler includes microcrystalline cellulose, lactose monohydrate, or both.

[0103] The lubricant may be present in the dosage forms described herein in an amount of from 0% to about 5% by weight. Non-limiting examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate. In some embodiments, the formulation includes magnesium stearate, stearic acid, or both.

[0104] The flow promoter may be present in the dosage forms described herein in an amount of 0 wt% to about 5 wt%. Non-limiting examples of flow promoters include talc, colloidal silicon dioxide, and corn starch. In some embodiments, the flow promoter is colloidal silicon dioxide.

[0105] The disintegrant may be present in the dosage forms described herein in an amount of 0 wt% to about 10 wt%. Non-limiting examples of disintegrants include croscarmellose sodium, crospovidone, starch, cellulose, and low-substituted hydroxypropyl cellulose. Croscarmellose sodium is a preferred disintegrant.

[0106] The film coating agent may be present in an amount of 0 wt% to about 5 wt%. Non-limiting examples of film coating agents include titanium dioxide, talc, and hypromellose or polyvinyl alcohol-based coatings containing, optionally, a colorant, available in some commercially available complete coating systems.

[0107] Examples of sustained-release dosage forms include tablets, caplets, capsules, etc. containing any of the sustained-release formulations described herein. The dosage form may further comprise a pharmaceutically acceptable coating, pigment, or dye.

[0108] The dosage form contains a sustained-release formulation that releases ruxolitinib relatively slowly when administered, characterized by specific pharmacokinetic parameters different from immediate-release formulations. The sustained-release dosage form can minimize potentially harmful spikes in drug plasma concentration associated with immediate-release formulations and can help provide a plasma level of the drug that is sustained, stable, and therapeutically effective. The dosage form can be administered to a human patient, for example, once a day, depending on the need for a therapeutic effect against the disease being treated.

[0109] Topical formulations and cream formulations In some embodiments, the pharmaceutical composition is a topical pharmaceutical formulation. In some embodiments described herein, the topical pharmaceutical formulation is suitable for topical application.

[0110] In some embodiments, the topical formulation contains about 0.5 wt% to about 1.5 wt% of nilotinib dihydrate, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 1.5 wt% of nilotinib dihydrate, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 1.0 wt% of nilotinib dihydrate, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 0.75 wt% of nilotinib dihydrate, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 0.5 wt% of nilotinib dihydrate, based on the free base, of the topical formulation.

[0111] In some embodiments, the topical formulation contains about 0.5 wt% to about 1.5 wt% of anhydrous crystalline nilotinib free base of the topical formulation. In some embodiments, the topical formulation contains about 1.5 wt% of anhydrous crystalline nilotinib free base of the topical formulation. In some embodiments, the topical formulation contains about 1.0 wt% of anhydrous crystalline nilotinib free base of the topical formulation. In some embodiments, the topical formulation contains about 0.75 wt% of anhydrous crystalline nilotinib free base of the topical formulation. In some embodiments, the topical formulation contains about 0.5 wt% of anhydrous crystalline nilotinib free base of the topical formulation.

[0112] In some embodiments, the topical formulation is prepared by dissolving nilotinib dihydrate in a solvent component. In some embodiments, the solvent component contains water. It is generally understood that when nilotinib dihydrate is completely dissolved in the solvent component, it exists in the formulation as nilotinib free base and loses its crystal structure upon dissolution.

[0113] 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 includes water. It is generally understood that when the anhydrous crystalline ruxolitinib free base is completely dissolved in the solvent component, it exists in the formulation as the ruxolitinib free base and its crystal structure is lost upon dissolution.

[0114] In some embodiments, the topical formulation contains from about 0.5 wt% to about 1.5 wt% of ruxolitinib, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 1.5 wt% of ruxolitinib, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 1.0 wt% of ruxolitinib, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 0.75 wt% of ruxolitinib, based on the free base, of the topical formulation. In some embodiments, the topical formulation contains about 0.5 wt% of ruxolitinib, based on the free base, of the topical formulation.

[0115] In some embodiments, the topical formulation contains ruxolitinib dihydrate in an amount of 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 0.06%, 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% in the formulation, based on the free base.

[0116] In some embodiments, the topical formulation contains ruxolitinib dihydrate in an amount 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 0.06 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% based on the free base of the formulation.

[0117] In some embodiments, the topical formulation contains (a) ruxolitinib free base in an amount of about 0.5% to about 1.5% of the formulation, and (b) ruxolitinib dihydrate in an amount 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 0.06 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% based on the free base of the formulation.

[0118] In some embodiments, the topical pharmaceutical formulation is prepared in a large batch size. In some embodiments, the topical pharmaceutical formulation is prepared in a batch size of 1000 kg or more.

[0119] In some embodiments, the present disclosure provides a topical pharmaceutical formulation comprising (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) ruxolitinib dihydrate in an amount 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 0.06 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%, or less than about 0.01 wt% 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 0.5 wt% to about 1.5 wt% 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 wt% 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 a large batch size. In some embodiments, the batch size is 1000 kg or more.

[0120] 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 0.06 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%, or less than about 0.001 wt% of ruxolitinib dihydrate, based on the free base, 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 wt% to about 1.5 wt% 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 wt% 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.

[0121] In some embodiments, provided herein is a process for releasing a batch of a topical pharmaceutical formulation described herein, the process comprising: (i) testing a sample of the topical pharmaceutical formulation for the absence of crystalline ruxolitinib dihydrate; and, if the sample passes the test of step (i), (ii) releasing the batch for general use. In some embodiments, testing comprises observing a sample of the formulation with an optical microscope to detect the absence or presence of crystals. In some embodiments, testing comprises observing a sample of the formulation with an optical microscope to detect the absence or presence of crystals, wherein the sample passes the test if no crystals are detected.

[0122] In some embodiments, the topical formulation is a cream formulation. In some embodiments, the cream formulation is an oil-in-water emulsion.

[0123] In some embodiments, the topical formulation is prepared by incorporating lucitanib dihydrate into the formulation. In some embodiments, the topical formulation is prepared by dissolving lucitanib dihydrate in a solvent component.

[0124] In some embodiments, the cream formulation is prepared by incorporating lucitanib dihydrate into an oil-in-water emulsion.

[0125] In some embodiments, the emulsion contains from about 0.5 wt% to about 1.5 wt% of lucitanib dihydrate, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 1.5 wt% of lucitanib dihydrate, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 1.0 wt% of lucitanib dihydrate, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 0.75 wt% of lucitanib dihydrate, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 0.5 wt% of lucitanib dihydrate, based on the free base, of the emulsion.

[0126] In some embodiments, the emulsion contains from about 0.5 wt% to about 1.5 wt% of lucitanib, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 1.5 wt% of lucitanib, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 1.0 wt% of lucitanib, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 0.75 wt% of lucitanib, based on the free base, of the emulsion. In some embodiments, the emulsion contains about 0.5 wt% of lucitanib, based on the free base, of the emulsion.

[0127] As used herein, "percent of lumixotinib on a free base basis" or "on a free base basis" in the context of an emulsion or a topical formulation prepared by incorporating lumixotinib dihydrate into an emulsion means that the % w / w is calculated based on the weight of the lumixotinib free base in the total emulsion. For example, in the case of a 1.5% (w / w) formulation of 100 grams, 1.68 grams of lumixotinib dihydrate needs to be incorporated into the emulsion or topical formulation to obtain 1.5 grams of the lumixotinib free base.

[0128] In some embodiments, the cream is a solubilized cream.

[0129] In some embodiments, the cream has a pH of from about 2.8 to about 3.6. In the context of pH, "about" refers to ±0.5 (preferably ±0.3, or more preferably ±0.2).

[0130] In some embodiments, the cream formulation is any of the cream formulations disclosed in U.S. Patent Publication No. 2015 / 0250790, which is hereby incorporated by reference in its entirety, except that lumixotinib dihydrate or anhydrous crystalline lumixotinib free base as described herein is used.

[0131] In some embodiments, the cream is an oil-in-water emulsion as described in US2015 / 0250790, which is hereby incorporated by reference in its entirety. In particular, Examples 3 - 6 of US2015 / 0250790 (in particular, Tables 3 - 5 and the accompanying text) are hereby incorporated by reference in their entirety.

[0132] In some embodiments, the oil component is present in an amount of from about 10 wt% to about 40 wt% of the emulsion.

[0133] In some embodiments, the oil component is present in an amount of from about 10 wt% to about 24 wt% of the emulsion.

[0134] In some embodiments, the oil component is present in an amount of about 15% to about 24% by weight of the emulsion.

[0135] In some embodiments, the oil component is present in an amount of about 18% to about 24% by weight of the emulsion.

[0136] In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.

[0137] In some embodiments, 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.

[0138] In some embodiments, the oil component comprises an occlusive agent component.

[0139] In some embodiments, the occlusive agent component is present in an amount of about 2% to about 15% by weight of the emulsion.

[0140] In some embodiments, the occlusive agent component is present in an amount of about 5% to about 10% by weight of the emulsion.

[0141] In some embodiments, the occlusive agent component comprises one or more substances selected from fatty acids (e.g., lanolinic acid), fatty alcohols (e.g., lanolin alcohol), hydrocarbon oils and waxes (e.g., petrolatum), polyhydric alcohols (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).

[0142] In some embodiments, the occluding agent component comprises one or more substances selected from lanolin fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.

[0143] In some embodiments, the occluding agent component comprises petrolatum.

[0144] In some embodiments, the occluding agent component comprises white petrolatum.

[0145] In some embodiments, the oil component comprises a hardening agent component.

[0146] In some embodiments, the hardening agent component is present in an amount of about 2 wt% to about 8 wt% of the emulsion.

[0147] In some embodiments, the hardening agent component is present in an amount of about 3 wt% to about 6 wt% of the emulsion.

[0148] In some embodiments, the hardening agent component is present in an amount of about 4 wt% to about 7 wt% of the emulsion.

[0149] In some embodiments, the hardening agent component comprises one or more substances independently selected from fatty alcohols.

[0150] In some embodiments, the hardening agent component comprises one or more substances independently selected from C 12-20 fatty alcohols.

[0151] In some embodiments, the hardening agent component comprises one or more substances independently selected from C 16-18 fatty alcohols.

[0152] In some embodiments, the hardening agent component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.

[0153] In some embodiments, the oil component includes a softening component.

[0154] In some embodiments, the softening component is present in an amount of about 5 wt% to about 15 wt% of the emulsion.

[0155] In some embodiments, the softening component is present in an amount of about 7 wt% to about 13 wt% of the emulsion.

[0156] In some embodiments, the softening component includes one or more substances independently selected from mineral oil and triglyceride.

[0157] In some embodiments, the softening component includes one or more substances independently selected from light mineral oil and medium-chain triglyceride.

[0158] In some embodiments, the softening component includes one or more substances independently selected from light mineral oil, medium-chain triglyceride, and dimethicone.

[0159] In some embodiments, water is present in an amount of about 35 wt% to about 65 wt% of the emulsion.

[0160] In some embodiments, water is present in an amount of about 40 wt% to about 60 wt% of the emulsion.

[0161] In some embodiments, water is present in an amount of about 45 wt% to about 55 wt% of the emulsion.

[0162] In some embodiments, the emulsifier component is present in an amount of about 1 wt% to about 9 wt% of the emulsion.

[0163] In some embodiments, the emulsifier component is present in an amount of about 2 wt% to about 6 wt% of the emulsion.

[0164] In some embodiments, the emulsifier component is present in an amount of about 3 wt% to about 5 wt% of the emulsion.

[0165] In some embodiments, the emulsifier component is present in an amount of about 4 wt% to about 7 wt% of the emulsion.

[0166] In some embodiments, the emulsion comprises an emulsifier component and a curing agent component, and the total amount of the emulsifier component and the curing agent component is at least about 8 wt% of the emulsion.

[0167] In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters.

[0168] In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.

[0169] In some embodiments, the emulsion further comprises a stabilizer component.

[0170] In some embodiments, the stabilizer component is present in an amount of about 0.05 wt% to about 5 wt% of the emulsion.

[0171] In some embodiments, the stabilizer component is present in an amount of about 0.1 wt% to about 2 wt% of the emulsion.

[0172] In some embodiments, the stabilizer component is present in an amount of about 0.3 wt% to about 0.5 wt% of the emulsion.

[0173] In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.

[0174] In some embodiments, the stabilizer component comprises xanthan gum.

[0175] In some embodiments, the emulsion further comprises a solvent component.

[0176] In some embodiments, the solvent component is present in an amount of about 10 wt% to about 35 wt% of the emulsion.

[0177] In some embodiments, the solvent component is present in an amount of about 15% to about 30% by weight of the emulsion.

[0178] In some embodiments, the solvent component is present in an amount of about 20% to about 25% by weight of the emulsion.

[0179] In some embodiments, the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0180] In some embodiments, the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.

[0181] In some embodiments, the emulsion is about 35% to about 65% by weight of water of the emulsion, about 10% to about 40% by weight of an oil component of the emulsion, about 1% to about 9% by weight of an emulsifier component of the emulsion, about 10% to about 35% by weight of a solvent component of the emulsion, about 0.05% to about 5% by weight of a stabilizer component of the emulsion, and about 0.5% to 1.5% by weight of ruxolitinib of the emulsion on a free base basis, on a free base basis.

[0182] In some embodiments, the emulsion is about 35% to about 65% by weight of water of the emulsion, about 10% to about 24% by weight of an oil component of the emulsion, about 1% to about 9% by weight of an emulsifier component of the emulsion, about 10% to about 35% by weight of a solvent component of the emulsion, about 0.05% to about 5% by weight of a stabilizer component of the emulsion, and about 0.5% to 1.5% by weight of ruxolitinib of the emulsion on a free base basis, on a free base basis.

[0183] In some embodiments, the emulsion is About 40 wt% to about 60 wt% water of the emulsion, About 15 wt% to about 30 wt% oil component of the emulsion, About 2 wt% to about 6 wt% emulsifier component of the emulsion, About 15 wt% to about 30 wt% solvent component of the emulsion, About 0.1 wt% to about 2 wt% stabilizer component of the emulsion, and Based on the free base, about 0.5 wt% to 1.5 wt% of ruxolitinib in the emulsion based on the free base, are included.

[0184] In some embodiments, the emulsion is About 40 wt% to about 60 wt% water of the emulsion, About 15 wt% to about 30 wt% oil component of the emulsion, About 2 wt% to about 6 wt% emulsifier component of the emulsion, About 15 wt% to about 24 wt% solvent component of the emulsion, About 0.1 wt% to about 2 wt% stabilizer component of the emulsion, and Based on the free base, about 0.5 wt% to 1.5 wt% of ruxolitinib in the emulsion based on the free base, are included.

[0185] In some embodiments, the emulsion is About 45 wt% to about 55 wt% water of the emulsion, About 15 wt% to about 24 wt% oil component of the emulsion, About 3 wt% to about 5 wt% emulsifier component of the emulsion, About 20 wt% to about 25 wt% solvent component of the emulsion, About 0.3 wt% to about 0.5 wt% stabilizer component of the emulsion, and Based on the free base, about 0.5 wt% to 1.5 wt% of ruxolitinib in the emulsion based on the free base, are included.

[0186] In some embodiments, the emulsion is About 45 wt% to about 55 wt% water of the emulsion, About 15 wt% to about 24 wt% oil component of the emulsion, About 4 wt% to about 7 wt% emulsifier component of the emulsion, About 20 wt% to about 25 wt% solvent component of the emulsion, About 0.3 wt% to about 0.5 wt% of a stabilizer component of the emulsion, and In terms of the free base, about 0.5 wt% to 1.5 wt% of the emulsion in terms of the free base of ruxolitinib.

[0187] In some embodiments, The oil component includes one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and dimethicone. The emulsifier component includes one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters. The solvent component includes one or more substances independently selected from alkylene glycols and polyalkylene glycols. The stabilizer component includes one or more substances independently selected from polysaccharides.

[0188] In some embodiments, The oil component includes one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium-chain triglycerides, and dimethicone. The emulsifier component includes one or more substances independently selected from glyceryl stearate and polysorbate 20. The solvent component includes one or more substances independently selected from propylene glycol and polyethylene glycol. The stabilizer component includes xanthan gum.

[0189] In some embodiments, the emulsion is About 35 wt% to about 65 wt% of water in the emulsion, About 2 wt% to about 15 wt% of an occlusive agent component in the emulsion, About 2 wt% to about 8 wt% of a hardening agent component in the emulsion, About 5 wt% to about 15 wt% of a softening component in the emulsion, About 1 wt% to about 9 wt% of an emulsifier component in the emulsion, About 0.05 wt% to about 5 wt% of a stabilizer component in the emulsion, About 10 wt% to about 35 wt% of a solvent component in the emulsion, and It contains about 0.5% to 1.5% by weight of ruxolitinib in the emulsion based on the free base, based on the free base.

[0190] In some embodiments, the emulsion about 40% to about 60% by weight of water in the emulsion, about 5% to about 10% by weight of the blocking agent component in the emulsion, about 2% to about 8% by weight of the curing agent component in the emulsion, about 7% to about 12% by weight of the softening component in the emulsion, about 2% to about 6% by weight of the emulsifier component in the emulsion, about 0.1% to about 2% by weight of the stabilizer in the emulsion, about 15% to about 30% by weight of the solvent component in the emulsion, and It contains about 0.5% to 1.5% by weight of ruxolitinib in the emulsion based on the free base, based on the free base.

[0191] In some embodiments, the emulsion about 45% to about 55% by weight of water in the emulsion, about 5% to about 10% by weight of the blocking agent component in the emulsion, about 3% to about 6% by weight of the curing agent component in the emulsion, about 7% to about 13% by weight of the softening component in the emulsion, about 3% to about 5% by weight of the emulsifier component in the emulsion, about 0.3% to about 0.5% by weight of the stabilizer component in the emulsion, about 20% to about 25% by weight of the solvent component in the emulsion, and It contains about 0.5% to 1.5% by weight of ruxolitinib in the emulsion based on the free base, based on the free base.

[0192] In some embodiments, the emulsion about 45% to about 55% by weight of water in the emulsion, about 5% to about 10% by weight of the blocking agent component in the emulsion, about 4% to about 7% by weight of the curing agent component in the emulsion, about 7% to about 13% by weight of the softening component in the emulsion, about 4% to about 7% by weight of the emulsifier component in the emulsion, About 0.3% to about 0.5% by weight of a stabilizer component of the emulsion, About 20% to about 25% by weight of a solvent component of the emulsion, and Based on the free base, about 0.5% to 1.5% by weight of the emulsion of the free base of nilotinib, are included.

[0193] In some embodiments, the emulsion is About 45% to about 55% by weight of water of the emulsion, About 7% by weight of a blocking agent component of the emulsion, About 4.5% to about 5% by weight of a curing agent component of the emulsion, About 10% by weight of a softening component of the emulsion, About 4% to about 4.5% by weight of an emulsifier component of the emulsion, About 0.4% by weight of a stabilizer component of the emulsion, About 22% by weight of a solvent component of the emulsion, and Based on the free base, about 0.5% to 1.5% by weight of the emulsion of the free base of nilotinib, are included.

[0194] In some embodiments, the total amount of the curing agent component and the emulsifier component is at least about 8% by weight of the emulsion.

[0195] In some embodiments, The blocking agent component includes petrolatum, The curing agent component includes one or more substances independently selected from one or more fatty alcohols, The softening component includes one or more substances independently selected from mineral oil and triglyceride, The emulsifier component includes one or more substances independently selected from glyceryl fatty acid esters and sorbitan fatty acid esters, The stabilizer component includes one or more substances independently selected from polysaccharides, The solvent component includes one or more substances independently selected from alkylene glycols and polyalkylene glycols.

[0196] In some embodiments, The occlusive agent component contains white petrolatum, The hardening agent component contains one or more substances independently selected from cetyl alcohol and stearyl alcohol, The softening component contains one or more substances independently selected from light mineral oil, medium-chain triglycerides, and dimethicone, The emulsifier component contains one or more substances independently selected from glyceryl stearate and polysorbate 20, The stabilizer component contains xanthan gum, The solvent component contains one or more substances independently selected from propylene glycol and polyethylene glycol.

[0197] In some embodiments, the emulsion further contains an antibacterial preservative component.

[0198] In some embodiments, the antibacterial preservative component is present in an amount of about 0.05 wt% to about 3 wt% of the emulsion.

[0199] In some embodiments, the antibacterial preservative component is present in an amount of about 0.1 wt% to about 1 wt% of the emulsion.

[0200] In some embodiments, the antibacterial preservative component contains one or more substances independently selected from alkyl parabens and phenoxyethanol.

[0201] In some embodiments, the antibacterial preservative component contains one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.

[0202] In some embodiments, the emulsion further contains a chelating agent component.

[0203] In some embodiments, the chelating agent component contains disodium edetate.

[0204] As used herein, the term "emulsifier component" refers, in one aspect, to a substance, or mixture of substances, that maintains elements or particles in suspension within a fluid medium. In some embodiments, the emulsifier component enables the oil phase to form an emulsion when combined with water. In some embodiments, the emulsifier component refers to one or more nonionic surfactants.

[0205] As used herein, the term "occlusive agent component" refers to a hydrophobic agent, or mixture of hydrophobic agents, that forms an occlusive film on the skin that reduces transepidermal water loss (TEWL) by preventing the evaporation of water from the stratum corneum.

[0206] As used herein, the term "hardening agent component" refers to a substance, or mixture of substances, that increases the viscosity and / or consistency of a cream, or improves the rheology of a cream.

[0207] As used herein, the term "softening agent component" refers to an agent that softens or soothes the skin, or soothes an irritated surface.

[0208] 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 the components within the cream. In some embodiments, the stabilizer component prevents the aggregation of an emulsion and stabilizes the droplets in an oil-in-water emulsion.

[0209] As used herein, the term "solvent component" is a liquid substance, or mixture of liquid substances, that can dissolve ruxolitinib dihydrate in a cream. In some embodiments, the solvent component is a liquid substance, or mixture of liquid substances, in which ruxolitinib or a pharmaceutically acceptable salt thereof has a suitable solubility. For example, the solubility of ruxolitinib free base is reported in Table 21 of US2015 / 0250790, which is hereby incorporated by reference in its entirety. Information on the solubility of ruxolitinib dihydrate is shown in Tables 2 and 3 below.

[0210] As used herein, the term "antibacterial and preservative component" refers to a substance or mixture of substances that inhibits the growth of microorganisms in the cream.

[0211] As used herein, the term "chelating agent component" refers to a compound or mixture of compounds having the ability to strongly bind to metal ions.

[0212] As used herein, "weight % of the emulsion" means that the percentage of the concentration of the components 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)] × 100.

[0213] As used herein, the term "component" can mean a single substance or a mixture of substances.

[0214] As used herein, the term "fatty acid" refers to saturated or unsaturated fatty acids. In some embodiments, the fatty acid is in a mixture of different fatty acids. In some embodiments, the fatty acid has on average from about 8 to about 30 carbons. In some embodiments, the fatty acid has on average about 12 - 20, 14 - 20, or 16 - 18 carbons. Suitable fatty acids include, but are not limited to, palmitic 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, cetostearic acid, isostearic acid, sesqui - oleic acid, sesqui - 9 - octadecenoic acid, sesqui - isooctadecenoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof.

[0215] As used herein, the term "fatty alcohol" refers to a saturated or unsaturated aliphatic alcohol. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has on average from about 12 to about 20, from about 14 to about 20, or from about 16 to about 18 carbon atoms. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, ceratyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.

[0216] 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 the formula -O-oxyalkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.

[0217] As used herein, the term "sorbitan fatty acid ester" 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.

[0218] As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for deriving sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), which includes 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 R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is hereby incorporated by reference in its entirety.

[0219] As used herein, the term "polyethoxylated sorbitan ester" refers to a compound or mixture thereof derived from the ethoxylation of sorbitan esters. The polyoxyethylene portion of the compound may be present between the fatty acid ester and the sorbitan moiety. As used herein, the term "sorbitan ester" refers to a compound or mixture of compounds derived from the esterification of sorbitol and at least one fatty acid. Fatty acids useful for the derivation of polyethoxylated sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has from about 4 to about 20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to, the Tween™ series (available from Uniqema), which includes Tween 20 (sorbitan monolaurate POE(20)), 21 (sorbitan monolaurate POE(4)), 40 (sorbitan monopalmitate POE(20)), 60 (sorbitan monostearate POE(20)), 60K (sorbitan monostearate POE(20)), 61 (sorbitan monostearate POE(4)), 65 (sorbitan tristearate POE(20)), 80 (sorbitan monooleate POE(20)), 80K (sorbitan monooleate POE(20)), 81 (sorbitan monooleate POE(5)), and 85 (sorbitan trioleate POE(20)). As used herein, the abbreviation "POE" refers to polyoxyethylene. The number following the abbreviation POE refers to the number of oxyethylene repeating units in the compound.Other suitable polyethoxylated sorbitan esters include polyoxyethylene sorbitan fatty acid esters listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is hereby incorporated by reference in its entirety. In some embodiments, the polyethoxylated sorbitan ester is a polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

[0220] As used herein, the term "glyceryl fatty acid ester" refers to mono-, di-, or triglycerides of fatty acids. The glyceryl fatty acid ester may optionally be substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids for deriving glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceryl fatty acid ester is a monoglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceryl fatty acid ester is glyceryl stearate.

[0221] As used herein, the term "triglyceride" refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium-chain triglyceride.

[0222] As used herein, the term "alkylene glycol" refers to a group of the formula -O-alkylene-, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).

[0223] As used herein, the term "polyethylene glycol" refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. 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 a lower alkyl, such as a methyl group. Also suitable are derivatives of polyethylene glycols having an esterifiable carboxy group. The polyethylene glycol useful in the present disclosure can be a polymer of any chain length or molecular weight and can include branches. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the 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.

[0224] Method Ruxolitinib inhibits JAK1 and JAK2 and is selective for JAK1 over JAK3. Aspects of the present disclosure relate to methods of treating JAK-related diseases or disorders in an individual (e.g., a patient), the method comprising administering to such an individual in need of such treatment a therapeutically effective amount or dose of a solid form described herein, a pharmaceutical formulation of the present disclosure, or a pharmaceutical composition. Examples of JAK-related diseases include those characterized by the expression of mutant JAK2, such as those having at least one mutation in the pseudokinase domain (e.g., JAK2V617F).

[0225] This specification provides 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.

[0226] Examples of JAK-related diseases include, for example, myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis or myelofibrosis with myeloid metaplasia (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), etc. In some embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, the myelofibrosis is primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. In some embodiments, the myeloproliferative disorder is polycythemia vera. In some embodiments, the myeloproliferative disorder is essential thrombocythemia.

[0227] In further embodiments, the JAK-related disease is a cancer characterized by solid tumors (such as prostate cancer, renal 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 (such as leukemia like 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 Sézary syndrome and mycosis fungoides.

[0228] Examples of JAK-related diseases include, for example, diseases involving the immune system, including, for example, organ transplant rejection (such as allograft 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.

[0229] Additional examples of JAK-related diseases include allergic conditions 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 coronaviruses (e.g., SARS-CoV-2).

[0230] Further 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 airway (e.g., of the upper airway including the nose and paranasal sinuses such as rhinitis or sinusitis, or of the lower airway including bronchitis, chronic obstructive pulmonary disease, etc.), inflammatory muscle diseases such as myocarditis, and other inflammatory diseases. Other inflammatory diseases treatable by the compounds of the present disclosure include systemic inflammatory response syndrome (SIRS) and septic shock.

[0231] Additional examples of JAK-related diseases include autoimmune diseases such as, for example, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, and autoimmune thyroid disorders.

[0232] The JAK inhibitors described herein can further be used to treat ischemic reperfusion injury, or diseases or conditions associated with inflammatory ischemic events such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue, such as those resulting from or associated with cancer. The JAK inhibitors described herein can further be used to treat restenosis, sclerodermatitis, or fibrosis. The JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis, such as diabetic retinopathy, cancer, or neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36, and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):19936-47. Epub 2004 Mar 2.

[0233] The JAK inhibitors described herein can further be used to treat gout, and an increase in prostate size, for example, resulting from benign prostatic hyperplasia or benign prostatic overgrowth.

[0234] Further examples of JAK-related diseases include skin diseases. In some embodiments, provided herein is a method of treating a skin disorder in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition described herein. In some embodiments, provided herein is a method of treating a skin disorder in a patient in need thereof, the method comprising administering to the affected area of the patient's skin a topical pharmaceutical formulation described herein. In some embodiments, provided herein is a method of treating a skin disorder, the method comprising applying a pharmaceutical composition described herein to an area of the skin of a patient in need thereof.

[0235] 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 blistering 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 plaque psoriasis or psoriasis vulgaris. In some embodiments, the skin disease is a 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.

[0236] The present disclosure further provides a method for treating dermatological side effects of other pharmaceuticals by administration of the compounds of the present disclosure. For example, many pharmaceuticals can cause unwanted allergic reactions that present as acneiform eruptions or related dermatitis. Exemplary pharmaceuticals with such unwanted side effects include, for example, anti-cancer agents such as gefitinib, cetuximab, erlotinib, and the like. The formulations of the present disclosure can be administered systemically or topically (e.g., localized to the vicinity of the dermatitis) in combination with (e.g., simultaneously or sequentially) a pharmaceutical having unwanted dermatological side effects. In some embodiments, where another pharmaceutical is topically applied in the absence of the formulation of the present disclosure and contact dermatitis, allergic contact sensitization, or a similar skin disorder results, the formulation of the present disclosure can be topically administered together with one or more other pharmaceuticals. Accordingly, the formulations of the present disclosure include topical formulations further comprising an additional pharmaceutical that may cause dermatitis, skin disorders, or related side effects.

[0237] In some embodiments, contacting JAK with the solid forms of the present disclosure includes administering a compound of the present disclosure to an individual or patient, such as a human, having JAK, and introducing, for example, a compound of the present disclosure into a sample containing a cell preparation or a purified preparation containing JAK.

[0238] As used herein, the terms "individual" or "patient" used in the same sense refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. In some embodiments, the patient is a human patient.

[0239] As used herein, the terms "treat" or "treatment" refer to one or more of (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the symptoms or overall condition of the disease, condition, or disorder, and (2) improving a disease, e.g., reducing the severity of a disease, etc., improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the symptoms or overall condition of the disease, condition, or disorder (i.e., improving the symptoms and / or overall condition).

[0240] In some embodiments, the compounds and compositions described herein can prevent a disease, condition, or disorder. Preventing or prophylaxis of a disease, condition, or disorder refers to administering a compound or composition described herein to an individual who may be susceptible to the disease, condition, or disorder but has not yet experienced or exhibited the symptoms or overall condition of the disease.

[0241] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human as sought by a researcher, veterinarian, physician, or other clinician, and includes one or more of the following: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or overall condition of the disease, condition, or disorder (i.e., preventing further development of the symptoms and / or overall condition), and (2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or overall condition of the disease, condition, or disorder (i.e., improving the symptoms and / or overall condition).

[0242] Combination therapy For example, one or more additional pharmaceutical agents such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressive agents, and Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors, or other agents as described in, for example, WO 2006 / 056399, can be used in combination with the compositions described herein for the treatment of JAK-related diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0243] Exemplary chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, lenalidomide, and DNA damaging agents such as, for example, melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine.

[0244] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0245] Exemplary Bcr-Abl inhibitors include compounds of the genus and species as disclosed in U.S. Patent No. 5,521,184, WO 04 / 005281, and Japanese Patent No. 7,745,437, and pharmaceutically acceptable salts thereof.

[0246] Exemplary suitable Flt-3 inhibitors include compounds as disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120, and pharmaceutically acceptable salts thereof.

[0247] Exemplary suitable RAF inhibitors include compounds as disclosed in WO 00 / 09495 and WO 05 / 028444, and pharmaceutically acceptable salts thereof.

[0248] Exemplary suitable FAK inhibitors include compounds as 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.

[0249] In some embodiments, the compositions described herein can be used in combination with one or more other kinase inhibitors, including imatinib, to treat patients resistant to imatinib or other kinase inhibitors.

[0250] In some embodiments, corticosteroids such as dexamethasone are administered to patients in combination with the compositions described herein, where dexamethasone is administered intermittently rather than continuously.

[0251] Kit The present disclosure also includes a pharmaceutical kit useful, for example, in the treatment or prevention of JAK-related diseases or disorders such as cancer, such kits comprising one or more containers containing a compound or composition. As will be apparent to those skilled in the art, such kits can further comprise one or more of various conventional pharmaceutical kit components, such as, for example, containers containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions indicating the amount of the administered component, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit, either as an insert or a label.

[0252] Additional embodiments Embodiment 1. A solid form which is crystalline ruxolitinib dihydrate.

Chemical formula

[0253] Embodiment 2. The solid form according to Embodiment 1, wherein the solid form is substantially isolated.

[0254] Embodiment 3. The solid form according to Embodiment 1 or 2, characterized in that the solid form has at least one XRPD peak converted to 2θ (±0.2 degrees) 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.

[0255] Embodiment 4. The solid form according to Embodiment 1 or 2, characterized in that the solid form has at least two XRPD peaks converted to 2θ (±0.2 degrees) 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.

[0256] Embodiment 5. The solid form is characterized by having at least three XRPD peaks converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 1 or 2.

[0257] Embodiment 6. The solid form is characterized by having at least four XRPD peaks converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 1 or 2.

[0258] Embodiment 7. The solid form is characterized by having at least five XRPD peaks converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 1 or 2.

[0259] Embodiment 8. The solid form is characterized by having at least six XRPD peaks converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 1 or 2.

[0260] Embodiment 9. The solid form is characterized by having XRPD peaks converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 1 or 2.

[0261] Embodiment 10. The solid form is characterized by having XRPD peaks converted to 2θ (±0.2 degrees) selected from 19.0, 22.7, and 23.1 degrees, and is the solid form according to Embodiment 1 or 2.

[0262] Embodiment 11. The solid form according to Embodiment 10, characterized in that the solid form has additional XRPD peaks converted to 2θ (±0.2 degrees) selected from 10.6 and 15.4 degrees.

[0263] Embodiment 12. The solid form according to Embodiment 11, characterized in that the solid form has additional XRPD peaks converted to 2θ (±0.2 degrees) selected from 11.6 and 25.7 degrees.

[0264] Embodiment 13. The solid form according to Embodiment 12, characterized in that the solid form has additional XRPD peaks converted to 2θ (±0.2 degrees) selected from 6.9 and 21.8 degrees.

[0265] Embodiment 14. The solid form according to Embodiment 13, characterized in that the solid form has additional XRPD peaks converted to 2θ (±0.2 degrees) selected from 12.9, 15.1, and 24.8 degrees.

[0266] Embodiment 15. The solid form according to any one of Embodiments 1 to 14, characterized in that the solid form has an XRPD pattern having characteristic peaks substantially as shown in Figure 2.

[0267] Embodiment 16. The solid form according to any one of Embodiments 1 to 14, characterized in that the solid form has an XRPD pattern having characteristic peaks substantially as shown in Figure 9.

[0268] Embodiment 17. The solid form according to any one of Embodiments 1 to 16, characterized in that the solid form has single crystal X-ray diffraction having the P212121 space group and a lattice composition unit (Z) of 8.

[0269] Embodiment 18. The solid form has the following unit cell parameters: a is about 9.97 Å, b is about 15.18 Å, c is about 23.64 Å, α is about 90°, β is about 90°, and γ is about 90°, the solid form according to Embodiment 17.

[0270] Embodiment 19. The solid form is characterized in that, in the DSC thermogram, it has an endothermic peak with a start temperature (±5 °C) of 61 °C and a maximum temperature (±5 °C) of 67 °C, the solid form according to any one of Embodiments 1 to 18.

[0271] Embodiment 20. The solid form is characterized in that, in the DSC thermogram, it has a first endothermic peak with a start 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, the solid form according to any one of Embodiments 1 to 18.

[0272] Embodiment 21. The solid form is characterized in that it has a DSC thermogram substantially as depicted in Figure 3, the solid form according to any one of Embodiments 1 to 18.

[0273] Embodiment 22. The solid form is characterized in that it has a DSC thermogram substantially as depicted in Figure 10, the solid form according to any one of Embodiments 1 to 18.

[0274] Embodiment 23. The solid form is characterized in that it has a TGA thermogram substantially as depicted in Figure 4, the solid form according to any one of Embodiments 1 to 22.

[0275] Embodiment 24. The solid form is characterized in that it has a TGA thermogram substantially as depicted in Figure 11, the solid form according to any one of Embodiments 1 to 22.

[0276] Embodiment 25. A solid form that is anhydrous crystalline ruxolitinib free base.

[0277] Embodiment 26. The solid form is the solid form according to Embodiment 25, which is substantially isolated.

[0278] Embodiment 27. The solid form is characterized by having at least one XRPD peak converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 25 or 26.

[0279] Embodiment 28. The solid form is characterized by having an XRPD peak converted to 2θ (±0.2 degrees) 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, and is the solid form according to Embodiment 25 or 26.

[0280] Embodiment 29. The solid form is characterized by having an XRPD peak converted to 2θ (±0.2 degrees) selected from 7.2, 13.2, and 15.8 degrees, and is the solid form according to Embodiment 25 or 26.

[0281] Embodiment 30. The solid form is characterized by having an additional XRPD peak converted to 2θ (±0.2 degrees) selected from 19.6 and 23.9 degrees, and is the solid form according to Embodiment 29.

[0282] Embodiment 31. The solid form is characterized by having an additional XRPD peak converted to 2θ (±0.2 degrees) selected from 11.5 and 15.4 degrees, and is the solid form according to Embodiment 30.

[0283] Embodiment 32. The solid form is characterized by having an additional XRPD peak converted to 2θ (±0.2 degrees) selected from 11.6 and 19.1 degrees, and is the solid form according to Embodiment 31.

[0284] Embodiment 33. The solid form is characterized by having an XRPD pattern with characteristic peaks substantially as shown in FIG. 13, and is the solid form according to any one of Embodiments 25 to 32.

[0285] Embodiment 34. The solid form is characterized by having an endothermic peak with an onset temperature (±5°C) of 83°C and a peak temperature (±5°C) of 93°C in a DSC thermogram, and is the solid form according to any one of Embodiments 25 to 33.

[0286] Embodiment 35. The solid form is characterized by having an endothermic peak with an onset temperature (±5°C) of 81°C and a peak temperature (±5°C) of 91°C in a DSC thermogram, and is the solid form according to any one of Embodiments 25 to 33.

[0287] Embodiment 36. The solid form is characterized by having a DSC thermogram substantially as depicted in FIG. 15 or FIG. 16, and is the solid form according to any one of Embodiments 25 to 33.

[0288] Embodiment 37. The solid form is characterized by having a TGA thermogram substantially as depicted in FIG. 17 or FIG. 18, and is the solid form according to any one of Embodiments 25 to 36.

[0289] Embodiment 38. A solid form that is ruxolitinib dihydrate:

Chemical formula

[0290] Embodiment 39. A solid form that is ruxolitinib dihydrate:

Chemical formula

[0291] Embodiment 40. The process according to embodiment 39, wherein the isolating comprises crystallizing the solid form from a solution comprising the free base of ruxolitinib and an aqueous solvent component.

[0292] Embodiment 41. The process according to embodiment 40, wherein the crystallizing comprises cooling the solution to crystallize the solid form.

[0293] Embodiment 42. The crystallizing comprises a) heating the solution comprising the free base of ruxolitinib and an aqueous solvent component; and b) after the heating, cooling the solution to crystallize the solid form, the process according to embodiment 40.

[0294] Embodiment 43. The crystallizing comprises a) heating the solution comprising the free base of ruxolitinib and an aqueous solvent component; and b) after the heating, cooling the solution; and c) after the cooling, adding seeds of crystalline ruxolitinib dihydrate to the solution; and d) after the addition of the seeds, stirring the solution to crystallize the solid form, the process according to embodiment 40.

[0295] Embodiment 44. The process according to any one of embodiments 39 to 43, wherein the solution is formed using amorphous free base of ruxolitinib.

[0296] Embodiment 45. In step a), the solution comprising the free base of ruxolitinib and a solvent mixture is heated to a temperature of about 40 °C to about 80 °C, the process according to any one of embodiments 42 to 44.

[0297] Embodiment 46. The process according to any one of Embodiments 42 to 44, wherein in step a), the solution containing the free base of nilotinib and the solvent mixture is heated to a temperature of about 50°C to about 70°C.

[0298] Embodiment 47. The process according to any one of Embodiments 42 to 44, wherein in step a), the solution containing the free base of nilotinib and the solvent mixture is heated to a temperature of about 55°C to about 65°C.

[0299] Embodiment 48. The process according to any one of Embodiments 42 to 47, wherein in step b), the solution is cooled to a temperature of about 10°C to about 40°C.

[0300] Embodiment 49. The process according to any one of Embodiments 42 to 47, wherein in step b), the solution is cooled to a temperature of about 15°C to about 35°C.

[0301] Embodiment 50. The process according to any one of Embodiments 42 to 47, wherein in step b), the solution is cooled to a temperature of about 20°C to about 30°C.

[0302] Embodiment 51. The process according to any one of Embodiments 42 to 47, wherein in step b), the solution is cooled to a temperature approximately equal to the ambient temperature.

[0303] Embodiment 52. The process according to any one of Embodiments 43 to 51, wherein in step d), the solution is stirred for about 1 to about 30 hours.

[0304] Embodiment 53. The process according to any one of Embodiments 43 to 51, wherein in step d), the solution is stirred for about 10 to about 20 hours.

[0305] Embodiment 54. The process according to any one of Embodiments 43 to 51, wherein in step d), the solution is stirred for about 14 to about 18 hours.

[0306] Embodiment 55. The process according to any one of Embodiments 39 to 54, wherein the aqueous solvent component is water.

[0307] Embodiment 56. The process according to any one of Embodiments 39 to 54, wherein the aqueous solvent component contains a polar protic solvent and water.

[0308] Embodiment 57. The process according to Embodiment 56, wherein the polar protic solvent is an alcohol.

[0309] Embodiment 58. The polar protic solvent is C 1-6 alcohol. The process according to Embodiment 56.

[0310] Embodiment 59. The C 1-6 alcohol is isopropanol. The process according to Embodiment 58.

[0311] Embodiment 60. The volume:volume ratio of the polar protic solvent to the water is from about 1:0.1 to about 1:10. The process according to any one of Embodiments 56 to 59.

[0312] Embodiment 61. The volume:volume ratio of the polar protic solvent to the water is from about 1:0.5 to about 1:5. The process according to any one of Embodiments 56 to 59.

[0313] Embodiment 62. The volume:volume ratio of the polar protic solvent to the water is from about 1:1 to about 1:3. The process according to any one of Embodiments 56 to 59.

[0314] Embodiment 63. The volume:volume ratio of the polar protic solvent to the water is from about 1:2 to about 1:2.5. The process according to any one of Embodiments 56 to 59.

[0315] Embodiment 64. The free base of ruxolitinib is ruxolitinib phosphate:

Chemical formula

[0316] Embodiment 65. The process according to Embodiment 64, wherein the free base of ruxolitinib is amorphous.

[0317] Embodiment 66. Reacting the ruxolitinib phosphate with the base comprises using about 1 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0318] Embodiment 67. Reacting the ruxolitinib phosphate with the base comprises using about 1 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0319] Embodiment 68. Reacting the ruxolitinib phosphate with the base comprises using about 1 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0320] Embodiment 69. Reacting the ruxolitinib phosphate with the base comprises using about 2 to about 10 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0321] Embodiment 70. Reacting the ruxolitinib phosphate with the base comprises using about 2 to about 5 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0322] Embodiment 71. Reacting the ruxolitinib phosphate with the base comprises using about 2 to about 3 molar equivalents of the base relative to the ruxolitinib phosphate, the process according to Embodiment 64 or 65.

[0323] Embodiment 72. The process according to any one of Embodiments 64 to 71, wherein reacting the lucanthone phosphate with a base comprises using an amount of the base sufficient to produce a pH of from about 7.5 to about 8.

[0324] Embodiment 73. The process according to any one of Embodiments 64 to 71, wherein reacting the lucanthone phosphate with a base comprises using an amount of the base sufficient to produce a pH of from about 7 to about 8.

[0325] Embodiment 74. The process according to any one of Embodiments 64 to 73, wherein the base is a hydroxide base.

[0326] Embodiment 75. The process according to any one of Embodiments 64 to 73, wherein the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

[0327] Embodiment 76. The process according to any one of Embodiments 64 to 73, wherein the base is KOH.

[0328] Embodiment 77. The process according to any one of Embodiments 64 to 73, wherein the base is NaOH.

[0329] Embodiment 78. The process according to any one of Embodiments 64 to 77, wherein the solvent component comprises water.

[0330] Embodiment 79. The process according to any one of Embodiments 64 to 77, wherein the solvent component comprises one or more aprotic solvents and water.

[0331] Embodiment 80. The process according to any one of Embodiments 64 to 77, wherein the solvent component comprises water, an ester solvent, a halogenated solvent, or a mixture thereof.

[0332] Embodiment 81. The process according to Embodiment 80, wherein the ester solvent is ethyl acetate.

[0333] Process according to embodiment 80, wherein the halogenated solvent is dichloromethane.

[0334] Process according to embodiment 80, wherein the solvent component comprises ethyl acetate, dichloromethane, and water.

[0335] Process according to any one of embodiments 64 to 83, wherein the loxoribine phosphate in the solvent component is cooled to a temperature of about 0 °C to about 10 °C.

[0336] Process according to any one of embodiments 64 to 83, wherein the loxoribine phosphate in the solvent component is cooled to a temperature of about 0 °C to about 5 °C.

[0337] A process for preparing a solid form of anhydrous crystalline loxoribine free base, the process comprising drying crystalline loxoribine dihydrate.

[0338] The process according to embodiment 86, wherein the drying comprises drying crystalline loxoribine dihydrate at approximately room temperature in a jar containing a desiccant.

[0339] The process according to embodiment 87, wherein the desiccant is P2O5.

[0340] A solid form of loxoribine dihydrate, the solid form being prepared by the process according to any one of embodiments 38 to 85.

[0341] A solid form of anhydrous crystalline loxoribine, the solid form being prepared by the process according to any one of embodiments 86 to 88.

[0342] A pharmaceutical composition comprising the solid form according to any one of embodiments 1 to 37, 89, and 90.

[0343] Embodiment 92. The pharmaceutical composition according to Embodiment 91, which is an oral dosage form.

[0344] Embodiment 93. The pharmaceutical composition according to Embodiment 92, wherein the oral dosage form is an immediate-release dosage form.

[0345] Embodiment 94. The pharmaceutical composition according to Embodiment 93, wherein the ruxolitinib dihydrate is present in an amount of about 5 to about 25 mg on a free base basis.

[0346] Embodiment 95. The pharmaceutical composition according to 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 on a free base basis.

[0347] Embodiment 96. The pharmaceutical composition according to Embodiment 93, wherein the oral dosage form is a sustained-release dosage form.

[0348] Embodiment 97. The pharmaceutical composition according to Embodiment 96, wherein the ruxolitinib dihydrate is present in an amount of about 10 to about 50 mg on a free base basis.

[0349] Embodiment 98. The pharmaceutical composition according to 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 on a free base basis.

[0350] Embodiment 99. The pharmaceutical composition according to Embodiment 91, wherein the composition is a topical formulation.

[0351] Embodiment 100. The pharmaceutical composition according to Embodiment 99, wherein the topical formulation is a cream formulation.

[0352] Embodiment 101. The pharmaceutical composition according to Embodiment 100, wherein the cream formulation contains an oil-in-water emulsion.

[0353] Embodiment 102. The cream preparation is the pharmaceutical composition according to Embodiment 101, which is prepared by incorporating loxicitinib dihydrate into the water-in-oil emulsion.

[0354] Embodiment 103. A topical pharmaceutical preparation containing loxicitinib free base and a solvent component, wherein the preparation is prepared by dissolving the solid form according to any one of Embodiments 1 to 37, 89, and 90 in the solvent component.

[0355] Embodiment 104. The topical pharmaceutical preparation according to any one of Embodiments 99 to 103, wherein the loxicitinib free base is present in an amount of about 0.5% to about 1.5% by weight of the loxicitinib free base in the preparation.

[0356] Embodiment 105. The topical pharmaceutical preparation according to Embodiment 104, wherein the loxicitinib free base is present in an amount of about 1.5% by weight of the loxicitinib free base in the preparation.

[0357] Embodiment 106. The topical pharmaceutical preparation according to any one of Embodiments 103 to 105, which contains loxicitinib dihydrate in an amount of less than about 0.9% by weight, less than about 0.8% by weight, less than about 0.7% by weight, less than about 0.6% by weight, less than about 0.5% by weight, less than about 0.4% by weight, less than about 0.3% by weight, less than about 0.2% by weight, less than about 0.1% by weight, less than about 0.09% by weight, less than about 0.08% by weight, less than about 0.07% by weight, less than 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, or less than about 0.01% by weight of the preparation on a free base basis.

[0358] Embodiment 107. A topical pharmaceutical formulation comprising (a) the free base of ruxolitinib in an amount of about 0.5% to about 1.5% of the formulation, and (b) ruxolitinib dihydrate present in an amount 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 0.06 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%, or less than about 0.01 wt%, based on the free base, of the topical pharmaceutical formulation.

[0359] Embodiment 108. The topical pharmaceutical formulation according to any one of Embodiments 99 to 107, wherein the topical pharmaceutical formulation is prepared in a large batch size.

[0360] Embodiment 109. The topical pharmaceutical formulation according to any one of Embodiments 103 to 107, wherein the topical pharmaceutical formulation is prepared in a batch size of 1000 kg or more.

[0361] Pharmaceutical formulation for topical use, comprising: (a) ruxolitinib, or a pharmaceutically acceptable salt thereof, and (b) ruxolitinib dihydrate present in an amount 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 0.06 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%, or less than about 0.001 wt% based on the free base of the formulation. The pharmaceutical formulation for topical use as described above.

[0362] Embodiment 111. The pharmaceutical formulation for topical use according to Embodiment 110, which is prepared in a large batch size.

[0363] Embodiment 112. The pharmaceutical formulation for topical use according to Embodiment 110, which is prepared in a batch size of 1000 kg or more.

[0364] Embodiment 113. The pharmaceutical formulation for topical use according to any one of Embodiments 110 to 112, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 wt% to about 1.5 wt% of the formulation based on the free base.

[0365] Embodiment 114. The pharmaceutical formulation for topical use according to Embodiment 113, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5 wt% of the formulation based on the free base.

[0366] Embodiment 115. The pharmaceutical formulation for topical use according to any one of Embodiments 110 to 114, wherein the ruxolitinib, or a pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.

[0367] Pharmaceutical formulation for topical use 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 0.06 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%, or less than about 0.01 wt% of ruxolitinib dihydrate, based on the free base, and the formulation is prepared in a large batch size, said pharmaceutical formulation for topical use.

[0368] Embodiment 117. The pharmaceutical formulation for topical use according to embodiment 116, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5 wt% to about 1.5 wt% of the formulation, based on the free base.

[0369] Embodiment 118. The pharmaceutical formulation for topical use according to embodiment 117, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is present in an amount of about 1.5 wt% of the formulation, based on the free base.

[0370] Embodiment 119. The pharmaceutical formulation for topical use according to any one of embodiments 116 to 118, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof is ruxolitinib phosphate.

[0371] Embodiment 120. The pharmaceutical formulation for topical use according to any one of embodiments 116 to 119, wherein the batch size is 1000 kg or more.

[0372] Process for releasing a batch of a topical pharmaceutical formulation according to any one of embodiments 116 to 120, comprising: (i) testing a sample of the topical pharmaceutical formulation for the absence of crystalline ruxolitinib dihydrate; and, if the sample passes the test of step (i), (ii) releasing the batch for general use.

[0373] The process according to embodiment 121, wherein the testing comprises observing a sample of the formulation with an optical microscope to detect the absence or presence of crystals, and the sample passes the test if no crystals are detected.

[0374] A method of treating a disease in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of embodiments 91 to 115, wherein the disease is myelofibrosis, polycythemia vera, acute graft-versus-host disease, or chronic graft-versus-host disease.

[0375] A method of treating a skin disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition according to any one of embodiments 91 to 115.

[0376] A method of treating a skin disorder in a patient in need thereof, comprising administering to the affected area of the patient's skin a topical pharmaceutical formulation according to any one of embodiments 99 to 115.

[0377] The method according to any one of embodiments 124 to 125, wherein the skin disorder is an autoimmune skin disease.

[0378] The method according to any one of embodiments 124 to 125, wherein the skin disorder is atopic dermatitis.

[0379] Embodiment 128. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is lichen planus.

[0380] Embodiment 129. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is hidradenitis suppurativa.

[0381] Embodiment 130. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is psoriasis.

[0382] Embodiment 131. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is plaque psoriasis.

[0383] Embodiment 132. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is a rash, skin irritation, or skin sensitization.

[0384] Embodiment 133. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is contact dermatitis or allergic contact dermatitis.

[0385] Embodiment 134. The method according to any one of Embodiments 124 to 125, wherein the skin disorder is bullous pemphigoid.

[0386] Embodiment 135. The method according to any one of Embodiments 124 to 134, wherein the patient is a human patient.

[0387] It is further understood that certain features of the present disclosure, which are described in connection with separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, the various features of the present disclosure that are described in a single embodiment for brevity may also be provided separately or in any suitable subcombination.

[0388] 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 various non-essential parameters that can be changed or modified to yield essentially the same results.

Example

[0389] The crystalline dihydrate form of ruxolitinib was discovered during a scale-up operation to 3200 kg of a topical product (prepared by a method similar to the smaller scale method described in Example 16) having 1.5% (w / w) ruxolitinib phosphate on a free base basis. The product was isolated by diluting with water, filtering, washing with water, and drying. Two approaches were used to prepare crystalline ruxolitinib dihydrate. The first approach is Scheme 1, Example 1, which produces crystalline ruxolitinib dihydrate from the isolated amorphous ruxolitinib free base. In this approach, crystalline ruxolitinib phosphate is neutralized with a base such as an aqueous potassium hydroxide (KOH) solution. Next, the resulting ruxolitinib free base is extracted into an organic solvent (EtOAc or DCM) or an organic solvent system (EtOAc and DCM). After distilling off the solvent(s), the ruxolitinib free base is obtained as an amorphous solid. Next, the amorphous ruxolitinib free base is crystallized in a mixed solvent system such as isopropanol (IPA) and water to produce crystalline ruxolitinib dihydrate.

[0390] A second approach for preparing crystalline loxoribineb dihydrate is Example 2 of Scheme 2, which involves crystallizing in aqueous isopropanol using the in situ generated loxoribineb free base. In this approach, the loxoribineb free base need not be isolated. Instead, a solution of the loxoribineb free base in DCM or ethyl acetate (EtOAc), or a mixture of EtOAc and DCM, is solvent-exchanged into isopropanol (IPA). Water is added and after seeding with loxoribineb dihydrate crystals isolated using the approach described above, crystalline loxoribineb dihydrate is produced.

[0391] The preparation and isolation of loxoribineb phosphate can be confirmed in WO2008 / 157208, which is hereby incorporated by reference in its entirety. The preparation and isolation of the L-tartrate dihydrate of Compound 3, the hydrochloride salt of Compound 2, and the loxoribineb free base can also be confirmed in US Patent Publication No. 20220056035, which is hereby incorporated by reference in its entirety.

[0392] Example 1. Preparation of Crystalline Loxoribineb Dihydrate from Isolated Amorphous Loxoribineb Free Base Scheme 1:

Chemical formula

[0393] Step 2: Crystallization of the amorphous loxoribine free base in aqueous isopropanol for the formation of crystalline loxoribine dihydrate To a solution of the amorphous ruxolitinib free base (9.32 g, 28.1 mmol) from Step 1 in isopropanol (IPA, 86 mL), water (214 mL) was gradually charged at ambient temperature. The resulting mixture was warmed to 55 - 65 °C to form a clear solution. Next, the obtained solution was cooled to ambient temperature, and then a seed of crystalline ruxolitinib dihydrate (20.9 mg) was introduced into the solution. Next, the crystallization mixture was stirred at ambient temperature for 16 hours to gradually crystallize the solid from the solution. The solid was collected by filtration, washed with cold water (50 mL), and dried under vacuum to a constant weight to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile dihydrate (9.03 g, theoretical value 9.62 g, 93.9%) as a white to off-white crystalline powder. For crystalline ruxolitinib dihydrate: chemical purity by HPLC > 99.9%; chiral purity by chiral HPLC > 99.9%; water content by KF 10.30%; 1 H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.79 (s, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 7.59 (dd, J = 3.7, 2.0 Hz, 1H), 6.99 (dd, J = 3.7, 1.4 Hz, 1H), 4.54 (td, J = 9.7, 4.0 Hz, 1H), 3.28 (dd, J = 17.1, 9.7 Hz, 1H), 3.19 (dd, J = 17.1, 4.0 Hz, 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); 1313C NMR (DMSO-d6, 126 MHz) δ 152.60, 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 N6O2 (MW, 342.40 for the case of ruxolitinib dihydrate), and C 17 H 18 N6 (MW, 306.37 for the case of ruxolitinib free base), LCMS (EI) m / e 307 (M + H for the case of ruxolitinib free base). + + H).

[0394] Alternative Step 2. Preparation of Crystalline Ruxolitinib Dihydrate without Seeding A 40 mL scintillation vial equipped with a stir bar was charged with (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (luxolitinib 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. Next, water (16.0 mL, 888 mmol) was 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 for an additional 17 hours at ambient temperature. The solid was collected by filtration and the wet cake was dried under in-house vacuum by pulling air across the entire filter cake. The desired product, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile dihydrate (luxolitinib dihydrate, 0.913 g, theoretical 1.236 g, 74% yield) was obtained as an off-white to pale pink crystalline powder. This was identical in all comparable aspects, including XRPD and DSC, to crystalline luxolitinib dihydrate made using seeding.

[0395] Example 2. Preparation of Crystalline Luxolitinib Dihydrate from In Situ Generated Luxolitinib Free Base Scheme 2

Chemical formula

[0396] Step 2: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (luxolitinib free base) A solution of (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride hydrochloride (the hydrochloride salt of Compound 2, 10.0 g, 31.6 mmol) in water (10.0 mL) was treated with a 30% aqueous solution of NaOH at 0 - 5 °C to a pH of 7 - 8. To the resulting aqueous solution, carbon (2.0 g) was added and the mixture was stirred at ambient temperature for 2 - 4 hours. The carbon was removed by filtration through a Celite bed and the wet carbon cake was washed with water (15 mL). Next, the resulting aqueous solution containing (E)-N-(3-(dimethylamino)-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)allylidene)-N-methylmethanaminium chloride (the chloride salt of Compound 2) was treated at ambient temperature with ethanol (30 mL) and (R)-3-cyclopentyl-3-hydrazinylpropanenitrile L-tartrate dihydrate (the L-tartrate dihydrate of Compound 3, 11.21 g, 33.0 mmol, 1.04 equivalents). Next, the resulting mixture was 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 cake was washed with ethanol (twice with 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. Next, to the residue, H2O (30 mL) and dichloromethane (DCM, 50 mL) were added and the mixture was treated with a 30% aqueous solution of sodium hydroxide (NaOH) to adjust the pH to about 10. The two layers were separated and the aqueous layer was extracted with DCM (30 mL). The combined organic extracts were filtered through a Celite bed and the Celite bed was washed with DCM (10 mL). Next, the solution of the free base of ruxolitinib in DCM was used directly in the subsequent process steps to produce crystalline ruxolitinib dihydrate.

[0397] Step 3: Preparation of Crystalline (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile Dihydrate (Crystalline Ruxolitinib Dihydrate) The solution of the free base of loxoribine in DCM was concentrated under reduced pressure to remove most of the DCM. Next, isopropanol (IPA, 50 mL) was charged to the residue, and the resulting solution was further concentrated under reduced pressure. Additional IPA (50 mL) was charged to the concentrated solution to completely exchange the solvent to IPA. Next, the resulting solution of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (loxoribine free base) in IPA was cooled to ambient temperature, and then water (208 mL) was gradually charged to the IPA solution at ambient temperature with stirring. When the addition of water was complete, the resulting mixture was heated to 55 - 65 °C to form a clear solution. Next, the resulting solution was cooled to ambient temperature, and then a seed (32 mg) of crystalline loxoribine dihydrate (isolated by the approach described above) was introduced into the solution. Next, the crystallization mixture was stirred at ambient temperature for 16 hours to gradually crystallize the solid 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 a constant weight to obtain loxoribine dihydrate (6.76 g, theoretical 10.82 g, 62.5%) as a white to off-white crystalline powder. This is identical to the material obtained in Example 1 in any comparable aspect.

[0398] Physicochemical properties of crystalline loxoribine dihydrate The structure of loxoribine dihydrate was determined by single crystal X-ray analysis. See Example 3. The physicochemical properties of crystalline loxoribine dihydrate were characterized by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). See Examples 4 - 7.

[0399] Example 3. Single crystal X-ray analysis of loxoribine dihydrate Approximate dimensions 0.260 × 0.190 × 0.120 mm 3Colorless block crystals were placed on the polymer loop in a random orientation. Preliminary inspection and data collection were carried out on a Bruker AXS D8 Quest diffractometer equipped with a copper anode micro-source sealed X-ray tube (Cu Kα λ = 1.54178 Å) and a PhotonIII_C14 charge accumulation and photon counting pixel array detector.

[0400] During data collection, the lattice constants and orientation matrix were obtained from least-squares refinement using the setting angles of 9104 reflections in the range of 3.4603° < θ < 78.3810°. The data were collected at room temperature up to a maximum diffraction angle (2θ) of 159.822°.

[0401] The crystal system is orthorhombic and the space group is P212121. The lattice parameters and calculated volume are a = 9.9731(11) Å, b = 15.1765(17) Å, c = 23.649(3) Å, α = 90°, β = 90°, γ = 90°, V = 3579.4(7) Å3. The formula weight is 342.40 g mol -1 , Z = 8, and the calculated density is 1.271 g cm -3 .

[0402] The single crystal structure of luxolitinib dihydrate was determined. The structure of luxolitinib dihydrate was determined to be a hydrated crystal form composed of two luxolitinib molecules and four water molecules in the asymmetric unit as shown in Figure 1.

[0403] Example 4A. Powder X-ray diffraction (XRPD) analysis of crystalline luxolitinib dihydrate. Powder X-ray diffraction (XRPD) was obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE (trademark) detector with a slit of 0.6 mm, (2) X-ray power at 40 kV and 25 mA, and (3) the sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees, stop angle 30 degrees, sampling 0.015 degrees, and scan speed 2 degrees / min.

[0404] XRPD analysis is a means of determining crystallinity. Here, XRPD analysis of a sample of ruxolitinib dihydrate revealed that it was a crystalline solid (Figure 2). The XRPD pattern is consistent with the XRPD pattern calculated from the single crystal structure. The XRPD peak data corresponding to Figure 2 are shown in Table 1. Figure 6 shows a comparison of the XRPD pattern of ruxolitinib dihydrate with the XRPD pattern of ruxolitinib phosphate. Another batch of ruxolitinib dihydrate also shows that the product is crystalline. See Table 2 and Figure 7.

Table 1-1

Table 1-2

Table 2-1

Table 2-2

[0405] Example 4B. Determination of XRPD Characteristics of Additional Representative Samples of Ruxolitinib Dihydrate (Method A) Additional representative samples of ruxolitinib dihydrate were analyzed.

[0406] Transmission geometry The XRPD pattern was collected using a PANalytical X’Pert PRO MPD or PANalytical Empyrean diffractometer with an incident beam of Cu radiation generated using an Optix long, fine focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays onto the detector through the specimen. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. The specimen of the sample was sandwiched between 3-μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extension, and anti-scatter knife edge were used to minimize the background generated by air. Soller slits were used for the incident beam and diffracted beam to minimize the spread from axial divergence. A scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Collector software v.5.5 were used to collect the diffraction pattern.

[0407] In most situations, peaks within the range of 2θ up to about 30° were selected. A rounding algorithm was used to round each peak to the nearest 0.1° or 0.01° of 2θ depending on the instrument and / or the inherent peak resolution used to collect the data. The positions of the peaks along the x-axis (° of 2θ) for both the figures and tables were determined using in-house software and rounded to one or two significant digits after the decimal point based on the above criteria. The variation in peak positions is shown within a range of ±0.2° of 2θ based on the recommendations outlined in the USP discussion on the variability of x-ray powder diffraction. The exactness and precision associated with any particular measurement reported herein have not been determined. Further, third-party measurements on samples prepared independently by different instruments can lead to variations exceeding ±0.2° of 2θ. For the list of interplanar spacings, the wavelength used to calculate the interplanar spacing was 1.5405929 Å, Cu-K α1 wavelength. The variation associated with the estimated values of the interplanar spacings was calculated for each interplanar spacing from the USP recommendations and presented in the respective data tables.

[0408] According to the USP guidelines, variable hydrates and solvates may exhibit peak broadening greater than 0.2° 2θ, so the peak broadening of 0.2° 2θ is not applicable to these materials.

[0409] In the case of a sample where there is only one XRPD pattern and no other method to evaluate whether the sample has a good approximation of the powder average, the peak table includes only the data identified as "prominent peaks". These peaks are a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks, preferably by identifying non-overlapping low-angle peaks with high intensity.

[0410] When multiple diffraction patterns are available, evaluation of particle statistics (PS) and / or preferred orientation (PO) is available. The reproducibility between XRPD patterns from multiple samples analyzed on a single diffractometer implies that the particle statistics are appropriate. The consistency of relative intensities between XRPD patterns from multiple diffractometers implies good orientation statistics. Alternatively, the observed XRPD pattern may be compared, if available, with an XRPD pattern calculated based on a single crystal structure. Two-dimensional scattering patterns using a area detector can also be used to evaluate PS / PO. If it is determined that the effects of both PS and PO can be ignored to a certain extent, the XRPD pattern is representative of the powder average intensity of the sample, and prominent peaks can be identified as "representative peaks". Generally, the more data collected to determine representative peaks, the more certain their classification can be.

[0411] "Characteristic peaks", when they exist, are a subset of the representative peaks and are used to distinguish one crystalline polymorph from another polymorph (a crystalline form having the same chemical composition). Characteristic peaks, when they exist, are determined by evaluating whether representative peaks of a crystalline polymorph of a compound exist within a range of 2θ of ±0.2° for all other known crystalline polymorphs of the compound. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak. Figure 9 shows the XRPD pattern of crystalline luthixolitinib dihydrate, Table 3A shows the observed peaks, and Table 3B shows the prominent peaks.

Table 3-1

Table 3-2

Table 3-3

Table 4-1

Table 4-2

[0412] Example 5. Differential Scanning Calorimetry (DSC) Analysis of Crystalline Luthixolitinib Dihydrate. DSC was obtained from a Differential Scanning Calorimetry, Discovery DSC2500 equipped with an autosampler from TA Instruments. The conditions of the DSC instrument were as follows: 20 - 300 °C at 10 °C / min; Tzero aluminum sample pans and lids; and a nitrogen gas flow rate of 50 mL / min.

[0413] The DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in Figure 3. The DSC thermogram showed one endothermic event corresponding to the dehydration process, with an onset temperature of 60.5 °C and a peak temperature of 66.7 °C. In another DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate, one endothermic event occurred at an onset temperature of 59.5 °C. In yet another DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate, one endothermic event with a peak temperature of 69.1 °C occurred.

[0414] Separate DSC thermograms were performed on the materials. In this experiment, DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter (Method B). Tau delay correction was performed using indium, tin, and zinc. Temperature and enthalpy were calibrated using octane, phenyl salicylate, indium, tin, and zinc. Next, the calibration was verified using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a hermetically sealed aluminum DSC pan, the weight was accurately recorded, and the sample was inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. Before sample analysis, holes were made in the lid of the pan. The sample was analyzed from -30 °C to 250 °C at 10 °C / min.

[0415] The DSC thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in Figure 10. A broad endothermic event was observed, accompanied by a second endotherm with an onset temperature of 68 °C, a peak temperature of 72 °C, and a further peak maximum of 110 °C.

[0416] Example 6A. Thermogravimetric analysis (TGA) of crystalline ruxolitinib dihydrate. TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500 equipped with an autosampler. The general experimental conditions for TGA were as follows: a ramp from 25 °C to 300 °C at 10 °C / min; a nitrogen purge gas flow rate of 25 mL / min; a platinum sample holder.

[0417] The TGA thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in Figure 4. A 10.4% weight loss below 100 °C due to dehydration was observed. The resulting anhydrous free base decomposed above 200 °C.

[0418] A representative sample of crystalline ruxolitinib dihydrate lost all hydrates from 30 °C to 80 °C and became an amorphous solid. The amorphous solid remained an amorphous solid even after adding one drop of water. After one day, when two drops of water were added, the amorphous solid became crystalline dihydrate.

[0419] Example 6B. Additional thermogravimetric analysis of crystalline ruxolitinib dihydrate Additional TGA thermograms were performed on the material. Thermogravimetric analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer (Method C). Temperature and enthalpy calibrations were performed using indium, tin, zinc, and phenyl salicylate and then verified using indium. Equilibrium was verified using calcium oxalate. The sample was placed in an aluminum pan. The pan was hermetically sealed, holes were made in the lid, and then the pan was inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference stage. The furnace was heated under nitrogen. The sample was analyzed from ambient temperature to 350 °C at 10 °C / min. In thermogravimetric analysis, generally, an equilibration period indicated in brackets on the thermogram occurs at the start of each analysis. The starting temperature for the associated weight loss calculations is selected at a point beyond this region (typically above 35 °C) for accuracy.

[0420] The TGA thermogram of a representative sample of crystalline ruxolitinib dihydrate is shown in Figure 11. The TGA analysis showed a 1.7% weight loss up to 90 °C, followed by a further 8.2% weight loss up to 178 °C. A 10.5% (9.9% observed) weight loss is consistent with the dihydrate.

[0421] Example 7A. Dynamic vapor sorption (DVS) analysis of crystalline ruxolitinib dihydrate. The DVS experiments were carried out on a TA Instruments VTI-SA+ Vapor Sorption Analyzer. Representative samples of crystalline ruxolitinib dihydrate were first pre-dried at 60 °C for 1 hour under dry N2 (0% RH). Next, the humidity was cycled at a constant temperature of 25 °C in 5% RH increments from 5% RH to 95% RH (adsorption) and back to 5% RH (desorption). The equilibrium criterion was 0.010 wt% per step for 5 minutes, with a maximum equilibrium time of 180 minutes.

[0422] In the pre-drying step at 60 °C, representative samples of crystalline ruxolitinib dihydrate were dehydrated to form amorphous ruxolitinib free base. Next, water was re-adsorbed up to 9.6% at 95% RH and maintained at a relatively stable state up to 5% RH. XRPD analysis showed that the resulting solid was crystalline ruxolitinib dihydrate after DVS (see Figure 8 and Table 4). The results of the DVS experiments performed on this representative sample of crystalline ruxolitinib dihydrate are shown in Figure 5.

Table 5-1

Table 5-2

[0423] Example 7B. Additional DVS Analysis Additional DVS on crystalline ruxolitinib dihydrate was collected on a Surface Measurement System DVS Intrinsic instrument (Method D). The sample was not dried before analysis. Adsorption and desorption data were collected at 10% RH increments from 5% to 95% RH under nitrogen purge. The equilibrium criteria used for the analysis were a weight change of 0.001 dm / dt in 5 minutes, a minimum step time of 30 minutes, a maximum equilibrium time of 180 minutes, and a data recording interval of 3 minutes. No data were collected on the initial water content of the sample.

[0424] During DVS analysis, it was shown that the weight of lucitinib dihydrate increased by 0.23% at relative humidities from 5 to 95% and decreased by 0.20% during desorption (Figure 12 and Table 5).

Table 6

[0425] Example 8. Hot-stage microscopy of crystalline lucitinib dihydrate A representative sample of crystalline lucitinib dihydrate was heated at a rate of 5 °C / min starting from a temperature of 25 °C. The crystals showed no significant change at temperatures below 60 °C. The crystals became darker from 62 °C to 70 °C, which corresponds to the dehydration process. Melting was observed at approximately 75 °C and was complete at 80 °C. No crystallization was observed after cooling to 25 °C.

[0426] Example 9. Water solubility of lucitinib dihydrate The solubility of a representative sample of crystalline lucitinib dihydrate was measured at 20 - 25 °C under different aqueous solutions (Table 6). The results are summarized in Table 6.

Table 7

[0427] Example 10. Solubility of crystalline lucitinib dihydrate in organic solvents The solubility of a representative sample of crystalline lucitinib dihydrate was measured in different organic solvents (Table 7). The results are summarized in Table 7. In polar solvents, the crystalline water of lucitinib dihydrate decreased. The resulting free base of lucitinib dissolved immediately in the organic solvent.

Table 8

[0428] Example 11. Characterization of single crystals of lucitinib dihydrate Preparation: Single crystals of loxoribineb dihydrate were prepared as follows. A vial was filled with 98.4 mg of amorphous loxoribineb and contacted with 1 ml of ethyl acetate. The resulting solution was dried over magnesium sulfate. The sample was seeded with crystalline loxoribineb dihydrate, and then 1 ml of heptane was added to obtain an oily substance. 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, and hexagonal flakes nucleated.

[0429] Data collection: Colorless plates approximately 0.56 × 0.36 × 0.08 mm 3 were placed in a polymer loop in a random orientation. Preliminary inspection and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu Kα λ = 1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0430] During data collection, the lattice constants and orientation matrix were obtained from least-squares refinement using the setting angles of 12431 reflections in the range of 4.7310° < θ < 75.4160°. The space group was determined to be P212121 (International Table No. 19) by the program CrysAlisPro.

[0431] The following Table 8 shows the crystal data and data collection parameters.

Table 9-1

Table 9-2

[0432] Calculated powder X-ray diffraction (XRPD) pattern: The calculated XRPD pattern of Cu radiation was created using Mercury and the atomic coordinates, space group, and unit cell parameters of the single crystal structure. See Figure 21.

[0433] Example 12. Relative Humidity Test of Luxolitinib Dihydrate To assist in determining the range of physical stability, luxolitinib dihydrate was held at selected relative humidities (see the table below). The dihydrate was transferred to vials and then placed, without capping, into jars containing saturated salt solutions for the specified period of time. [Table 10]

[0434] The dihydrate form was physically stable above 11% RH during the time tested and was observed to convert to the anhydrous crystalline free base form (Form I) at undetermined values below 11% RH. The XRPD peak positions were constant between XRPD patterns and did not represent a variable system. [Table 11]

[0435] Example 13. Water Slurry Experiment Limited water activity slurry experiments were conducted using luxolitinib dihydrate (see the table below). The effect of water activity (a w ) on the hydration state of the dihydrate was investigated through competitive water activity milling experiments (slurries) in various aqueous solvent mixtures. The resulting solid phases were characterized by XRPD. The experiments establish physically stable forms at various a w . Water activity is also related to relative humidity in that RH% = a w × 100. Thus, it is possible to directly relate the stability of the anhydrous / hydrate system in slurry experiments to the stability in the solid state. The literature suggests that slurry techniques at controlled water activity provide an accurate method for rapidly predicting physically stable forms in anhydrous / hydrate systems. This method is particularly useful when the relatively slow reaction rate of the conversion in the solid state prevents reaching true equilibrium within a reasonable time frame. This is because solvent-mediated conversion accelerates the conversion process.

[0436] The crystalline dihydrate form was observed under all the conditions tested.

Table 12

[0437] Example 14. Dehydration of LY2835219 Dihydrate Dehydration of LY2835219 dihydrate results in the isolation of anhydrous crystalline LY2835219 free base (Form I) (see the table below). Form I is described in more detail in Example 15.

Table 13

[0438] Example 15. Anhydrous Crystalline LY2835219 Free Base Dehydration of LY2835219 dihydrate as described in Example 14 results in the isolation of anhydrous crystalline LY2835219 free base (Form I). Drying over P2O5 gives the most crystalline product, and the XRPD pattern of Form I was successfully indexed using Method A of XRPD (see Figure 13 and Tables 9A and 9B).

Table 14-1

Table 14-2

Table 14-3

Table 15-1

Table 15-2

[0439] Differences in the XRPD patterns of Form I are observed with respect to the degree of crystallinity. The degree of crystallinity is affected by the method of desolvation. Materials showing higher crystallinity are formed when dehydration is carried out at a slower rate such as storage on P2O5 compared to vacuum drying or heating (Figure 14).

[0440] Two samples of Form I were thermally analyzed by DSC Method B and TGA Method C. The thermal data is consistent with the anhydrous solid. TGA showed a weight loss of 0.07% up to 230 °C (Figure 17), and DSC showed a single endothermic event with an onset at 83 °C (Figure 15). The event is broad and the signal returns to the baseline around 140 °C. No signs of crystallization are observed after the estimated melting at 83 °C.

[0441] A second sample of Form I showed a greater weight loss in TGA with a 0.4% weight loss up to 98 °C and no measurable additional weight loss was observed until after 260 °C (Figure 18). By DSC, a single endothermic event with an onset at 81 °C is observed (Figure 16). A tendency for exotherm is observed prior to the endothermic onset at 81 °C, which may be related to an increase in the crystallinity of Form I of the sample prior to melting at 81 °C. The second sample of Form I was observed to have a small amount of diffuse scattering compared to the first sample, meaning that the material may contain defects or a small amount of amorphous content.

[0442] DVS data generated via DVS Method D was collected and Form I was determined to be hygroscopic (Figure 19). Minimal water uptake was observed from 5 to 55% RH with a 0.26% weight gain. From 55 to 95% RH, a 10.6% weight gain was observed (equivalent to 2 moles of water and confirmed to be the dihydrate by various humidity XRPD and RH stress tests). Hysteresis is observed during desorption. Only a 1% weight loss is observed from 95 to 15% RH, followed by an additional 4.8% from 15 to 5% RH. The sample after DVS was observed to be Form I but was less crystalline than the starting material (Figure 20).

Table 16

[0443] Example 16. Cream formulation prepared starting from ruxolitinib dihydrate Using 0.5, 1.0, and 1.5 weight % (free base equivalent) of ruxolitinib dihydrate in the formulation, an oil-in-water cream formulation is prepared. The three strengths of the formulation are the same except for the adjustment of the amount of purified water based on the amount of the active ingredient. All excipients used in the formulation are of official grade (i.e., USP / NF or BP) or are approved for use in topical products. Representative 400 kg batch quantitative formulations of 0.5, 1.0, and 1.5% cream formulation ruxolitinib dihydrate are also shown in Tables 11, 12, and 13, respectively. [Table 17] [Table 18] [Table 19]

[0444] The oil-in-water cream formulation is synthesized on any 400 kg scale according to the following procedure. Generally, an overhead mixer with high shear mixing blades and low shear mixing blades is suitable for this process. Procedure 1. Prepare the parabens phase by mixing methylparaben and propylparaben with a portion of propylene glycol (see % in Tables 11 - 13). 2. Next, prepare the xanthan gum phase by mixing xanthan gum with propylene glycol (see % in Tables 11 - 13). 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 this phase to 70 - 80 °C until melted to form a homogeneous mixture. 4. Next, an aqueous phase is prepared by mixing purified water, polyethylene glycol, and disodium EDTA. This phase is heated to 70 - 80 °C. 5. Combine the aqueous phase from Step 4, the parabens phase from Step 1, and ruxolitinib dihydrate to form a mixture. 6. Next, add the xanthan gum phase from Step 2 to the mixture from Step 5. 7. Next, combine the oil phase from Step 3 with the mixture from Step 6 under high - shear mixing to form an emulsion. 8. Next, add phenoxyethanol to the emulsion from Step 7. Continue mixing, and then cool the product under low - shear mixing.

[0445] Example 17. Sustained - release dosage form of ruxolitinib dihydrate A 25 mg sustained - release formulation of ruxolitinib dihydrate is prepared according to the following process. The formulation components are shown in Table 14. The percentages are by weight. [Table 20]

[0446] Process Step 1. Add microcrystalline cellulose, ruxolitinib phosphate, lactose monohydrate, and hypromellose to a suitable blender and mix. Step 2. Transfer the mixture from Step 1 to a suitable granulator and mix. Step 3. Add purified water while mixing. Alternatively, dry - granulate the mixture. Step 4. Screen the granules from Step 3. Step 5. Transfer the granules from Step 4 to a suitable dryer and dry until the loss on drying (LOD) is less than 3%. Step 6. Screen the granules from Step 5. Step 7. Mix colloidal silicon dioxide with the granules from Step 6 in a suitable blender. Step 8. Mix and blend stearic acid and magnesium stearate with the blend from Step 7. Step 9. Compress the final blend of Step 8 using a suitable rotary tablet press.

[0447] In addition to what is described herein, various modifications of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety into this specification.

Claims

1. It is crystalline ruxolitinib dihydrate, in solid form: 【Chemistry 1】 The solid form is a solid form that is substantially isolated.

2. The solid form according to claim 1, characterized in that the solid form has 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 with respect to 2θ (±0.2 degrees).

3. The solid form according to claim 1, characterized in that the solid form has 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 with respect to 2θ (±0.2 degrees).

4. The solid form according to claim 1, characterized in that the solid form has an XRPD pattern having a characteristic peak substantially shown in Figure 2.

5. The solid form according to claim 1, characterized in that the solid form has single-crystal X-ray diffraction having a P212121 space group and lattice composition unit (Z) 8.

6. The solid form according to claim 5, wherein the solid form has the following unit cell parameters: a is about 9.97 Å, b is about 15.18 Å, c is about 23.64 Å, α is about 90°, β is about 90°, and γ is about 90°.

7. The solid form according to claim 1, characterized in that the solid form has an endothermic peak in the DSC thermogram with an initial temperature (±5°C) of 61°C and a maximum temperature (±5°C) of 67°C.

8. The solid form according to claim 1, characterized in that the solid form substantially has a DSC thermogram as shown in Figure 3.

9. The solid form according to claim 1, characterized in that the solid form substantially has the TGA thermogram shown in Figure 4.

10. This is the solid form of anhydrous crystalline ruxolitinib free base.

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

12. The solid morphology according to claim 10, characterized in that the solid morphology has 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 with respect to 2θ (±0.2 degrees).

13. The solid form according to claim 10, characterized in that the solid form has an XRPD pattern having a characteristic peak substantially shown in Figure 13.

14. The solid form according to claim 10, characterized in that the solid form has an endothermic peak in the DSC thermogram with a starting temperature (±5°C) of 83°C and a maximum temperature (±5°C) of 93°C.

15. The solid form according to claim 10, characterized in that the solid form substantially has a DSC thermogram shown in Figure 15 or Figure 16.

16. The solid form according to claim 10, characterized in that the solid form substantially has a TGA thermogram as shown in Figure 17 or Figure 18.

17. The solid form according to any one of claims 1 to 9 is ruxolitinib dihydrate: 【Chemistry 2】 A process for preparing, The process comprises isolating the solid form from a solution containing ruxolitinib free base and an aqueous solvent component.

18. The process according to claim 17, wherein the aqueous solvent component comprises a polar protic solvent and water, and the polar protic solvent is isopropanol.

19. The aforementioned ruxolitinib free base is ruxolitinibrinate: 【Transformation 3】 It is prepared by a process that includes reacting it with a base in a solvent component, Reacting ruxolitinibrinate with a base involves using about 2 to about 3 molar equivalents of the base relative to the ruxolitinibrinate. The aforementioned base is a hydroxide base, The process according to claim 17, wherein the solvent component comprises water, an ester solvent, a halogenated solvent, or a mixture thereof, the ester solvent being ethyl acetate, and the halogenated solvent being dichloromethane.

20. A process for preparing the solid form according to any one of claims 10 to 16, comprising drying crystalline ruxolitinib dihydrate.

21. The process according to claim 20, wherein the drying comprises drying crystalline ruxolitinib dihydrate in a jar containing a desiccant at approximately room temperature.

22. A pharmaceutical composition comprising the solid form described in any one of claims 1 to 16.

23. The pharmaceutical composition according to claim 22, which is in oral dosage form.

24. The pharmaceutical composition according to claim 23, wherein the oral dosage form is an immediate-acting dosage form.

25. The pharmaceutical composition according to claim 22, wherein the solid form is ruxolitinib dihydrate present in an amount of about 5 to about 25 mg based on free base.

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

27. The pharmaceutical composition according to claim 22, wherein the solid form is ruxolitinib dihydrate present in an amount of about 10 to about 50 mg based on free base.

28. The pharmaceutical composition according to claim 22, which is a topical preparation.

29. The pharmaceutical composition according to claim 28, wherein the topical preparation is a cream preparation.

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

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

32. A process for releasing a batch of the pharmaceutical composition according to claim 28, comprising: (i) testing a sample of the pharmaceutical composition for the absence of crystalline ruxolitinib dihydrate; and, if the sample passes the test of step (i), (ii) releasing the batch for general use.

33. The process according to claim 32, wherein the test comprises observing a sample of the pharmaceutical composition with an optical microscope to detect the absence or presence of crystals, and the sample passes the test if no crystals are detected.

34. The pharmaceutical composition according to claim 22 for treating a disease in a patient requiring treatment for the disease, wherein the disease is myelofibrosis, polycythemia vera, acute graft-versus-host disease, or chronic graft-versus-host disease.

35. The pharmaceutical composition according to claim 22 for treating a skin disorder in a human patient requiring treatment of a skin disorder.

36. A pharmaceutical composition according to claim 28 for treating a skin disorder in a human patient requiring treatment of a skin disorder, wherein the pharmaceutical composition is administered to the affected area of ​​the patient's skin.

37. The pharmaceutical composition according to claim 35, wherein the skin disorder is an autoimmune skin disease.

38. The aforementioned skin disorder Atopic dermatitis, or Lichen planus, or Suppurative hidradenitis, or Psoriasis, or Skin rash, skin irritation, or skin sensitization, Contact dermatitis or allergic contact dermatitis, It is bullous pemphigoid. The pharmaceutical composition according to claim 37.

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