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KR-102964463-B1 - Crystalline form of duxolitinib

KR102964463B1KR 102964463 B1KR102964463 B1KR 102964463B1KR-102964463-B1

Abstract

The present disclosure relates to polymorph form 1 of 1 H -pyrazole-1-propanitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5 -d 8 )-4-(7 H -pyrrolo[2,3- d ]pyrimidine-4-yl)-, (β R )-, phosphate (1:1) (duoxolitinib phosphate). Additionally, a therapeutic method using polymorph form 1 of duoxolitinib phosphate and a method for preparing polymorph form 1 of duoxolitinib phosphate are disclosed.

Inventors

  • 와이드먼, 션

Assignees

  • 썬 파마슈티칼 인더스트리즈 인코포레이티드

Dates

Publication Date
20260512
Application Date
20250205
Priority Date
20240510

Claims (20)

  1. Polymorphs of compounds of chemical formula I: Chemical Formula I The polymorph is form I; Form I is characterized by a powder X-ray diffraction pattern containing at least three peaks at an angle (°2θ) selected from 4.03°± 0.2°2θ, 14.54°± 0.2°2θ, 24.95°± 0.2°2θ, and 25.29°± 0.2°2θ.
  2. The polymorph according to claim 1, further characterized in that the polymorph has a powder X-ray diffraction pattern including peaks at angles (°2θ) of 4.03°± 0.2°2θ, 14.54°± 0.2°2θ, 24.95°± 0.2°2θ, and 25.29°± 0.2°2θ.
  3. The polymorph according to claim 2, the polymorph further features a powder X-ray diffraction pattern comprising one or more additional peaks at an angle (°2θ) selected from 14.77°± 0.2°2θ, 20.87°± 0.2°2θ, 21.76°± 0.2°2θ, and 26.36°± 0.2°2θ.
  4. The polymorph according to claim 2, the polymorph further features a powder X-ray diffraction pattern comprising at least two additional peaks at an angle (°2θ) selected from 14.77°± 0.2°2θ, 20.87°± 0.2°2θ, 21.76°± 0.2°2θ, and 26.36°± 0.2°2θ.
  5. The polymorph according to claim 2, the polymorph further features a powder X-ray diffraction pattern comprising at least three additional peaks at an angle (°2θ) selected from 14.77°± 0.2°2θ, 20.87°± 0.2°2θ, 21.76°± 0.2°2θ, and 26.36°± 0.2°2θ.
  6. The polymorph according to claim 2, further characterized by a powder X-ray diffraction pattern comprising four additional peaks at angles (°2θ) of 14.77°± 0.2°2θ, 20.87°± 0.2°2θ, 21.76°± 0.2°2θ, and 26.36°± 0.2°2θ.
  7. The polymorph according to claim 1, wherein the polymorph further features a powder X-ray diffraction pattern comprising at least one additional peak at an angle (°2θ) selected from 7.55°± 0.2°2θ, 8.36°± 0.2°2θ, 15.94°± 0.2°2θ, and 20.41°± 0.2°2θ.
  8. The polymorph according to claim 1, wherein the polymorph further features a powder X-ray diffraction pattern comprising at least two additional peaks at an angle (°2θ) selected from 7.55°± 0.2°2θ, 8.360°± 0.2°2θ, 15.940°± 0.2°2θ, and 20.41°± 0.2°2θ.
  9. The polymorph according to claim 1, wherein the polymorph further features a powder X-ray diffraction pattern comprising at least three additional peaks at an angle (°2θ) selected from 7.55°± 0.2°2θ, 8.360°± 0.2°2θ, 15.940°± 0.2°2θ, and 20.41°± 0.2°2θ.
  10. In claim 1, the polymorph is further characterized by a powder X-ray diffraction pattern as illustrated in FIG. 1. Fig. 1.
  11. In claim 1, the polymorph is a polymorph having one or more of (a), (b), and (c) additional features: (a) Differential scanning calorimetry (DSC) spectrum including endothermic onset at 194.3℃±1.0℃ and a peak at 197.4℃±1.0℃ (10℃/min); (b) Fourier transform (FT)-Raman spectrum as shown in Fig. 3: Fig. 3; and (c) Thermogravimetric-Fourier Transform Infrared (TG-FTIR) thermal analysis curve as shown in Fig. 4: Fig. 4.
  12. A polymorph according to claim 11, further characterized by at least 90% deuterium incorporation at each specified deuteriumated position as determined by 1 H-NMR.
  13. A polymorph according to claim 11, further characterized by at least 95% deuterium incorporation at each specified deuteriumated position as determined by 1 H-NMR.
  14. A pharmaceutical composition comprising the polymorph of claim 1 and a pharmaceutically acceptable carrier, for treating a disease, pathological condition, or disorder selected from the group consisting of: Psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancer, dermatitis, herpetic dermatitis, dermatomyositis, vitiligo, contact dermatitis, xerosis, ichthyosis, suppurative hidradenitis, urticaria, lichen planus, prurigo nodosum, vasculitis, subacute cutaneous lupus erythematosus (CLE), chronic idiopathic pruritus, polycythemia vera, essential thrombocytopenia, myelofibrosis, asthma, chronic obstructive pulmonary disease, chronic lung allograft dysfunction, bronchiolitis obliterans syndrome, pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, cottonpractice, pneumoconiosis, bronchiectasis, hypersensitivity pneumoconiosis, lung cancer, mesothelioma and sarcoidosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease, myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, Dry eye syndrome, keratitis, iritis, lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes, ankylosing spondylitis, psoriatic arthritis, acute and/or chronic graft-versus-host disease, and alopecia areata.
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Description

Crystalline form of duxolitinib The present disclosure relates to polymorph form 1 of 1 H -pyrazole-1-propanitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5 -d 8 )-4-(7 H -pyrrolo[2,3- d ]pyrimidine-4-yl)-, (β R )-, phosphate (1:1) (duoxolitinib phosphate). Additionally, a therapeutic method using polymorph form 1 of duoxolitinib phosphate and a method for preparing polymorph form 1 of duoxolitinib phosphate are disclosed. Duruxolitinib phosphate, known by the chemical name 1H -pyrazole-1-propanitrile, 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 a Janus kinase (JAK) inhibitor. U.S. Patent No. 10,561,659 reports the use of duuxolitinib phosphate for the treatment of hair loss disorders. PCT publications WO2020163653 and WO/2022/036030 report the manufacturing process of duuxolitinib. Often, a given activator may exist in an amorphous form or as a mixture of amorphous and crystalline forms. Polymorphic forms may exist in some activators. Polymorphic forms may occur when the activator crystallizes into a specific lattice arrangement. In some cases, the activator may 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. The present disclosure relates to a polymorph of 1 H -pyrazole-1-propanitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5 -d 8 )-4-(7 H -pyrrolo[2,3- d ]pyrimidine-4-yl)-, (β R )-, phosphate (1:1), wherein the polymorph is form 1 comprising a powder X-ray diffraction pattern (XPRD) comprising three or more peaks expressed at a 2θ angle selected from 4.03 ± 0.2, 14.54 ± 0.2, 24.95 ± 0.2, and 25.29 ± 0.2 degrees. In some embodiments, XPRD includes peaks represented by 2θ angles at 4.03± 0.2 degrees, 14.54± 0.2 degrees, 24.95± 0.2 degrees, and 25.29± 0.2 degrees, respectively. In some embodiments, the XPRD of polymorph form 1 further comprises at least one additional peak represented by a 2θ angle selected from 14.77, 20.87, 21.76, and 26.36. In some embodiments, the XPRD further comprises at least two additional peaks represented by a 2θ angle 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 comprises at least three additional peaks represented by a 2θ angle selected from 14.77±0.2, 20.87±0.2, 21.76±0.2, and 26.36±0.2. In some embodiments, XPRD further includes at least four additional peaks represented by 2θ angles at 14.77± 0.2, 20.87± 0.2, 21.76± 0.2, and 26.36± 0.2, respectively. In some embodiments, the XPRD of polymorph form 1 further comprises at least one additional peak represented by a 2θ angle 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 comprises at least two additional peaks represented by a 2θ angle 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 comprises at least three additional peaks represented by a 2θ angle selected from 7.55± 0.2, 8.36± 0.2, 15.94± 0.2, and 20.41± 0.2. In some embodiments, polymorphic form 1 substantially has an XRPD pattern as illustrated in FIG. 1. In some embodiments, polymorph form 1 further features one or more of (a) a DSC spectrum including endothermic onset at 194.3 ± 1.0°C and a peak at 197.4 ± 1.0°C (10°C/min); (b) an FT-Raman spectrum substantially as shown in FIG. 3; and (c) a TG-FTIR thermal analysis curve substantially as shown in FIG. 4. In some embodiments, polymorph form 1 has at least 90% deuterium incorporation at each specified deuteriumized position as determined by 1H-NMR. In some embodiments, polymorph form 1 has at least 95% deuterium incorporation at each specified deuteriumized position as determined by 1H-NMR. In some embodiments, polymorph form 1 is substantially free of 1H -pyrazole-1-propanitrile, β-(cyclopentyl-2,2,3,3,4,4,5,5 -d8 ) -4-( 7H -pyrrolo[2,3- d ]pyrimidine-4-yl)-, ( βS )-, phosphate (1:1) when determined by 1H-NMR. In some embodiments, polymorph form 1 is substantially free of amorphous 1H -pyrazole-1-propanitrile, 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 some embodiments, polymorph form 1 is substantially anhydrous. In some embodiments, the polymorph is substantially crystalline. In some embodiments, the present disclosure provides a pharmaceutical composition comprising polymorph form 1 described herein and a pharmaceutically acceptable carrier. In some embodiments, the ratio of the amount of polymorph form 1 to the sum of the amounts of other polymorph forms in the pharmaceutical composition is at least 90:10 (wt/wt). In some embodiments, the ratio of the amount of polymorph form 1 to the sum of the amounts of other polymorph forms in the pharmaceutical composition is at least 95:5. In some embodiments, the ratio of the amount of polymorph form 1 to the sum of the amounts of other polym