Crystalline form of durkisolitinib

Abstract

This disclosure relates to polymorph 1 of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1)(durxolitinibrinate). Also disclosed are a treatment method using polymorph 1 of durxolitinibrinate and a method for producing polymorph 1 of durxolitinibrinate.

Description

Technical Field

[0001] The present disclosure relates to polymorphic form 1 of 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-, (βR)-, phosphate (1:1) (duxolitinib phosphate). Also disclosed are methods of treatment using polymorphic form 1 of duxolitinib phosphate, and methods of making polymorphic form 1 of duxolitinib phosphate.

Background Art

[0002] Duxolitinib phosphate, known by the chemical name 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-, -(βR)-, -phosphate (1:1), is a Janus kinase (JAK) inhibitor. U.S. Patent No. 10,561,659 reports the use of duxolitinib phosphate for the treatment of hair loss disorders. PCT Publications WO2020163653 and WO / 2022 / 036030 report processes for the preparation of duxolitinib.

[0003] In many cases, a given active agent can exist in an amorphous form or as a mixture of an amorphous form and a crystalline form. Polymorphic forms can be present in some active agents. Polymorphic forms can occur when the active agent crystallizes in a particular lattice arrangement. In some examples, an active agent can form two or more different polymorphic forms. In some embodiments, each polymorphic form results in different thermodynamic properties, stability properties, pharmacokinetic properties, or other desirable properties.

Summary of the Invention

[0004] This disclosure relates to a polymorph of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1), wherein the polymorph comprises a powder X-ray diffraction pattern (XPRD) comprising three or more peaks represented by 2θ degrees selected from 4.03±0.2°, 14.54±0.2°, 24.95±0.2°, and 25.29±0.2°. In some embodiments, the XPRD comprises peaks represented by 2θ degrees at 4.03±0.2°, 14.54±0.2°, 24.95±0.2°, and 25.29±0.2°, respectively.

[0005] In some embodiments, the XPRD of polymorphism 1 includes at least one additional peak represented by 2θ degrees selected from 14.77, 20.87, 21.76, and 26.36. In some embodiments, the XPRD further includes at least two additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, the XPRD further includes at least three additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, the XPRD further includes at least four additional peaks represented by 2θ degrees at each of 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2.

[0006] In some embodiments, the XPRD of polymorphism 1 further includes at least one additional peak represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, the XPRD further includes at least two additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, the XPRD further includes at least three additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2.

[0007] In some embodiments, polymorph 1 has an XRPD pattern substantially as shown in Figure 1.

[0008] In some embodiments, polymorphism 1 is further characterized by (a) a DSC spectrum (10°C / min) including an endothermic onset at 194.3±1.0°C and a peak at 197.4±1.0°C, (b) an FT-Raman spectrum substantially shown in Figure 3, and (c) a TG-FTIR thermogram substantially as shown in Figure 4.

[0009] In some embodiments, Polymorphic form 1 is 1 It has at least 90% deuterium incorporation at each of the designated deuteration positions, as determined by 1H-NMR. In some embodiments, polymorph 1 is 1 Each of the designated deuteration sites, as determined by 1H-NMR, has at least 95% deuterium incorporated.

[0010] In some embodiments, polymorph 1 is substantially free of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βS)-,phosphate (1:1) as determined by 1H-NMR. In some embodiments, polymorph 1 is substantially free of amorphous 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1).

[0011] In some embodiments, polymorph 1 is substantially anhydrous. In some embodiments, the polymorph is substantially crystalline.

[0012] In some embodiments, the Disclosure provides a pharmaceutical composition comprising polymorph 1 as described herein and a pharmaceutically acceptable carrier. In some embodiments, the ratio of the amount of polymorph 1 to the sum of the amounts of other polymorphs in the pharmaceutical composition is at least 90:10 (wt / wt). In some embodiments, the ratio of the amount of polymorph 1 to the sum of the amounts of other polymorphs in the pharmaceutical composition is at least 95:5. In some embodiments, the ratio of the amount of polymorph 1 to the sum of the amounts of other polymorphs in the pharmaceutical composition is at least 99:1.

[0013] In some embodiments, the Disclosure provides a method for treating in a patient a disease, disorder, or condition mediated alone or partially by Janus-related kinase (JAK), the method comprising administering to the patient a polymorph of Form 1 described herein, or a pharmaceutical composition comprising Polymorph 1 described herein.

[0014] In some embodiments, the Disclosure provides a method for preparing polymorph 1 as described herein, comprising (i) forming a slurry of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1) in isopropanol or an isopropanol / water mixture, and (ii) isolating form 1 of durkisolitinibrinate from the slurry, for example, by filtration. In some embodiments, the slurry is formed in the isopropanol / water mixture in a ratio of about 80:20 to about 99:1, or about 80:20 to about 98:2. In some embodiments, the slurry is formed in the isopropanol / water mixture in a ratio of about 90:10. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows the normalized X-ray powder diffraction (XRPD) of morph 1 of durkosolitinibrinate (1:1). [Figure 2] Figure 2 shows a differential scanning calorimetry (DSC) thermogram of form 1 of durkosolitinibrinate (1:1). [Figure 3] Figure 3 shows the FT-Raman spectrum of form 1 of durkisolitinibrinate (1:1). [Figure 4] Figure 4 shows the TG-FTIR thermogram of form 1 of durkosolitinibrinate (1:1). [Modes for carrying out the invention]

[0016] This disclosure relates to a polymorph of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1)(durxolitinibulinate), a method for producing durkisolitinibulinate, a pharmaceutical composition comprising durkisolitinibulinate, and the use of durkisolitinibulinate for treating, preventing or improving a disease or condition, including administering the polymorph of the present invention.

[0017] The term 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1) can be represented by the compound of formula I.

[0018] [ka] 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1) is also referred herein interchangeably to durkisolitinibrinate and durkisolitinibrinate (1:1). Those skilled in the art will understand that for each position shown in Formula I as deuterium (i.e., D), deuterium does not have to be incorporated into 100% of the position and will still fall within the scope of the term durkisolitinibrinate. In some embodiments, the term “durxosolitinibrinate” means a population of durkisolitinibrinate molecules, for example, given a preparation of durkisolitinibrinate, where at least 90% of each designated deuterated position contains deuterium, or 1As determined by 1H-NMR, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of each designated deuterated position refers to a material containing deuterium.

[0019] In some embodiments, the present disclosure relates to 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-,(βR)-, phosphate form 1. "1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-,(βR)-, phosphate" can be used interchangeably with the terms "form 1 of 1H-pyrazole-1-propanenitrile", β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-,(βR)-, phosphate (1:1)), "form 1 of duruxolitinib phosphate", "form 1 of duruxolitinib phosphate (1;1)", "duruxolitinib phosphate form 1", "duruxolitinib phosphate polymorphic form 1" and "form 1 polymorph" in this specification.

[0020] When the term "1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-,(βR)-, phosphate" or "duruxolitinib phosphate" is used without specifying a crystalline form, this term refers to a compound in crystalline, amorphous, or any other form, or a combination of forms.

[0021] The various polymorphic forms of a given compound, e.g., duloxetine phosphate, can have different properties such as solubility, dissolution rate, stability of the suspension, stability during milling, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration performance, drying, density, melting point, decomposition stability, stability to prevent phase change to other forms, color, and even chemical reactivity. More importantly, in some embodiments, the various forms of low molecular weight compounds such as duloxetine phosphate can change their dissolution, dissolution performance, pharmacokinetics, and bioavailability, which can, in some cases, affect the efficacy and safety performance of the compound.

[0022] In particular, in some embodiments, the crystalline form of duloxetine phosphate, e.g., duloxetine phosphate Form 1, affects its dissolution and absorption in vivo, thereby potentially affecting its clinical therapeutic effect and safety to some extent. In some embodiments, the crystalline form of duloxetine phosphate can be important for drug substance control. The present disclosure relates to duloxetine phosphate Form 1 and its compositions and kits, methods for manufacturing duloxetine phosphate Form 1, and methods for treating, preventing, or ameliorating a disease, disorder, or condition by administering a therapeutically effective amount of duloxetine phosphate Form 1.

[0023] The present disclosure provides a novel polymorphic form of duloxetine phosphate, Form 1. In some embodiments, duloxetine phosphate Form 1 is an anhydrous, non-solvated crystalline form. This application describes the chemical and physical characteristics of this polymorphic form and discloses methods for manufacturing this polymorphic form.

[0024] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have meanings generally understood by those skilled in the art. Furthermore, unless otherwise required by context, singular terms shall include plural forms, and plural terms shall include singular forms. As used herein, “a” or “an” may mean one or more. As used herein, when used in conjunction with the term “including,” the term “a” or “an” may mean one or more. As used herein, “another” or “further” may mean at least two or more.

[0025] Throughout this application, the term “approximately” is used to indicate that a value includes the inherent variation of error in the method / apparatus used to determine the variation present between values ​​or the test subject. Typically, the term “approximately” means, depending on the context, to include variability less than approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0026] The use of the term “or” in the claims is used to mean “and / or” unless it is expressly indicated to refer only to substitutes or the substitutes are mutually exclusive, however this disclosure supports the definitions that refer only to substitutes and “and / or”.

[0027] Where used herein, the terms “comprising” (and any variant or form of “comprising,” e.g., “comprise” and “comprises”), “having” (and any variant or form of “having,” e.g., “have” and “has”), or “containing” (and any variant or form of “containing,” e.g., “contains” and “contain”) are comprehensive or open-ended and do not exclude additional, undescribed elements or method steps. Any embodiment considered herein is intended to be implementable with respect to the polymorphs, methods, and / or kits of the Disclosure. Furthermore, the methods of the Disclosure can be achieved using the polymorphs, and / or kits of the Disclosure.

[0028] The term “for example” and its corresponding abbreviation “for example” (whether italicized or not) mean that the specific terms listed are representative examples and embodiments of this disclosure, and are not intended to be limited to the specific examples referenced or cited unless otherwise expressly stated.

[0029] As used herein, “between” refers to a range that includes the end of the range. For example, the numbers between x and y explicitly include the numbers x and y, as well as any numbers that fall within x and y.

[0030] As used herein, the term “room temperature” generally refers to a range of 4°C to 30°C, 18°C ​​to 22°C, 19°C to 21°C, or 20±5°C.

[0031] Embodiment 1 can be described by one or more solid-state analysis methods, for example, by its powder X-ray diffraction pattern, differential scanning calorimetry (DSC), FT-Raman spectroscopy, and / or thermogravimetric analysis.

[0032] In some embodiments, Embodiment 1 can be determined by its X-ray diffraction pattern (XRPD) measured by 2θ. For characteristic diffraction peaks represented by the 2θ(2q) angle, the term "approximately" means that the listed values ​​vary by 0.2° or less, for example, by approximately X°. This means X ± 0.2°, preferably X ± 0.1°. Therefore, in some embodiments, any of the 2q angles listed herein can be ±0.1.

[0033] This disclosure provides durkisolitinibulinate form 1. In some embodiments, durkisolitinibulinate form 1 includes a powder X-ray diffraction pattern (XPRD) containing three or more peaks represented by 2θ degrees selected from 4.03±0.2°, 14.54±0.2°, 24.95±0.2°, and 25.29±0.2°.

[0034] In some embodiments, durkisolitinib durkisolitinibrate form 1 includes peaks at least 4.03±0.2, 14.54±0.2, and 24.95±0.2 2θ degrees. In some embodiments, durkisolitinibrate form 1 includes peaks at least 4.03±0.2, 14.54±0.2, and 25.29±0.2 2θ degrees. In some embodiments, durkisolitinibrate form 1 includes peaks at least 4.03±0.2, 24.95±0.2, and 25.29±0.2 2θ degrees. In some embodiments, durkisolitinibrate form 1 includes peaks at least 14.54±0.2, 24.95±0.2, and 25.29±0.2 2θ degrees. In some embodiments, durkisolitinibrinate form 1 includes peaks represented by 2θ degrees at 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, respectively.

[0035] In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least one additional peak represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least two additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least three additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least four additional peaks represented by 2θ degrees at 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2, respectively.

[0036] In some embodiments, durkisolitinibrinate polymorph I further includes at least one additional peak represented by a 2θ degree selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, durkisolitinibrinate polymorph I further includes at least two additional peaks represented by a 2θ degree selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, durkisolitinibrinate polymorph I further includes at least three additional peaks represented by a 2θ degree selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, the durkisolitinibrinate polymorph I further includes four additional peaks, represented at 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2, which are expressed at 2θ degrees.

[0037] In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least two additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2. In some embodiments, durkisolitinibrinate polymorph I includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, and further includes at least three additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.2.

[0038] In some embodiments, durkisolitinibrinate polymorph I includes a peak represented by 2θ degrees, such as (i) Table 2, column A, (ii) Table 2, columns A and B, or (iii) one or more peaks from Table 2, columns A and B, and column C, for example, one of one, two, three, or four peaks from column C.

[0039] [Table 1-1] [Table 1-2] [Table 1-3]

[0040] In some embodiments, durkisolitinibrinate polymorph I has an X-ray diffraction pattern substantially as shown in Figure 1.

[0041] In some embodiments, durkisolitinibrinate form 1 can be determined by differential scanning calorimetry (DSC) by determining the endothermic onset and peak of the polymorph. In some embodiments, the DSC spectrum can be determined at various rates, e.g., 2°C / min to 10°C / min, 4°C / min to 6°C / min, or 5°C / min. In some embodiments, the DSC spectrum can be determined at rates, e.g., 5°C / min to 30°C / min, 8°C / min to 15°C / min, or 10°C / min. In some embodiments, the DSC spectrum can be determined at rates, e.g., 30°C / min to 70°C / min, 40°C / min to 60°C / min, or 50°C / min.

[0042] In some embodiments, any of the DSC endothermic onset temperature and / or peak temperatures described herein may be ±1.0°C. In some embodiments, any of the enumerated DSC endothermic onset temperature and / or peak temperatures may be ±0.5°C, ±0.2°C, or ±0.1°C. For example, when durkisolitinibulinate form 1 is described as having a DSC spectrum exhibiting an endothermic onset at 194.3 ± 1.0°C and a peak at approximately 197.4°C at a rate of 10°C / min. In some embodiments, durkisolitinibulinate form 1 is described as having a DSC spectrum including an endothermic peak at 197.4 ± 1.0°C, 197.4 ± 0.5°C, 197.4 ± 0.2°C, 197.4 ± 0.1°C, or 197.4°C, when determined at a rate of 10°C / min.

[0043] In some embodiments, durkisolitinibulinate form 1 is characterized by a DSC spectrum (10°C / min) containing endothermic peaks at approximately 190.0±1.0°C to approximately 200.0±1.0°C, approximately 195.0±1.0°C to approximately 200.0±1.0°C, approximately 196.0±1.0°C to approximately 198.0±1.0°C, or approximately 197.0±1.0°C to approximately 198.0±1.0°C. In some embodiments, durkisolitinibulinate form 1 is characterized by a DSC spectrum (10°C / min) containing an endothermic peak at 197.4±1.0°C.

[0044] In some embodiments, durkisolitinibrinate form 1 is characterized by an FT-Raman spectrum having four or more, five or more, six or more, or seven or more peaks from the following wavenumbers (cm-1): 1624, 1604, 1562, 1545, 1496, 1472, 1440, 1399, 1388, 1350, 1303, 1284, 1245, 1229, 1220, 1211, 1187, 1162, 1146, 1122, 1067, 1025, 980, 948, 931, 915, 817, 798, 753, 695, 675, 653, 594, 516, 416, 383, 364, 330, 280, 252, 221, 198, and 172. In some embodiments, durkisolitinibrinate form 1 is characterized by an FT-Raman spectrum as shown in Figure 3.

[0045] In some embodiments, durkisolitinibulinate form 1 is characterized by thermogravimetric (TG) analysis. In some embodiments, TG analysis is combined with spectroscopic methods such as Fourier transform infrared (FT-IR) spectroscopy, i.e., TG-FTIR. In some embodiments, durkisolitinibulinate form 1 is characterized by a TG-FTIR spectrum as shown in Figure 4.

[0046] In some embodiments, the durksolitinibrinate form 1 described herein is 1 At least 90% of deuterium is incorporated into each of the designated deuteration sites, as determined by H-NMR, for example, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of deuterium.

[0047] In some embodiments, the durkisolitinib phosphate form 1 described herein is substantially free of the (S) enantiomer of durkisolitiniburate. Thus, in some embodiments, the durkisolitiniburate form 1 contains less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% (mol / mol) of the (S) enantiomer of durkisolitiniburate. In some embodiments, the durkisolitiniburate form 1 is substantially free of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βS)-,phosphate (1:1) as determined by 1H-NMR.

[0048] In some embodiments, durkisolitinibulinate form 1 is substantially free of amorphous 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1). Therefore, in some embodiments, durkisolitinibulinate form 1 contains less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% (wt / wt) of amorphous durkisolitinibulinate.

[0049] In some embodiments, durkisolitinibulinate form 1 is substantially free of durkisolitinibulinate of any other polymorphic form. Thus, in some embodiments, durkisolitinibulinate form 1 contains less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% (wt / wt) of durkisolitinibulinate of any other polymorphic form. In some embodiments, the ratio of the amount of polymorph of form 1 to the sum of the amounts of other polymorphic forms is at least 90:10 (wt / wt). In some embodiments, the ratio of the amount of polymorph of form 1 to the sum of the amounts of other polymorphic forms is at least 95:5 (wt / wt). In some embodiments, the ratio of the amount of polymorph of form 1 to the sum of the amounts of other polymorphic forms is at least 99:1 (wt / wt). In some embodiments, the ratio of the amount of polymorph 1 to the sum of the amounts of other polymorphs is at least 99.5:0.5(wt / wt). In some embodiments, the ratio of the amount of polymorph 1 to the sum of the amounts of other polymorphs is at least 99.9:0.1(wt / wt). In some embodiments, other polymorphs are not detected using standard techniques.

[0050] In some embodiments, durkisolitinibulinate form 1 is stable, i.e., the polymorph does not transform into another polymorph (or amorphous form) for a certain period of time when stored at room temperature. In some embodiments, durkisolitinibulinate form 1 is stable for at least one week, at least one month, at least three months, at least six months, at least nine months, or at least one year when stored at room temperature. In some embodiments, stability is measured by any method known to those skilled in the art, e.g., XRPD, DSC, FT-Raman spectroscopy and / or thermogravimetric analysis. In some embodiments, stability can be measured by observing the XPRD spectrum at T=0 and T=X, where X is the period of stability, and the polymorph is considered stable if, as determined by the polymorph determination method, e.g., XPRD, DSC, FT-Raman spectroscopy and / or thermogravimetric analysis, it does not substantially change over time, e.g., produces a spectrum. In some embodiments, stability is measured using XPRD.

[0051] In some embodiments, durkisolitinibulinate form 1 is substantially anhydrous. Therefore, in some embodiments, when measured by Karl Fischer coulometry (USP 921), the water content of durkisolitinibulinate form 1 is less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.08%, or less than 0.06% (wt / wt). In some embodiments, the presence and amount of water are measured by TGA and / or proton NMR analysis. In some embodiments, durkisolitinibulinate form 1 is substantially free of any solvent, for example, any solvent is less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% (wt / wt). In some embodiments, the presence and amount of solvent are measured by TGA and / or proton NMR analysis. In some embodiments, the polymorphs are substantially crystalline.

[0052] In some embodiments, durkisolitinibrinate form 1 contains cadmium (Cd) at concentrations of 10 ppm or less, 5 ppm or less, 2 ppm or less, or 1 ppm or less.

[0053] In some embodiments, durkisolitinibrinate form 1 contains 10 ppm or less of lead (Pb), 5 ppm or less of Pb, 2 ppm or less of Pb, or 1 ppm or less of Pb.

[0054] In some embodiments, durkisolitinibrinate form 1 contains 10 ppm or less of arsenic (As), 5 ppm or less of As, 2 ppm or less of As, or 1 ppm or less of As.

[0055] In some embodiments, durkisolitinibrinate form 1 contains 10 ppm or less of mercury (Hg), 5 ppm or less of Hg, 2 ppm or less of Hg, or 1 ppm or less of Hg.

[0056] In some embodiments, durkisolitinibrinate form 1 contains 10 ppm or less of cobalt (Co), 5 ppm or less of Co, 2 ppm or less of Co, or 1 ppm or less of Co.

[0057] In some embodiments, durkisolitinibrinate form 1 contains vanadium (V) at a concentration of 10 ppm or less, V at a concentration of 5 ppm or less, V at a concentration of 2 ppm or less, or V at a concentration of 1 ppm or less.

[0058] In some embodiments, durkisolitinibrinate form 1 contains 10 ppm or less of nickel (Ni), 5 ppm or less of Ni, or 2 ppm or less of Ni.

[0059] In some embodiments, durkisolitinibrinate form 1 contains rhodium (Ro) at a concentration of 250 ppm or less, 200 ppm or less, 100 ppm or less, or 50 ppm or less.

[0060] In some embodiments, durkisolitinibrinate form 1 is substantially enantiomerically pure. In some embodiments, durkisolitinibrinate form 1 contains 0.80% or less of the S-enantiomer as measured by HPLC. In some embodiments, durkisolitinibrinate form 1 contains 0.70%, 0.60%, 0.50%, 0.40%, or 0.30% or less of the S-enantiomer as measured by HPLC.

[0061] In some embodiments, durkisolitinibrinate form 1 is substantially free of 4-(1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, i.e., less than 0.20% w / w (as measured by HPLC). In some embodiments, durkisolitinibrinate form 1 contains less than 0.10% or 0.05% w / w of 4-(1H-pyrazole-4-yl)-7H-pyrrolo[2,3-d]pyrimidine as measured by HPLC.

[0062] In some embodiments, durkisolitinibulinate form 1 is substantially free of impurities as measured by HPLC. In some embodiments, durkisolitinibulinate form 1 contains 2.0% or less, 1.0% or less, or 0.5% or less (w / w) total impurities as measured by HPLC.

[0063] In some embodiments, durkisolitinibulinate form 1 is suitable for use in pharmaceutical compositions. In some embodiments, the present disclosure provides pharmaceutical compositions comprising durkisolitinibulinate form 1 and a pharmaceutically acceptable carrier. In some embodiments, the term “pharmaceutically acceptable” means a substance suitable for use in humans and / or animals that does not have excessive adverse side effects (such as toxicity, irritation, and allergies), i.e., has a reasonable benefit / risk ratio.

[0064] In some embodiments, the Disclosure provides unit dosage forms comprising durkosolitinibulinate Form 1, together with a pharmaceutically acceptable carrier or diluent, in amounts ranging from about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) in free base equivalents. In certain embodiments, the amount of durkosolitinibulinate Form 1 is about 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of durkosolitinibulinate Form 1 is 4 mg, 8 mg, 12 mg, or 16 mg (free base equivalent). In certain embodiments, the amount of durkosolitinibulinate Form 1 is 5.3 mg. In certain embodiments, the amount of durkosolitinibulinate Form 1 is 10.5 or 10.6 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 is 15.8 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 is 21.1 mg. In certain embodiments, the unit dosage form is a tablet or a capsule.

[0065] In some embodiments, the pharmaceutical compositions described herein may include other therapeutic agents.

[0066] In some embodiments, the pharmaceutical compositions of the Disclosure are formulated for parenteral administration, including being formulated for oral, intravenous, topical, or transdermal administration. In some embodiments, the pharmaceutical compositions of the Disclosure are formulated for oral delivery. In some embodiments, the pharmaceutical compositions comprising durkosolitinibulinate Form 1 described herein are formulated in the form of pills, tablets, capsules, syrups, lozenges, or liquid formulations. Formulations of pills, tablets, and hard gelatin capsules may include additional excipients known to those skilled in the art.

[0067] In some embodiments, the pharmaceutical compositions comprising durkosolitinibrinate form 1 described herein are dosage forms suitable for the treatment of diseases, disorders, or conditions.

[0068] In some embodiments, the Disclosure provides methods for treating diseases, disorders, or conditions mediated alone or partially by Janus-related kinases (JAKs). In one embodiment, the Disclosure includes administering an effective amount of durkosolitinibulinate form 1 to a subject requiring treatment.

[0069] The term “a disease, disorder, or condition mediated alone or partially by Janus-related kinase (JAK)” refers to a disease, condition, or disorder that can be treated with compounds that modulate the activity of Janus-related kinase 1 (JAK1) and / or Janus-related kinase 2 (JAK2). These diseases, conditions, or disorders include skin diseases such as psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, herpetiform dermatitis, dermatomyositis, vitiligo, alopecia, contact dermatitis, xerosis, ichthyosis, hidradenitis suppurativa, urticaria, lichen planus, prurigo nodosa, vasculitis, cutaneous lupus erythematosus (CLE), and proliferative, autoimmune, and / or inflammatory skin diseases, as well as hyperproliferative disorders or cancers, including polycythemia vera, essential thrombocytopenia, and myelofibrosis, and asthma, chronic obstructive pulmonary disease, chronic transplant lung failure (e.g., bronchiolitis obliterans), pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, cotomatosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, and lung cancer. Examples of autoimmune diseases and conditions for which immunosuppression would be desirable to treat or prevent acute and / or chronic graft-versus-host diseases (e.g., graft-versus-host diseases in organ transplantation) include, but are not limited to, respiratory diseases such as mesothelioma and sarcoidosis, gastrointestinal diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, and cancer, eye diseases such as myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, and iritis, and systemic conditions such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, type 1 diabetes and diabetic complications, cancer, ankylosing spondylitis, and psoriatic arthritis, as well as other autoimmune diseases and conditions for which immunosuppression would be desirable to treat or prevent acute and / or chronic graft-versus-host diseases (e.g., graft-versus-host diseases in organ transplantation). In certain embodiments, diseases or conditions mediated alone or partially by Janus-associated kinase (JAK) include alopecia, such as alopecia areata.

[0070] In certain embodiments, durkosolitinibulinate form 1 is administered in amounts ranging from about 2 mg to about 48 mg (free base equivalent) per day. In certain embodiments, durkosolitinibulinate form 1 is administered in amounts ranging from about 8 mg to about 32 mg (free base equivalent) per day. In certain embodiments, durkosolitinibulinate form 1 is administered in amounts of about 8 mg / day, about 12 mg / day, about 16 mg / day, about 24 mg / day, or about 32 mg / day (free base equivalent). In some embodiments, durkosolitinibulinate form 1 is administered with a pharmaceutically acceptable carrier or diluent in amounts ranging from about 4 mg to about 50 mg (e.g., about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg) in free base equivalent. In certain embodiments, the amount of durkosolitinibulinate form 1 administered per day is approximately 4 mg, 8 mg, 16 mg, 24 mg, 32 mg, or 48 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 administered at one time is 4 mg, 8 mg, 12 mg, or 16 mg (free base equivalent). In certain embodiments, the amount of durkosolitinibulinate form 1 administered per day is 5.3 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 administered per day is 10.5 or 10.6 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 administered per day is 15.8 mg. In certain embodiments, the amount of durkosolitinibulinate form 1 administered per day is 21.1 mg. In certain embodiments, durkosolitinibrinate form 1 is administered in a unit dose form, for example, an oral unit dose in the form of a tablet or capsule.

[0071] In some embodiments, the disclosure provides a method for preparing durkisolitinibrinate form 1. In some embodiments, the method includes forming a slurry of durkisolitinibrinate using a solvent, for example, a C2-C4 alcohol, or a mixture of two solvents, for example, a C2-C4 alcohol and a cosolvent, for example, water. In some embodiments, the C2-C4 alcohol is ethanol, propanol, or isopropanol. In some embodiments, the method includes forming a slurry of durkisolitinibrinate using isopropanol and water. In some embodiments, the method includes forming a slurry of durkisolitinibrinate using isopropanol. In some embodiments, the method includes forming a slurry of durkisolitinibrinate using ethanol.

[0072] In some embodiments, the slurry is formed in an isopropanol / water mixture in a ratio of approximately 10:90 to approximately 90:10, approximately 30:70 to approximately 70:30, or approximately 50:50. In some embodiments, the slurry is formed in an isopropanol / water mixture in a ratio of approximately 80:20 to approximately 98:2, approximately 85:15 to approximately 95:5, approximately 88:12 to approximately 92:8, or approximately 90:10. In some embodiments, the slurry is formed in an isopropanol / water mixture in a ratio of approximately 90:10. In some embodiments, the slurry is formed at a temperature of approximately 5°C to approximately 30°C, or approximately 15°C to approximately 25°C. In some embodiments, the slurry is mixed for approximately 10 minutes to approximately 24 hours, approximately 20 minutes to approximately 12 hours, or approximately 1 hour to approximately 6 hours.

[0073] In some embodiments, a slurry is formed, and the solvent is isopropanol. In some embodiments where the solvent is isopropanol, the slurry is formed at temperatures of about 20°C to about 90°C, about 50°C to about 75°C, or about 70°C.

[0074] In some embodiments, a slurry is formed, and the solvent is ethanol. In some embodiments where the solvent is ethanol, the slurry is formed at temperatures of about 20°C to about 90°C, about 50°C to about 75°C, or about 70°C. In some embodiments, the pH is adjusted to about 3 to about 7, or about 4 to about 5.

[0075] In some embodiments, durkisolitinibulinate is dissolved in a solvent at 20°C to 70°C to form a solution. In some embodiments, this may be referred to as the “dissolution temperature”. In some embodiments, durkisolitinibulinate is dissolved in a solvent at 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C to 70°C to form a solution. In some embodiments, durkisolitinibulinate is dissolved in a solvent at 25°C to 30°C, 30°C to 35°C, 35°C to 40°C, 40°C to 45°C, or 45°C to 50°C, 50°C to 60°C, 60°C to 70°C, or 70°C to 80°C to form a solution.

[0076] In some embodiments, the amount of durkisolitinibrinate dissolved in the solution is less than 10% (wt / vol), less than 5% (wt / vol), less than 4% (wt / vol), or less than 3% (wt / vol) of the solvent. In some embodiments, the concentration of durkisolitinibrinate is below the saturation point of a given solvent and temperature. For example, if the saturation point of durkisolitinibrinate at a given solvent and temperature is "X mg / mL", the concentration of durkisolitinibrinate is less than "X mg / mL", for example, less than 20%, less than 50%, or less than 80%.

[0077] In some embodiments, the durkisolitinibulinate dissolved in the solvent is dissolved in the solvent to form a solution, which is then cooled to the incubation temperature. In some embodiments, the incubation temperature is maintained for a "certain period of time". In some embodiments, the period is more than 1 hour, more than 2 hours, more than 3 hours, more than 4 hours, more than 5 hours, more than 6 hours, more than 8 hours, more than 10 hours, more than 12 hours, more than 15 hours, more than 20 hours, more than 24 hours, more than 2 days, or more than 3 days. In some embodiments, the incubation temperature period is about 1 hour to about 48 hours, about 2 hours to about 36 hours, about 3 hours to about 24 hours, about 4 hours to about 20 hours, or about 6 hours to about 18 hours. In some embodiments, the incubation temperature is about 1°C to about 10°C for a certain period of time. In some embodiments, the incubation temperature is about 2°C to about 8°C, about 3°C ​​to about 7°C, or about 4°C to about 6°C for a certain period of time.

[0078] In some embodiments, durkisolitinibrinate is mixed with a solvent to form a slurry, which is mixed for about 2 to 12 hours, about 3 to 8 hours, or about 4 to 7 hours. In some embodiments, the slurry is mixed for more than 4 hours, more than 5 hours, or more than 6 hours.

[0079] In some embodiments, the temperature change from the dissolution temperature to the incubation temperature can be performed over a defined period, i.e., over a given rate of change or temperature over a given time. In some embodiments, the cooling from the dissolution temperature to the incubation temperature is at a rate of about 0.02°C / min to about 1°C / min until the incubation temperature is reached. In some embodiments, the cooling to the incubation temperature is at a rate of about 0.05°C / min to about 0.5°C / min until the incubation temperature is reached. In some embodiments, the cooling to the incubation temperature is at a rate of about 0.1°C / min to about 0.3°C / min until the incubation temperature is reached.

[0080] In some embodiments, the incubation temperature is maintained for a certain period, after which the solvent is removed and the durkisolitinibrine salt is crystallized. In some embodiments, the crystallization process can be initiated using a seed crystal or other initiating composition. In some embodiments, the solvent is removed and polymorphs are formed over a specific time, i.e., the removal time. Those skilled in the art will understand that as the concentration of the solvent decreases, the concentration of durkisolitinibrine salt increases until the crystallization process begins. Those skilled in the art will also understand that many factors, such as the amount of solvent removed, the type of solvent removed, temperature, pressure, etc., can affect the solvent removal time.

[0081] In some embodiments, the particle morphology in the slurry, i.e., the particles, can be isolated immediately after mixing is complete without requiring an incubation period.

[0082] In some embodiments, the solvent is removed by evaporation. Those skilled in the art will understand that the evaporation rate is determined by many factors, including but not limited to the identity of the solvent, temperature, and pressure. In some embodiments, evaporation is carried out at the incubation temperature. In some embodiments, the evaporation temperature may change over time, for example. In some embodiments, the evaporation temperature is constant. In some embodiments, evaporation is carried out at a temperature higher than the incubation temperature. In some embodiments, evaporation is carried out at temperatures above 5°C, above 10°C, above 15°C, above 20°C, above 25°C, or above 30°C. In some embodiments, evaporation is carried out between 5°C and 40°C, 10°C and 35°C, and 15°C and 30°C. In some embodiments, evaporation is carried out between approximately 20°C and approximately 35°C. In some embodiments, if two or more solvents are present, the evaporation temperature may be maintained at a first temperature until the first solvent evaporates, and then changed to a second temperature. In some embodiments, evaporation may be carried out at a variety of temperatures. In some embodiments, evaporation is carried out at 1 atmosphere. In some embodiments, evaporation is carried out at less than 1 atmosphere.

[0083] In some embodiments, solvent removal is carried out by filtration. For example, in some embodiments, the solvent is removed using a membrane or a semipermeable membrane. In some embodiments, when a semipermeable membrane is used, the solvent is replaced with various solvents, where durkisolitinipurine forms crystals in the various solvents. In some embodiments, the filter has a pore size of less than 50 μm, less than 30 μm, or less than 25 μm. In some embodiments, the filter has a pore size of 22 μm. Various filters are known in the art. In some embodiments, filter I is nonreactive with polymorphs. In some embodiments, the filter is a hydrophobic filter. In some embodiments, the filter is a polytetrafluoroethylene (PTFE) filter, for example, a PTFE filter having a pore size of 22 μm.

[0084] In some embodiments, the solvent is removed by freeze-drying.

[0085] In some embodiments, durkisolitinibrinate form 1 is isolated from the slurry by filtration. In some embodiments, the present disclosure provides a process for the preparation of durkisolitinibrinate form 1 as described herein, the method comprising (i) forming a slurry of 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1) in isopropanol or an isopropanol / water mixture, and (ii) isolating durkisolitinibrinate form 1 from the slurry by filtration. [Examples]

[0086] Synthesis of 1H-pyrazole-1-propanenitrile,β-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1) Form 1. A) 49.3 mg of durkosolitinibrinate was added to 2.0 ml of 2-propanol-water 9:1 solution, and the mixture was stirred at 600 rpm for approximately 3 days at ambient temperature to obtain a suspension. The suspension was then filtered (0.22 μm, PTFE) to obtain a white polycrystalline powder, which matched Form 1 by XRPD.

[0087] B) 55.9 mg of durkosolitinibulinate was added to 3.0 ml of 2-propanol to obtain a suspension, which was stirred at 70°C and 600 rpm for 6 days. The suspension was then filtered (0.22 μm, PTFE) to obtain a white polycrystalline powder, which was consistent with Form 1 by XRPD.

[0088] C) To a solution of 100.6 mg of durkosolitinib as a free base in 1.0 ml of EtOH, 15.2 μl (0.5 equivalents) of phosphoric acid (85% aqueous solution) was added with vigorous stirring. A very thick slurry precipitate formed within a few seconds. An additional 1.0 ml of EtOH was added to maintain the slurry in a fluid state. After stirring the slurry at ambient temperature for a further 2 days, the solid was isolated by centrifugation and filtration and dried in a vacuum oven at ambient temperature. The pH of the mother liquor was measured to be 4.66. Analysis of the obtained solid by XRPD and Raman showed it to be consistent with morphology 1.

[0089] D) Step 1: The solution of wet durkisolitinibrinate in isopropanol was transferred to the reactor through a cartridge filter and stirred at 20-25°C for 5 minutes before IPC analysis was performed to measure the concentration of durkisolitinibrinate. The concentration was adjusted to more than 70 mg / ml and less than 100 mg / ml by concentrating under vacuum at 84°C or below, or by adding isopropanol. The mixture was heated to 60-65°C and a portion of the "isopropanol acidic solution of wet durkisolitinibrinate" was added according to the following formula.

[0090] Formula I: kg (85%) of added H3PO4 = [Total weight of "measured solution of wet durkisolitinibrinate in isopropanol" × concentration of durkisolitinibrinate / 100] × 0.39.

[0091] Equation II: Amount of "moist durkisolitinibrinate isopropanol acid solution" loaded = (Total weight of "moist durkisolitinibrinate isopropanol acid solution" / Amount of H3PO4 (85%) loaded for the preparation of "moist durkisolitinibrinate isopropanol acid solution" × Result of Equation I).

[0092] Procedure 2: The wet product was dried under vacuum at 45°C for 16 hours. The dried product was discharged from the dryer and sieved through a 1.0 mm sieve to obtain durkosolitinibulinate form 1.

[0093] Next, the particles obtained from Examples A), B), C), and / or D) were subjected to XPRD, thermal analysis, FT-RAMAN, and TG-FTIR as described below, and they were consistent with durkisolitinibrinate form 1.

[0094] XRPD X-ray powder diffraction (XRPD) data were obtained using a Stoe Stadi P with a Mythen 1K detector, Cu-Kα1 radiation, standard measurement conditions: transmission, 40kV and 40mA tube output, curved Ge monochromator, 0.02°²θ step size, 48-second step time, 1.5–50.5°²θ scan range, detector mode: step scan, and 1°²θ detector step. Samples (10–20 mg of powder) were measured between two acetate or Kapton foils. No special treatment was used in sample preparation, except for applying slight pressure to disperse the powder on the irradiated surface area. Ambient air was used for all measurements, and each sample was rotated during measurement.

[0095] Using the above conditions, the 2θ peak value and the intensity of durkisolitinibrinate form 1 (Example D) were measured, as shown in Table 3.

[0096] [Table 2]

[0097] Figure 1 shows the complete XPRD of durkisolitinibrinate form 1.

[0098] thermal analysis Differential scanning calorimetry (DSC) thermograms of particles were recorded using a TA Instruments Q2000 instrument. Sealed (airtight) gold or aluminum sample pans were filled with the sample under ambient conditions. Measurements were performed at a heating rate of 10°C / min. The melting point is understood as the peak value.

[0099] As shown in Figure 2, the DSC of durxolitinibrinate form 1 was measured to be 197.4 ± 1.0°C.

[0100] FT Raman FT-Raman spectra were recorded using a Bruker MultiRAM FT-Raman system equipped with a near-infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. Resolution: 2 cm -1 64 scans were performed at 3500~-50cm -1 Although it accumulated within the range, the filter cutoff effect reduced it to 100cm. -1 Only data exceeding a certain threshold is evaluated. The nominal laser power is typically 100 or 300 mW.

[0101] The FT-Raman spectrum of durkisolitinibrinate form 1 is shown in Figure 3.

[0102] TG-FTIR Thermogravimetric analysis was performed using a Netzsch Thermo-Microbalance TG209 connected to a Bruker FT-IR spectrometer Vector 22. The sample was placed in an aluminum sample pan with a pinhole or sealed gold pan, under an N2 atmosphere, and heated at a rate of 10°C / min.

[0103] The TG-FTIR spectrum of durkisolitinibrinate form 1 is shown in Figure 4.

Claims

1. 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d ８ A polymorph of )-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1), wherein the polymorph is a polymorph of form 1 having a powder X-ray diffraction pattern (XPRD) that includes three or more peaks represented by 2θ degrees selected from 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees.

2. The polymorph according to claim 1, wherein the XPRD includes peaks represented by 2θ degrees at 4.03±0.2, 14.54±0.2, 24.95±0.2, and 25.29±0.2 degrees, respectively.

3. The polymorph according to claim 2, wherein the XPRD further comprises at least one additional peak represented by 2θ degrees selected from 14.77, 20.87, 21.76, and 26.

36.

4. The polymorph according to claim 2, wherein the XPRD further comprises at least two additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.

2.

5. The polymorph according to claim 2, wherein the XPRD further comprises at least three additional peaks represented by 2θ degrees selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.

2.

6. The polymorph according to claim 2, wherein the XPRD further comprises at least four additional peaks represented by 2θ degrees at 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2, respectively.

7. The polymorph according to any one of claims 1 to 6, wherein the XPRD further comprises at least one additional peak represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.

2.

8. The polymorph according to any one of claims 1 to 6, wherein the XPRD further comprises at least two additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.

2.

8. The polymorph according to any one of claims 1 to 6, wherein the XPRD further comprises at least three additional peaks represented by 2θ degrees selected from 7.55±0.2, 8.36±0.2, 15.94±0.2, and 20.41±0.

2.

10. The polymorph according to claim 1, wherein the polymorph substantially has an XRPD pattern as shown in Figure 1.

11. a. DSC spectrum (10°C / min) including endothermic onset at 194.3±1.0°C and a peak at 197.4±1.0°C. b. The FT Raman spectrum shown in Figure 3, and c. A polymorph according to any one of claims 1 to 10, further characterized substantially by one or more TG-FTIR thermograms shown in Figure 4.

11. １ The polymorph according to any one of claims 1 to 10, comprising at least 90% deuterium incorporation at each of the designated deuteration sites as determined by 1H-NMR.

12. １ The polymorph according to claim 11, comprising at least 95% deuterium incorporation at each of the designated deuteration sites determined by 1H-NMR.

13. １ Determined by 1H-NMR, 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d ８ A polymorph according to any one of claims 1 to 12, substantially free of )-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βS)-,phosphate (1:1).

14. Amorphous 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d ８ A polymorph according to any one of claims 1 to 13, substantially free of )-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1).

15. A polymorph according to any one of claims 1 to 14, which is substantially anhydrous.

16. A polymorph according to any one of claims 1 to 15, which is substantially crystalline.

17. A pharmaceutical composition comprising a polymorph according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. The composition according to claim 17, wherein the ratio of the amount of polymorph of form 1 to the sum of the amounts of the other polymorphs is at least 90:10 (wt / wt).

19. The composition according to claim 17, wherein the ratio of the amount of polymorph of form 1 to the sum of the amounts of the other polymorphs is at least 95:

5.

20. The composition according to claim 17, wherein the ratio of the amount of polymorph of form 1 to the sum of the amounts of the other polymorphs is at least 99:

1.

21. A method for treating a disease, disorder, or condition in a patient that is mediated alone or partially by Janus-related kinase (JAK), comprising administering to the patient a polymorph according to any one of claims 1 to 16, or a pharmaceutical composition according to any one of claims 17 to 20.

22. (i) 1H-pyrazole-1-propanenitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5-d in isopropanol or an isopropanol / water mixture ８ A method for preparing the polymorph according to any one of claims 1 to 16, comprising (ii) forming a slurry of )-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-,(βR)-,phosphate (1:1), and (ii) isolating form 1 of durkisolitinibrinate from the slurry by filtration.

23. The method according to claim 22, wherein the slurry is formed in an isopropanol / water mixture in a ratio of about 80:20 to about 98:

2.

23. The method according to claim 22, wherein the slurry is formed in an isopropanol / water mixture in a ratio of about 90:10.

Images