Crystalline form of 3-cyano-1-[4-[6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-A]pyrazine-4-yl]-1H-pyrazole-1-yl]cyclobutaneacetonitrile and its use

Abstract

To provide: novel crystalline forms of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, form 1 anhydrous free base and form 2 monohydrate; a pharmaceutical composition containing them; preparations thereof; and uses thereof.SOLUTION: The present invention discloses: novel crystalline forms of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile, form 1 anhydrous free base and form 2 monohydrate; a pharmaceutical composition containing them; preparations thereof; and uses thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the crystalline form of an anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. The present invention also relates to the crystalline form of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. The present invention also relates to pharmaceutical compositions comprising any of the above crystalline forms, and methods for preparing them. The present invention further relates to the use of any of the above crystalline forms in the treatment of various diseases. [Background technology]

[0002] (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile has the chemical formula C 20 H 17 N9 and the following structural formula:

[0003] [ka] It holds.

[0004] The synthesis of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is described in U.S. Patent No. 10,144,738, which has been transferred to the assignee of this application, and the entire contents of that patent are incorporated herein by reference. The crystalline forms of the anhydrous free base of form 1 and the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile are useful as inhibitors of protein kinases such as the enzyme Janus kinase (JAK), and are therefore therapeutically useful as immunosuppressants for organ transplantation, xenografting, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease (IBD), psoriasis, type 1 diabetes and complications derived from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other indications where immunosuppression would be desirable. The present invention relates to novel solid forms of the anhydrous free base and monohydrate of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, which have improved material properties for use in the manufacture of pharmaceutical dosage forms.

[0005] Based on chemical structure, it is not possible to predict with some degree of certainty whether a compound will crystallize, under what conditions it will crystallize, or how many crystalline solid forms, or any of those solid forms, may exist for a compound. A key characteristic of any crystalline drug is its polymorphic behavior. Generally, the crystalline form of a drug is preferred, in some cases, to the amorphous form of the drug and drug intermediates due to their superior stability. For example, in many situations, amorphous drugs are observed to transform into crystalline drugs during storage. Since the amorphous and crystalline forms of a drug typically have different physical and chemical properties, such interconversion can be undesirable for safety reasons in pharmaceutical use. The different physical properties exhibited by different solid forms of a pharmaceutical compound can affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (important in determining bioavailability). Differences in stability can result in changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form containing a particular polymorph may fade more rapidly than a dosage form containing a different polymorph), mechanical changes (e.g., a kinetically favorable crystalline form may change to a thermodynamically more stable crystalline form, causing the tablet to disintegrate during storage), or both (e.g., a tablet containing one polymorph may be more susceptible to breakage at high humidity).

[0006] Differences in solubility between polymorphs can, in extreme circumstances, lead to a transition to a less potent crystalline form or to overexposure. In addition, the physical properties of the crystalline form can also be important in pharmaceutical processing. For example, certain crystalline forms may form solvates more readily than others, or they may be more difficult to filter and wash away impurities (i.e., particle shape and size distribution may differ between one crystalline form and others).

[0007] Since different physical forms offer different benefits, there is no single ideal physical form for any drug. Searching for the most stable form is difficult, and the results are unpredictable. Therefore, it is important to seek various intrinsic drug forms that can be used in various formulations, such as salts, polymorphs, and amorphous forms. Selecting a drug form for a specific formulation or therapeutic application requires considering various properties; the best form for a particular use may possess one particularly important desirable property, while other properties are acceptable or barely acceptable.

[0008] For a drug to be successful, it must meet certain general requirements that it may be a therapeutically effective treatment for patients. These requirements fall into two categories: (1) requirements for the successful manufacture of the dosage form, and (2) requirements for the successful delivery and placement of the drug formulation after it has been administered to the patient.

[0009] Different crystalline solid forms of the same compound often possess different solid properties, such as melting point, solubility, dissolution rate, hygroscopicity, powder flow, mechanical properties, chemical stability, and physical stability. These solid properties can offer advantages in filtration, drying, and dosage form manufacturing operations. Therefore, once various crystalline solid forms of the same compound are identified, the optimal crystalline solid form, and even the different solid properties of each crystalline solid form, can be determined under any given set of processing and manufacturing conditions.

[0010] Molecular polymorphs can be obtained by several methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, quenching, slow cooling, vapor diffusion, and sublimation. Polymorphs can be detected, identified, classified, and characterized using, but are not limited to, well-known techniques such as differential scanning thermal analysis (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, solid-state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, and hot-stage optical microscopy.

[0011] The present invention relates to the crystalline form of the anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. The present invention also relates to the crystalline form of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. The present invention also relates to a composition comprising a pharmaceutical composition containing either the anhydrous free base of Form 1 or the monohydrate of Form 2 of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. The present invention further relates to a process for preparing the anhydrous free base of Form 1 and the monohydrate of Form 2 of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] U.S. Patent No. 10,144,738 [Patent Document 2] U.S. Patent No. 4,485,045 [Patent Document 3] U.S. Patent No. 4,544,545 [Patent Document 4] U.S. Patent No. 5,013,556 [Patent Document 5] U.S. Patent No. 3,773,919 [Non-Patent Document]

[0013] [Non-Patent Document 1] B.C. Finnin and T.M. Morgan, J. Pharm. Sci., vol. 88, pp. 955 - 958, 1999 [Non-Patent Document 2] Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975 [Non-Patent Document 3] Edited by Liberman et al., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980 [Non-Patent Document 4] Edited by Kibbe et al., Handbook of Pharmaceutical Excipients (Third Edition), American Pharmaceutical Association, Washington, 1999 [Non-Patent Document 5] Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing (2000) [Summary of the Invention] [Problems to be Solved by the Invention]

[0014] For example, since drug formulations that exhibit enhanced biological availability or stability are consistently sought, new or more pure polymorphs of drug molecules are still needed. The anhydrous free base of Form 1 and the crystalline form of the monohydrate of Form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile described herein serve to meet these and other needs.

Means for Solving the Problems

[0015] The present invention provides a crystalline form of the anhydrous free base of Form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile.

[0016] In one aspect, the present invention is I) (a) 1, 2, 3, 4, 5, or more than 5 peaks selected from the group consisting of the peaks in Table 1 at °2θ ± 0.2°2θ; or (b) a powder X-ray powder diffraction pattern comprising peaks at 2θ values essentially the same as those shown in FIG. 1; II) (a) cm -1 ±2 cm -1 1, 2, 3, 4, 5 or more than 5 wavenumber (cm -1 ) values selected from the group consisting of the values in Table 5; (b) cm -1 ±2 cm -1 1, 2, 3, 4, 5, or more than 5 wavenumber (cm -1 ) values selected from the group consisting of the characteristic values in Table 5; or (c) a Raman spectrum comprising wavenumber (cm -1 ) values essentially the same as those shown in FIG. 4; III) (a) 1, 2, 3, 4, 5, or more than 5 resonance (ppm) values ​​selected from the group consisting of values ​​in Table 3 within ppm ± 0.2 ppm; (b) 1, 2, 3, 4, 5, or more than 5 resonance (ppm) values ​​selected from the group consisting of characteristic values ​​in Table 3 within ppm ± 0.2 ppm. 13 (c) Solid-state NMR spectrum (ppm); or (c) Resonance (ppm) values ​​essentially the same as those shown in Figure 3; and IV) Any two or three combinations of the embodiments described above (I)(a)-(b), (II)(a)-(c), or (III)(a)-(c) (provided they are not mutually exclusive). The crystalline form of an anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile has one or more characteristics selected from the group consisting of the above.

[0017] The present invention provides a crystalline form of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile.

[0018] In another embodiment, the present invention is I) (a) One, two, three, four, five, or more peaks selected from the group consisting of peaks in Table 2 at °2θ ± 0.2°2θ; or (b) a powder X-ray diffraction pattern containing peaks at essentially the same 2θ values ​​as shown in Figure 2; II) (a) cm -1 ±2cm -1 Then, one, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in Table 6. -1 ) value; (b) cm -1 ±2cm -1 Then, one, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of characteristic values ​​in Table 6. -1) value; or (c) essentially the same wavenumber (cm) as shown in Figure 6 -1 Raman spectrum including ) values; III) (a) 1, 2, 3, 4, 5, or more than 5 resonance (ppm) values ​​selected from the group consisting of values ​​in Table 4 within ppm ± 0.2 ppm; (b) 1, 2, 3, 4, 5, or more than 5 resonance (ppm) values ​​selected from the group consisting of characteristic values ​​in Table 4 within ppm ± 0.2 ppm. 13 (c) Solid-state NMR spectrum (ppm); or (c) Resonance (ppm) values ​​essentially the same as those shown in Figure 5; and IV) Any two or three combinations of the embodiments described above (I)(a)-(b), (II)(a)-(c), or (III)(a)-(c) (provided they are not mutually exclusive). The crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate has one or more characteristics selected from the group consisting of the above.

[0019] In another embodiment, the present invention also provides a pharmaceutical composition comprising a free anhydrous base of form 1 of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile and a pharmaceutically acceptable carrier.

[0020] In another embodiment, the present invention also provides a method for treating a disease in a mammal, comprising administering to a mammal in need a therapeutically effective amount of an anhydrous free base of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any embodiment described herein, wherein the disease is selected from rheumatoid arthritis, lupus, psoriasis, psoriatic arthritis, atopic dermatitis, and inflammatory bowel disease.

[0021] In another embodiment, the present invention also provides a pharmaceutical composition comprising a monohydrate of Form 2 of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile and a pharmaceutically acceptable carrier.

[0022] In another aspect, the present invention also provides a method for treating a disease in a mammal, comprising administering to a mammal in need a therapeutically effective amount of a crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any embodiment described herein, wherein the disease is selected from rheumatoid arthritis, lupus, psoriasis, psoriatic arthritis, atopic dermatitis, and inflammatory bowel disease. [Brief explanation of the drawing]

[0023] [Figure 1]This shows the powder X-ray diffraction pattern of the crystalline form of the anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitride. [Figure 2] This shows the powder X-ray diffraction pattern of the crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate form 2. [Figure 3] The solid-state 13C nuclear magnetic resonance spectrum of the crystalline form of the anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is shown. [Figure 4] The Raman spectrum of the crystalline form of the anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is shown. [Figure 5] The solid-state 13C nuclear magnetic resonance spectrum of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is shown. [Figure 6] The Raman spectrum of the crystalline form of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is shown. [Modes for carrying out the invention]

[0024] The present invention relates to crystalline forms of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, comprising an anhydrous free base of form 1 and a monohydrate of form 2. The present invention also relates to pharmaceutical compositions comprising each crystalline form and methods for preparing such forms. The present invention further relates to the use of the above crystalline forms in the treatment of various diseases.

[0025] Several analytical methods exist that can be used by those skilled in solid-state chemistry to analyze solid forms. As used herein, the term “analyze” means to obtain information about the solid structure of a solid form. For example, powder X-ray diffraction (PXRD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, as well as for characterizing and identifying the crystalline solid forms of compounds. Powder X-ray diffraction (PXRD) is also suitable for quantifying the amount of one (or more) crystalline solid forms in a mixture. In powder X-ray diffraction, X-rays are directed at a crystalline powder, and the intensity of the diffracted X-rays is measured as a function of the angle between the X-ray source and the beam diffracted by the sample. These diffracted X-ray intensities can be plotted as peaks on a graph, where the x-axis is the angle between the X-ray source and the diffracted X-rays (known as the “2θ” angle), and the y-axis is the intensity of the diffracted X-rays. This graph is called a powder X-ray diffraction pattern or powder pattern. Different crystalline solid forms exhibit different powder patterns, because the location of the peaks on the x-axis is intrinsic to the solid structure of the crystal.

[0026] Such powder patterns, or a portion thereof, can be used as identification fingerprints for crystalline solid forms. Therefore, a powder pattern of an unknown sample can be taken and compared to a reference powder pattern. A positive match would indicate that the unknown sample is in the same crystalline solid form as the reference. An unknown sample containing mixtures in solid form can also be analyzed by adding and subtracting powder patterns of known compounds.

[0027] When selecting peaks in a powder pattern to characterize a crystalline solid morphology, or when using a reference powder pattern to identify a morphology, one morphology may identify peaks or sets of peaks that are not present in other solid morphologies.

[0028] As used herein, the term “characterize” means selecting a suitable set of data that can distinguish one solid morphology from another. In powder X-ray diffraction, that set of data is the position of one or more peaks. Selecting which powder X-ray diffraction peaks define a particular morphology is said to be the act of characterizing that morphology.

[0029] As used herein, the term “identify” means selecting characteristic data for a solid morphology and using that data to determine whether that morphology is present in a sample. In powder X-ray diffraction, these data are the x-axis positions of one or more peaks that characterize the desired morphology, as discussed above. For example, once a selection of X-ray diffraction peaks is determined to characterize a particular solid morphology, those peaks can be used to determine whether that morphology is present in a sample.

[0030] When characterizing and / or identifying crystalline solid forms of the same chemical compound using powder X-ray diffraction, it is often unnecessary to use the entire powder pattern. Often, a smaller subset of the entire powder pattern is sufficient for characterization and / or identification. By selecting a set of peaks that distinguish a crystalline solid form of a compound from other crystalline solid forms, those peaks can be relied upon both for characterizing the form and for identifying it in, for example, an unknown mixture. Additional data, such as additional peaks from other analytical techniques or from the powder pattern, can be added to characterize and / or identify the form; for example, additional polymorphs should be identified later.

[0031] Due to differences in equipment, samples, and sample preparation, peak values ​​are sometimes reported with the modifier "approximately" preceding them. This is a common practice in solid-state chemistry due to inherent variations in peak values. The typical precision of the 2θx axis value of a peak in a powder pattern is approximately plus or minus 0.2°2θ. Therefore, a diffraction peak such as "approximately 9.2°2θ" means that, when measured with most X-ray diffractometers under most conditions, the peak could exist between 9.0°2θ and 9.4°2θ. The variability in peak intensity is a result of how individual crystals are oriented in the sample container relative to the external X-ray source (known as "preferred orientation"). This orientation does not provide structural information about the crystal.

[0032] Powder X-ray diffraction is just one of several analytical techniques that can be used to characterize and / or identify crystalline solid morphologies. Spectroscopic techniques such as Raman (including micro-Raman), infrared, and solid-state NMR spectroscopy can also be used to characterize and / or identify crystalline solid morphologies. These techniques can also be used to quantify the amount of one or more crystalline solid morphologies in a mixture, and peak values ​​can also be reported with the modifier "approximately" preceding the peak value. Typical variability of peak values ​​associated with FT-Raman and FT-Infrared measurements is plus or minus 2 cm. -1 It is to that extent. 13 C or 19 The typical variability of peak values ​​associated with the fluorine chemical shift is approximately plus or minus 0.2 ppm for crystalline materials. The typical variability of values ​​associated with the starting temperature of differential scanning thermal analysis is approximately plus or minus 5°C.

[0033] As used herein, the term "room temperature" refers to a temperature range of 20°C to 23°C.

[0034] In the first aspect, the present invention is I) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ; II) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 18.0°, 20.6°, 22.8° and 27.0°2θ ± 0.2°2θ; and III) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ The crystalline form of an anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile has one or more characteristics selected from the group consisting of the above.

[0035] Accordingly, the present invention provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile having a powder X-ray diffraction pattern with peaks at 20.6°, 22.8°, and 27.0°2θ±0.2°2θ. The present invention also provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile having a powder X-ray diffraction pattern with peaks at 18.0°, 20.6°, 22.8° and 27.0°2θ±0.2°2θ. The present invention further provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile having a powder X-ray diffraction pattern with peaks at 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ.

[0036] In addition, the present invention provides a pharmaceutical composition comprising a crystalline form of an anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile; and a pharmaceutically acceptable carrier.

[0037] In one particular embodiment, the present invention provides a pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline morphology includes peaks at 20.6°, 22.8°, and 27.0°2θ±0.2°2θ. In another embodiment, the present invention provides a pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline morphology includes peaks at 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ. In yet another embodiment, the present invention provides a pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline morphology includes peaks at 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ.

[0038] In a second aspect, the present invention is I) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 7.4°, 26.2°, 28.5°2θ ± 0.2°2θ; II) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 7.4°, 15.7°, 26.2°, 28.5°2θ ± 0.2°2θ; and III) Powder X-ray diffraction patterns including the following 2θ values ​​measured using Cu wavelength radiation: 7.4°, 10.4°, 15.7°, 26.2°, 28.5°2θ ± 0.2°2θ This includes a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate (form 2) having one or more characteristics selected from the group consisting of the above.

[0039] Accordingly, the present invention provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate having a powder X-ray diffraction pattern with peaks at 7.4°, 26.2°, and 28.5°2θ±0.2°2θ with respect to 2θ. The present invention also provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate having a powder X-ray diffraction pattern containing peaks at 7.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ. The present invention further provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate having a powder X-ray diffraction pattern containing peaks at 7.4°, 10.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ.

[0040] In addition, the present invention provides a pharmaceutical composition comprising the crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate and a pharmaceutically acceptable carrier. In certain embodiments, the present invention provides the pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline form has peaks at 7.4°, 26.2°, and 28.5°2θ±0.2°2θ. In other embodiments, the present invention provides the pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline form has peaks at 7.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ. In another embodiment, the present invention provides the pharmaceutical composition having a powder X-ray diffraction pattern in which the crystalline form includes peaks at 7.4°, 10.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ.

[0041] The present invention also provides a crystalline pharmaceutical composition according to any of the embodiments described herein, comprising a topical formulation selected from creams, transdermal patches, ointments, eye drops, lotions, and gels. In a particular embodiment, the present invention provides the pharmaceutical composition wherein the topical formulation contains about 0.1% to about 5.0% (w / v) of an anhydrous free base or monohydrate of form 1 or form 2 of crystalline (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile.

[0042] In addition, the present invention provides a method for treating a disease in a mammal, comprising administering to a mammal in need a therapeutically effective amount of a crystalline form of the anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis, and atopic dermatitis. In certain embodiments, the present invention provides the method wherein the crystalline form has a powder X-ray diffraction pattern with peaks at 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ. In certain other embodiments, the present invention provides the crystalline morphology having a powder X-ray diffraction pattern including peaks at 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ. In yet other certain embodiments, the present invention provides the crystalline morphology having a powder X-ray diffraction pattern including peaks with respect to 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ.

[0043] The present invention also provides a method for treating a disease in a mammal, comprising administering to a mammal in need a therapeutically effective amount of a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis, and atopic dermatitis. In certain embodiments, the present invention provides the method wherein the crystalline form has a powder X-ray diffraction pattern with peaks at 7.4°, 26.2°, and 28.5°2θ±0.2°2θ. In some other specific embodiments, the present invention provides the crystalline morphology having a powder X-ray diffraction pattern including peaks at 7.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ. In yet another specific embodiment, the present invention provides the crystalline morphology having a powder X-ray diffraction pattern including peaks with respect to 7.4°, 10.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ.

[0044] The present invention also provides a method for topically treating a disease in a mammal, comprising administering to a mammal in need, by topical administration, a therapeutically effective amount of the crystalline form of anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of vitiligo, alopecia, psoriasis, and atopic dermatitis. In certain embodiments, the present invention provides the method wherein the crystalline form has a powder X-ray diffraction pattern with peaks at 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ. In certain other embodiments, the present invention provides the method wherein the crystal morphology has a powder X-ray diffraction pattern having peaks at 18.0°, 20.6°, 22.8° and 27.0°2θ±0.2°2θ. In yet other certain embodiments, the present invention provides the method wherein the crystal morphology has a powder X-ray diffraction pattern having peaks with respect to 8.1°, 18.0°, 20.6°, 22.8° and 27.0°2θ±0.2°2θ.

[0045] The present invention also provides a method for topically treating a disease in a mammal, comprising administering to a mammal in need, by topical administration, a therapeutically effective amount of the crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile monohydrate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of vitiligo, alopecia, psoriasis, and atopic dermatitis. In certain embodiments, the present invention provides the method wherein the crystalline form has a powder X-ray diffraction pattern with peaks at 7.4°, 26.2°, and 28.5°2θ±0.2°2θ. In some other specific embodiments, the present invention provides the method wherein the crystal morphology has a powder X-ray diffraction pattern that includes peaks at 7.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ. In yet another specific embodiment, the present invention provides the method wherein the crystal morphology has a powder X-ray diffraction pattern that includes peaks at 7.4°, 10.4°, 15.7°, 26.2°, and 28.5°2θ±0.2°2θ.

[0046] Accordingly, the present invention provides pharmaceutical compositions comprising the crystalline forms disclosed herein, methods for preparing such forms, and further, pharmaceutical compositions for use in pharmaceuticals, as well as for use in the treatment of diseases such as lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis, psoriatic arthritis, and atopic dermatitis. The present invention also provides for the use of such pharmaceutical compositions in the manufacture of pharmaceuticals for the treatment of diseases such as lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis, and atopic dermatitis.

[0047] The present invention further provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitride prepared by recrystallizing an anhydrous free base of Form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitride prepared from a suitable solvent. The present invention further provides a crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitriel, prepared by recrystallizing the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitriel from a suitable solvent.

[0048] The present invention also provides a topical formulation of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, an anhydrous free base of form 1, or a monohydrate of form 2, prepared by combining its crystalline form with an excipient suitable for transdermal administration.

[0049] Methods of treating the diseases and syndromes listed herein are understood to involve administering a therapeutically effective amount of the polymorphs of the present invention, or compositions containing them, to an individual in need of such treatment. As used herein, the term “treating” when referring to a disease is intended to mean preventing, inhibiting, and / or relieving the disease.

[0050] As used herein, the terms “individual” or “patient” as used interchangeably refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, goats, horses, or primates, most preferably humans. As used herein, the term “therapeutic dose” means: (1) Prevention of disease; for example, prevention of disease, condition or disability in individuals who may be predisposed to disease, condition or disability but have not yet experienced or displayed the pathology or overall symptoms of that disease; (2) Inhibition of disease; for example, inhibition of disease, condition or disorder in an individual experiencing or displaying the pathology or overall symptoms of disease, condition or disorder (i.e., cessation or slowing of further progression of the pathology and / or overall symptoms); and (3) Remission of disease; for example, remission of disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or overall symptoms of a disease, condition or disorder (i.e., reversal of pathology and / or overall symptoms). This refers to the amount of an active compound or pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal, individual, or human, as requested by a researcher, veterinarian, physician, or other clinician, including one or more of the above.

[0051] Dosage and formulation of medication The present invention also includes pharmaceutical compositions that utilize one or more of these crystalline forms together with one or more pharmaceutically acceptable carriers, excipients, vehicles, etc.

[0052] The crystalline form of the present invention may be administered in an amount effective to treat the conditions described herein, either as the crystalline compound itself or, alternatively, as a pharmaceutically acceptable salt. For the purposes of administration and administration, the crystalline compound itself or a pharmaceutically acceptable salt thereof will simply be referred to as the compound of the present invention.

[0053] The compounds of the present invention are administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally, or topically.

[0054] The compound of the present invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used so that the compound enters the bloodstream directly from the mouth.

[0055] In another embodiment, the compounds of the present invention may also be administered directly into the bloodstream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and injection techniques.

[0056] In another embodiment, the compounds of the present invention may be administered topically to the skin or mucous membrane, i.e., by skin or transdermally. In another embodiment, the compounds of the present invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or transvaginally. In another embodiment, the compounds of the present invention may be administered directly to the eyes or ears.

[0057] The dosage regimen for the compounds of the present invention and / or compositions containing such compounds is based on various factors including the patient's type, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimen can vary widely. In one embodiment, the total daily dose of the compounds of the present invention is typically about 0.01 to about 100 mg / kg (i.e., mg of the compounds of the present invention per kg of body weight) for the treatment of the indications discussed herein. In another embodiment, the total daily dose of the compounds of the present invention is about 0.1 to about 50 mg / kg, and in yet another embodiment, about 0.5 to about 30 mg / kg.

[0058] For oral administration, the above composition can be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, and 500 milligrams of the active ingredient for symptomatic adjustment of the dosage for patients. The pharmaceutical product typically contains about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg of the active ingredient. Intravenously, the dose may range from about 0.01 to about 10 mg / kg / min during constant-rate infusion.

[0059] Suitable subjects according to the present invention include mammals. Mammals according to the present invention include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, etc., and include mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of any sex and at any developmental stage.

[0060] In another embodiment, the present invention comprises a pharmaceutical composition. Such a pharmaceutical composition comprises a compound of the present invention provided together with a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present. As used herein, “pharmaceutically acceptable carrier” includes all physiologically compatible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. Examples of pharmaceutically acceptable carriers include water, physiological saline, phosphate buffer solution, dextrose, glycerol, ethanol, and one or more combinations thereof, and isotonic agents, such as sugars, sodium chloride, or polyalcohols, such as mannitol or sorbitol, may be included in the composition. A pharmaceutically acceptable substance such as a wetting agent that enhances the shelf life or efficacy of the antibody or antibody moiety, or a small amount of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers.

[0061] The compositions of the present invention may exist in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., for injection and infusible solutions), dispersants or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic use.

[0062] Typical compositions are generally in the form of injectable and infusible liquid formulations, such as compositions similar to those used for passive immunization in humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0063] The oral administration in solid dosage form may also be provided in separate units such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in powder or granular form. In another embodiment, the oral administration form may be sublingual, such as lozenges. In such solid dosage forms, the crystalline compound is usually combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms may contain a buffer or may be prepared using an enteric coating.

[0064] In another embodiment, oral administration may be in liquid form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, liquids, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), and / or fragrances.

[0065] In another embodiment, the present invention includes parenteral administration forms. "Pareral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Preparations for injection (i.e., sterile aqueous or oily suspensions for injection) can be formulated according to known fields using appropriate dispersants, wetting agents, and / or suspending agents.

[0066] In another embodiment, the present invention includes topical administration forms. "Topical administration" includes, for example, transdermal administration via a transdermal patch or ion electrophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain crystalline compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the crystalline compounds of the present invention are administered via a transdermal device, administration is achieved using a patch of either a reservoir and porous membrane type or a solid matrix variant. Typical formulations for this purpose include gels, hydrogels, lotions, liquids, creams, ointments, sprays, bandages, foams, films, skin patches, cachets, implants, sponges, fibers, adhesive bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation enhancers can be incorporated—see, for example, BCFinnin and TMMorgan, J.Pharm.Sci., vol.88, pp. 955-958, 1999.

[0067] Accordingly, topical formulations of the crystalline form of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile of this disclosure can be administered using such preparations that encompass all conventional methods of administration by passing through the surface of the body and the inner layers of body passages, including epithelial and mucous membrane tissues, including transdermal, epidermal, buccal, pulmonary, ocular, intranasal, vaginal, and rectal administration modes. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Such topical formulations can be prepared in combination with additional pharmaceutically acceptable excipients. Excipients that may be essential for clinical efficacy are one or more permeabilisers, such as one or more saturated or cis-unsaturated C10-C18 aliphatic alcohols. Such aliphatic alcohols include C16-C18 aliphatic alcohols, most preferably C18 aliphatic alcohols. Examples of cis-unsaturated C16-C18 aliphatic alcohols include oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol, and linolenyl alcohol. Saturated C10-C18 aliphatic alcohols useful as permeabilisers include decyl alcohol, lauric alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol. Alternatively, other permeabilisers that can be used to prepare topical formulations include C10-C18 fatty acids, which in the case of saturation may include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and arachidic acid. Alternatively, the above-mentioned permeation enhancers may be effective cis-unsaturated fatty acids such as palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9-octadecenoic acid), cis-vaccenoic acid (cis-11-octadecenoic acid), linoleic acid (cis-9,12-octadecadienoic acid), γ-linolenic acid (cis-6,9,12-octadecatrienoic acid), linolenic acid (cis-9,12,15-octadecatrienoic acid), and arachidonic acid (cis-5,8,11,14-eicosatetraenoic acid).The above-mentioned permeation enhancer, for example, selected from C10 to C18 aliphatic alcohols, is used in an amount ranging from about 0.1 to about 5% (w / v), more preferably 1 to about 4%, and even more preferably 1 to about 3% (w / v).

[0068] The topical formulations contain (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile in a therapeutically effective dose that can be administered daily or twice daily to patients in need. These amounts range from about 0.1% to about 5.0% (w / v), more preferably from about 0.1% to about 3.0% (w / v). Other excipients that enhance the stability of these formulations include aldehyde scavengers such as glycerin and propylene glycol, as well as antioxidants such as butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, ascorbic acid (vitamin C), polyphenols, tocopherol (vitamin E), and their derivatives.

[0069] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present invention are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or ocular administration may be in the form of ultrafine-ground suspensions or solution drops in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and ocular administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, cachets, lenses, and particle or vesicle systems such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as geran gum, can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by ion electrophoresis.

[0070] For intranasal or inhalation administration, the crystalline compounds of the present invention are conveniently delivered in the form of a solution or suspension from a pump-type spray container squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder from a dry powder inhaler (either alone or as a mixture, e.g., a dry blend with lactose, or as mixed component particles, e.g., mixed with phospholipids such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or from a nebulizer with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, e.g., chitosan or cyclodextrin.

[0071] In another embodiment, the present invention includes a rectal administration form. Such a rectal administration form may be, for example, a suppository. Cocoa butter is a conventional suppository base, but various alternatives can be used if appropriate.

[0072] Other carrier substances and administration methods known in the pharmaceutical field may also be used. The pharmaceutical compositions of the present invention can be prepared by any well-known pharmacy technique, such as effective formulations and administration procedures. The above considerations regarding effective formulations and administration procedures are well-known in the art and are described in standard textbooks. Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Handbook of Pharmaceutical Excipients (Part III), American Pharmaceutical Association, Washington, 1999.

[0073] The crystalline compounds of the present invention can be used alone or in combination with other therapeutic agents. The present invention provides any use, method or composition as defined herein, of using the crystalline compounds herein, or pharmaceutically acceptable solvates thereof, in combination with one or more other therapeutic agents discussed herein.

[0074] The administration of two or more compounds in combination means that all of the above compounds are administered within a sufficiently close time interval for the presence of one compound to alter the biological effect of any of the other compounds. Two or more compounds can be administered in parallel, simultaneously, or sequentially. In addition, parallel administration can be achieved by mixing the above compounds before administration, or by administering the above compounds at the same or different administration sites, but at the same time, but in different dosage forms.

[0075] The terms "simultaneous administration," "co-administration," "parallel administration," and "administer in parallel" all refer to administering the above compounds in combination.

[0076] In another embodiment, the present invention provides a treatment method comprising administering the crystalline compound of the present invention in combination with one or more other pharmaceutical components, wherein the one or more other pharmaceutical components can be selected from the agents described herein.

[0077] These drugs and the crystalline compounds of the present invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer's solution, and dextrose solution. Specific administration plans, i.e., dosage, timing, and repetition, will depend on the individual and their medical history.

[0078] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosage and concentration used and include buffers such as phosphates, citrates, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); and low molecular weight (less than approximately 10 residues) polypeptides. It may contain proteins such as serum albumin, gelatin, or Ig; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0079] Liposomes containing these agents and / or compounds of the present invention are prepared by methods known in the art, such as those described in U.S. Patents 4,485,045 and 4,544,545. Liposomes with extended circulation time are disclosed in U.S. Patent 5,013,556. Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a specified pore size to obtain liposomes with a desired diameter.

[0080] These drugs and / or compounds of the present invention can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, using colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0081] Sustained-release preparations can be used. A suitable example of a sustained-release preparation comprises a semipermeable matrix of a solid hydrophobic polymer containing the antibody / compound of the present invention, the matrix being in the form of a molded article, e.g., a film, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate), or poly(vinyl alcohol)), polylactide (U.S. Patent No. 3,773,919), L-glutamic acid and 7-ethyl-L-glutamate copolymers, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOT (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyrate.

[0082] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The crystalline compounds of the present invention are generally placed in containers with a sterile access port, such as intravenous fluid bags or vials with a stopper that can be pierced by a subcutaneous injection needle.

[0083] Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid®, Liposyn®, Infonutrol®, Lipofandin®, and Lipipysan®. The above active ingredients can be dissolved in a pre-mixed emulsion composition, or alternatively, in an emulsion formed by mixing with oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or tonsil oil) and phospholipids (e.g., egg phospholipid, soybean phospholipid, or soybean lecithin) and water. It will be found that other components, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. A suitable emulsion should typically contain up to 20%, e.g., 5–20%, of oil. The fat emulsion may contain fat droplets of 0.1–1.0 μm, particularly 0.1–0.5 μm, and have a pH in the range of 5.5–8.0.

[0084] The compounds described in these instructions can be prepared by methods known in the art. The reagents used in the preparation of these compounds are commercially available or can be prepared by standard procedures described in the literature. For example, the compounds of the present invention can be prepared according to the methods illustrated in the following examples.

[0085] The present invention uses various abbreviations that are well known to those skilled in the art, including: aq.: water-based CH3CN: Acetonitrile DCM: Dichloromethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide æ:ethyl acetate EtOH: Ethanol FT-IR: Fourier Transform Infrared HOAc: Acetic acid MeOH: methanol PXRD: Powder X-ray diffraction ss 13 C NMR: Solid 13C nuclear magnetic resonance THF: Tetrahydrofuran TLC: Thin-layer chromatography [Examples]

[0086] The following non-limiting embodiments are provided solely to illustrate the present invention. Those skilled in the art will understand that there are numerous equivalents and variations that, though not illustrated, further form part of this teaching.

[0087] (Example 1) Preparation of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile form 2 monohydrate Recrystallization was carried out at 20-30°C by suspending Form 1 (20 g) of anhydrous (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile in THF (595 mL), methanol (70 mL), and water (35 mL). The mixture was heated under reflux for 30 minutes. The resulting solution was transferred to a preheated (65°C) container via a HALAR® filter and subsequently washed with a preheated THF-methanol-water (85-10-05% v / v / v) mixture (spec-free operation). The sample was stirred for 30 minutes, then the mixture was cooled to 5°C for 4.5 hours, and subsequently transferred to a filter dryer and washed with a cold (5°C) THF-water mixture at 95-05% v / v. The precipitate was dried at room temperature (under humidified conditions) until the THF residue was ≤0.02%, yielding Form 2 monohydrate as a white, fluid powder.

[0088] (Example 2) Preparation of Form 1 of the anhydrous free base (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile Recrystallization, 20-30℃ (1st round, 3rd round) The procedure was carried out by suspending Form 2 monohydrate (20 g) of -3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile in THF (595 mL), methanol (70 mL), and water (35 mL). The mixture was heated under reflux for 30 minutes. The resulting solution was transferred to a preheated (65°C) container via a HALAR® filter and subsequently washed with a preheated THF-methanol-water (85-10-05% v / v / v) mixture (outside of specifications). The sample was stirred for 30 minutes and then cooled back to 50°C. The sample was then distilled under partial vacuum, with the jacket temperature controlled between 50°C and 70°C. A final volume of approximately 15 mL / g was achieved by distillation. 15 mL / g of ethyl acetate (300 mL) was added to the sample. The sample was distilled again, and after distillation, the final volume was adjusted to 15 mL / g. The same procedure was repeated twice to obtain THF, methanol, and water (limit: THF and methanol at a concentration of 2% by weight or less, and water at a concentration of 0.5% by weight or less. The ) was removed. The sample was stirred for 30 minutes, then the mixture was cooled to 20°C for 4.5 hours, and then transferred to a filter dryer and washed with 3 mL / g of ethyl acetate. The precipitate was dried at 50°C until the ethyl acetate residue was ≤0.02%, to obtain anhydrous free base of form 1 as a white, fluid powder.

[0089] (Example 3) Preparation of Form 2 monohydrate of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile 4-Chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine (2.0 g, 8.6 mmol, 100% by mass) and (1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile (2.8 g, 9.0 mmol, 100% by mass) were combined in THF (22 mL) and water (24 mL) in the presence of sodium bicarbonate (1.40 g, 16.7 mmol, 100% by mass). The mixture was heated to 35°C for 5 minutes. In a separate container, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14 mg, 0.01744 mmol, 98% by mass) was charged, degassed with nitrogen, and then the catalyst was charged in THF. Next, the catalyst solution was added to the reaction mixture at 35°C, and then heated to 65°C for 2 hours. 1 mL of tetrahydrofuran 1,2-bis(diphenylphosphino)ethane (20 mg, 0.05020 mmol, 100% by mass) was added, and the reaction mixture was stirred at 65°C for 60 minutes. Next, the sample was cooled to 20°C and stirred for 90 minutes. The solid was filtered, and then the filtered cake was returned to the reactor and re-slurred in water. The slurry was transferred to a filter dryer and washed with water. The above solid was dried at room temperature (under humidified conditions) until the THF residue was ≤0.02%, to obtain the monohydrate of Form 2 as a white, fluid powder.

[0090] Instruments and analytical methods: Powder X-ray diffraction (PXRD) API PXRD patterns were collected using a Bruker D8 Endeavour powder X-ray diffractometer equipped with an automated sample changer, a theta-2 theta goniometer, and a Lynxeye XE-T detector with a 4.00° PSD window size. The primary motorized slit was set to 11.0 mm for continuous illumination, and the antiscattering slit was set to a constant distance of 2.20 mm. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data were collected at the Cu wavelength using a step size of 0.019 degrees and a scan time of 10 minutes scanning from 2.0 to 55.0 degrees 2θ. Samples were prepared by placing the powder in a Si low-background cavity holder. The sample powder was compressed using a glass slide to ensure that the appropriate sample height was achieved. Data were collected using Bruker DIFFRAC software, and analysis was performed using DIFFRAC EVA software. The collected PXRD patterns were imported into Bruker DIFFRAC EVA software. Peak selection was performed using the "peak search function" of the software mentioned above, and then carefully checked and corrected to ensure that all peak positions were accurately assigned. Peaks were classified between 2 and 32°²θ. A typical error of ±0.2°²θ in peak position applies to this data. Various factors, including (a) sample preparation (e.g., sample height), (b) instrument, (c) calibration, (d) operator (including errors present when determining peak locations), and (e.g., properties of the material (e.g., selective orientation and transparency errors), can introduce slight errors associated with this measurement. Therefore, the peaks are judged to have a typical associated error of ±0.2°²θ. If two peaks are judged to overlap in the list, the lower intensity peak is removed from the list. Peaks that exist as shoulders on adjacent peaks of higher intensity are also removed from the peak list. Shoulders may be >0.2°²θ from the position of adjacent peaks, but they are not judged to be distinguishable from adjacent peaks. To obtain absolute peak positions, the powder pattern should be aligned with a reference.This could be a simulated powder pattern from the same morphological crystal structure analyzed at room temperature, or an internal standard, such as silica or corundum. Simulated powder patterns of morphs 1 and 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitride were obtained from the single-crystal structure. The simulated powder patterns from the single-crystal structure were obtained via calculations using Mercury 4.1.0, which is part of the CCDC 5.40 Software Suite.

[0091] PXRD reflection assignment: The peak value was assigned to the maximum intensity of a given reflection. Figure 1 shows the PXRD profile of form 1 of (1R,3R)-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitriel in anhydrous free base. The peak list is included in Table 1. Several peaks were selected as characteristic peaks of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitriel in anhydrous free base. The PXRD profile for the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile is shown in Figure 2. The peak list is included in Table 2. Several peaks were selected as characteristic of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile.

[0092] [Table 1]

[0093] Five characteristic peaks located at 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°²θ are recommended as diagnostic peaks for the anhydrous form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile.

[0094] [Table 2]

[0095] Five characteristic peaks located at 7.4°, 10.4°, 15.7°, 26.2°, and 28.5°²θ are recommended as diagnostic peaks for the monohydrate of form 2.

[0096] Solid-state NMR: Solid-state NMR (ssNMR) analysis using Bruker-BioSpin Avance III (trademark) 500MHz. 1 The analysis was performed using a CPMAS probe mounted on a (H-frequency) NMR spectrometer. The material was packed into a 4 mm rotor sealed with a standard drive cap. A magic angle rotation speed of 15.0 kHz was used. During spectrum acquisition, a phase-modulated proton decoupling field of 80–90 kHz was applied. 13 C ssNMR spectra were collected using a proton decoupling cross-polarization magic angle rotation (CPMAS) experiment. The cross-polarization contact time was set to 3 ms and the recycle delay to 60 seconds. The number of scans was adjusted to obtain a suitable signal-to-noise ratio, with 768 scans collected for the API and an additional, typically ≥4096 scans, collected for the drug product. Crystalline adamantane was used as an external standard. 13 Using the C CPMAS experiment, with its upfield resonance set to 29.5 ppm, 13 The 1C chemical shift scale was used as the reference.

[0097] Automated peak picking was performed using Bruker-BioSpin TopSpin® version 3.5 software. Generally, a threshold of 5% relative intensity was used for preliminary peak selection. The output of automated peak picking was visually verified to ensure effectiveness, and manual adjustments were made as necessary. While specific solid-state NMR peak values ​​are reported herein, these values ​​may vary due to differences in instrumentation, sample, and sample preparation. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual settings of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

[0098] In the crystalline form (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, in its anhydrous form 1 and monohydrate form 2. 13 The 13C solid-state NMR peak lists are shown in Tables 3 and 4, respectively.

[0099] [Table 3]

[0100] Resonances at 131.4, 60.2, 143.5, 121.2, and 120.5 ppm are characteristic peaks for the anhydrous form 1.

[0101] [Table 4]

[0102] Resonances at 130.9, 120.8, 142.8, 40.0, and 61.8 ppm are characteristic peaks for the monohydrate of form 2.

[0103] FT-Raman spectroscopy Raman spectra were collected using a RAM II FT-Raman module mounted on a Vertex 70 FTIR spectrometer (Bruker Optik GmbH). The instrument was equipped with a 1064 nm solid-state (Nd:YAG) laser and a liquid nitrogen-cooled germanium detector. Prior to data acquisition, instrument performance and calibration were validated using a white light source and polystyrene and naphthalene references. The Raman spectral peaks for the above crystalline forms are shown in Table 2. Samples were prepared and analyzed in a shortened NMR tube. A sample rotation instrument (Ventacon, UK) was used during measurement to maximize the volume of material exposed to the laser during data acquisition. The backscattered Raman signal from the sample was optimized, and data were collected using a 500 mW laser output at 2 cm². -1 The spectra were collected by spectral analysis. A Blackmann-Harris 4-term apodization function was applied to minimize spectral aberrations. The spectra were analyzed using a tuned scan count of 3500–50 cm⁻¹. -1 The spectrum was generated between these parameters to ensure proper signal-to-noise ratio. The spectrum was normalized by setting the intensity of the maximum intensity peak to 2.00. The peaks were then identified using the automatic peak picking function of OPUS v8.2 software (Bruker Optik GmbH), with the sensitivity set to 2%. The peak positions and relative peak intensities were extracted and presented in a table. The variation in peak position in this experimental setup was ±2 cm. -1 Within this range. Since FT-Raman and dispersion-Raman are similar techniques, it is expected that the peak positions reported in this literature for FT-Raman spectra will coincide with those observed using dispersion-Raman measurements, assuming proper instrument calibration.

[0104] [Table 5]

[0105] 1498, 2923, 1246, 1443, and 2971 cm -1However, it was selected as a characteristic peak in the anhydrous form of morphology 1.

[0106] [Table 6-1]

[0107] [Table 6-2]

[0108] 1507, 3122, 2934, 1330 and 1255 cm -1 However, it was selected as a characteristic peak in the monohydrate of form 2.

[0109] Variations, modifications, and other embodiments of those described herein will be conceivable to those skilled in the art without departing from the spirit and essential features of this teaching. Therefore, the scope of this teaching should be defined not by the preceding illustrative descriptions, but rather by the following claims, and all variations falling within the meaning and scope of the equivalents of the claims are intended to be encompassed therein.

[0110] Any printed publication, including but not limited to patents, patent applications, books, technical manuals, trade publications, and journal articles, described or referenced herein is incorporated herein in whole for any purpose. Non-limitingly, the present invention includes the following embodiments. [Aspect 1] (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, crystalline form of anhydrous free base. [Aspect 2] The crystal morphology according to Embodiment 1, characterized by a powder X-ray diffraction pattern containing peaks at 20.6°, 22.8°, and 27.0°2θ±0.2°2θ with respect to 2θ. [Aspect 3] The crystal morphology according to Embodiment 1, characterized by a powder X-ray diffraction pattern containing peaks at 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ with respect to 2θ. [Aspect 4] The crystal morphology according to Embodiment 1, characterized by a powder X-ray diffraction pattern containing peaks at 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ±0.2°2θ with respect to 2θ. [Aspect 5] A crystalline form according to any one of embodiments 1 to 4, which is non-hygroscopic. [Aspect 6] A crystalline form according to any one of embodiments 1 to 5, which is substantially pure. [Aspect 7] Solids selected from the group consisting of 60.2, 131.4, and 143.5 ppm ± 0.2 ppm. 13 A crystalline form according to any one of embodiments 1 to 6, characterized by the 1C nuclear magnetic resonance chemical shift. [Aspect 8] 1246, 1498, and 2923 cm -1 ±2cm -1 A crystalline form according to any one of embodiments 1 to 7, characterized by a set of Raman bands located therein. [Aspect 9] Powder X-ray diffraction patterns with peaks at 20.6°, 22.8°, and 27.0°2θ±0.2°2θ, and solids selected from the group consisting of 60.2 and 131.4 ppm±0.2 ppm. 13 The crystal morphology described in Embodiment 1, characterized by the 1C nuclear magnetic resonance chemical shift. [Aspect 10] Regarding 2θ, the powder X-ray diffraction pattern includes peaks at 20.6°, 22.8°, and 27.0°2θ±0.2°2θ, as well as at 1498 cm⁻¹. -1 ±2cm -1 The crystal morphology described in embodiment 1, characterized by a set of Raman bands located therein. [Aspect 11] 1498cm -1 ±2cm -1Solids selected from the set of Raman bands located in the area, as well as from the group consisting of 60.2 and 131.4 ppm ± 0.2 ppm. 13 The crystal morphology described in Embodiment 1, characterized by the 1C nuclear magnetic resonance chemical shift. [Aspect 12] (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, crystalline form of monohydrate. [Aspect 13] The crystal morphology according to embodiment 12, characterized by a powder X-ray diffraction pattern containing peaks at 7.4°, 26.2°, and 28.5°2θ±0.2°2θ with respect to 2θ. [Aspect 14] A topical preparation of an anhydrous free base of form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, which is prepared by combining its crystalline form with an excipient suitable for transdermal administration. [Aspect 15] A topical preparation of the monohydrate of form 2 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile, which is prepared by combining its crystalline form with an excipient suitable for transdermal administration.

Claims

1. A method for preparing Form 1 of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile (Form 1 anhydrous free base), This method is Suspend 20 g of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile form 2 monohydrate in a mixture containing 595 mL of tetrahydrofuran (THF), 70 mL of methanol, and 35 mL of water at 20-30°C; The mixture is heated under reflux; The mixture is filtered into a container preheated to 65°C; The mixture is washed with a preheated solution containing THF, methanol, and water; The mixture is cooled to 50°C; The mixture is distilled at a temperature between 50°C and 70°C to obtain a distilled sample of approximately 15 mL / g; Ethyl acetate is added to the distilled sample, and the sample is distilled again, and the addition of ethyl acetate and distillation are repeated until the THF content is 2% by weight or less, and the methanol and water content is 0.5% by weight or less; The sample is cooled; Form 1 anhydrous free base is isolated from the sample by filtration, and hereafter, the Form 1 anhydrous free base may be washed with ethyl acetate; and, The anhydrous free base of the above form 1 is dried until the ethyl acetate residue is ≤0.02%. This includes, Herein, the anhydrous free base of form 1 is characterized by a powder X-ray diffraction pattern that includes peaks at 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ with respect to 2θ. The aforementioned method.

2. The anhydrous free base of the aforementioned form 1 is analyzed by powder X-ray diffraction, which shows peaks at 8.1°, 18.0°, 20.6°, 22.8°, and 27.0°2θ ± 0.2°2θ with respect to 2θ. The method according to claim 1, characterized as follows.

3. The method according to any one of claims 1 to 2, wherein the anhydrous free base of the above-mentioned form 1 is non-hygroscopic.

4. The anhydrous free base of the above-mentioned form 1 is a solid selected from the group consisting of 60.2 ppm, 131.4 ppm, and 143.5 ppm ± 0.2 ppm. １３ The method according to any one of claims 1 to 3, characterized by a 1C nuclear magnetic resonance chemical shift.

5. The anhydrous free base of the above-mentioned form 1 is 1246, 1498, and 2923 cm⁻¹. －１ ±2cm －１ The method according to any one of claims 1 to 4, characterized by a set of Raman bands present.

6. A method for preparing (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrile form 2 monohydrate (form 2 monohydrate), This method is Suspend 20 g of (1R,3R)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-yl)cyclobutan-1-carbonitrili anhydrous free base form 1 in a mixture containing 595 ml of tetrahydrofuran (THF), 70 ml of methanol, and 35 ml of water at 20-30°C; The mixture is heated under reflux; The mixture is filtered into a container preheated to 65°C; The mixture is washed with a preheated solution containing THF, methanol, and water; The mixture is cooled to 5°C; Form 2 monohydrate is isolated by filtration and washed with a THF-water mixture; and then, The above-mentioned Form 2 monohydrate is dried until the THF residue is ≤0.02%. This includes, Herein, the above-mentioned form 2 monohydrate is characterized by a powder X-ray diffraction pattern containing peaks at 7.4°, 26.2°, and 28.5°2θ ± 0.2°2θ with respect to 2θ. The aforementioned method.

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