Crystal forms of a peptide inhibitor of interleukin-23 receptor

Abstract

The present disclosure relates to crystalline forms of a peptide inhibitor of the interleukin-23 receptor, corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation diseases and related disorders.

Description

CRYSTAL FORMS OF A PEPTIDE INHIBITOR OF INTERLEUKIN-23 RECEPTORCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 627,444, filed January 31 , 2024, which is incorporated herein by reference in its entiretyFIELD

[0002] The present invention relates to peptide inhibitors of the interleukin-23 receptor (IL- 23R) corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation diseases and related disorders.Background

[0003] The interleukin-23 (IL-23) cytokine is a heterodimer composed of an unique pl 9 subunit and the p40 subunit shared with IL- 12, which is a cytokine involved in the development of interferon-y (IFN-y)-producing T helper 1 (THI) cells. Although IL-23 and IL- 12 both contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL- 12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant to these diseases, presumably due to a reduced number of CD4+T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12RP1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-Stat signaling molecules Jak2, Tyk2, Statl, Stat3, Stat4, and Stat5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL- 12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL- 12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0004] IL-23 has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBDs revealed a primary role of interleukin-23 receptor (IL-23R) and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells including Thl7 cells, y5 T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expressionand protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 mediates this effect by promoting the development of a pathogenic CD4+T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).

[0005] As discussed in WO 2021 / 146441 and US 2021 / 0261622, the disclosures of which are incorporated herein by reference in their entireties, the following peptide is a potent inhibitor of IL-23R:

[0006] This peptide is referred to herein as the compound of Formula (I).

[0007] The ongoing need to treat and prevent IL-23 and / or IL-23R associated diseases, especially those associated with autoimmune inflammation (e.g., inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease (CD), psoriasis, or psoriatic arthritis) coupled with the potent activity of the compound of Formula (I) demonstrates that there is a need for novel crystalline forms as well as methods of making the same. The crystalline forms disclosed herein meet this and other needs.Brief Summary

[0008] The present disclosure provides, inter alia, crystalline forms of a compound of Formula(I) having the structure:

[0009] The present disclosure provides crystalline forms of a compound of Formula (I) having the structure:wherein the crystalline form is Form (A) or Form (B).

[0010] In some embodiments, the crystalline form is characterized as having an XRPD pattern which has been designated as compound of Formula (I), Form A.

[0011] In some embodiments, the crystalline form is characterized as having an XRPD pattern which has been designated as compound of Formula (I), Form B.

[0012] In some embodiments, the crystalline form is characterized as having an XRPD pattern which has been designated as compound of Formula (I), Form A, characterized as having an X- ray powder diffraction (XRPD) pattern comprising peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20.

[0013] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20.

[0014] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound ofFormula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 26 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.2° 20.

[0015] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 26 ± 0.2° 26. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 26 ± 0.2° 26.

[0016] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 26 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 26 ± 0.2° 26. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 26 ± 0.2° 26. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 26 ± 0.2° 26.

[0017] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°,10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20.

[0018] In some embodiments, the compound of compound of Formula (I) designated as Form A is a free base.

[0019] In some embodiments, the crystalline form designated as compound of Form A is characterized as having a XRPD pattern substantially as shown in FIG. 1.

[0020] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an endotherm peak at about 75.78 °C, as determined by differential scanning calorimetry (DSC). In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an endotherm peak at about 75.8 °C, as determined by differential scanning calorimetry (DSC). In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having an endotherm peak at about 211.56 °C, as determined by DSC. In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having a DSC thermogram substantially as shown in FIG. 2.

[0021] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having a weight loss of about 10.9% from about 25 °C to about 150 °C, as determined by thermogravimetric analysis (TGA). In some embodiments, the crystalline form designated as Form A is characterized as having a TGA thermogram substantially as shown in FIG. 3.

[0022] In some embodiments, the crystalline form designated as compound of Formula (I), Form A is characterized as having a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4.

[0023] In some embodiments, the crystalline form is characterized as having an XRPD pattern which has been designated as compound of Formula (I), Form B, characterized as having an X- ray powder diffraction (XRPD) pattern comprising peaks at 7.4°, 9.8°, 11.4°, and 16.6° 20 ± 0.2° 20.

[0024] In some embodiments, the crystalline form designated as compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.4°, 7.9°, 9.8°, 10.1°, 11.4°, 12.5°, 15.7° and 16.6° 20 ± 0.2° 20. In some embodiments, the crystalline form designated as compound of Formula (I), Form B is characterized as having an XRPD pattern comprising peaks 7.4°, 7.9°, 9.8°, 10.1°, 11.4°, 12.5°, 15.7° and 16.6° 20 ± 0.2° 20.

[0025] The present disclosure further provides a pharmaceutical composition comprising the crystalline forms of the compound of Formula (I), as described herein, and one or more pharmaceutically acceptable excipients.

[0026] The present disclosure further provides a method for treating a disease or disorder associated with Interleukin 23 (IL-23) / Interleukin 23 Receptor (IL-23R), comprising administering to a subject in need thereof a crystalline form of the compound of Formula (I) or a pharmaceutical composition as described herein.

[0027] In some embodiments, the disease or disorder is selected from multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, Celiac disease (nontropical Sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency- 1, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, enteropathy associated withseronegative arthropathies, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

[0028] In some embodiments, the disease or disorder is selected from ulcerative colitis (UC), Crohn’s disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA). In some embodiments, the disease or disorder is selected from generalized pustular psoriassi (GPP) and erythrodermic psoriasis (EP).Brief Description of the Drawings

[0029] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of a compound of Formula (I), Form A.

[0030] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of a compound of Formula (I), Form A.

[0031] FIG. 3 shows a thermogravimetric analysis (TGA) thermogram of a crystalline form of a compound of Formula (I), Form A.

[0032] FIG. 6 shows a dynamic vapor sorption (DVS) curve of a crystalline form of a compound of Formula (I), Form A.

[0033] FIG. 5 shows an XRPD pattern of a crystalline form of a compound of Formula (I), Form A, following DVS analysis.

[0034] FIG. 6 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of a compound of Formula (I), Form B.Detailed Description

[0035] The present disclosure relates to crystalline forms of a peptide inhibitor of IL-23R and pharmaceutically acceptable compositions thereof. In particular, the present disclosure relates to a crystalline free base form (i.e., a salt-free form) of the compound of Formula I:(I), and pharmaceutically acceptable compositions thereof.Definitions

[0036] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0037] As used in the specification and in the claims, the terms “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named features, groups, ingredients, or steps and does not exclude the presence of additional features, groups, ingredients, or steps. The term “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” or “contain(s),” can include embodiments encompassed by the term "consisting essentially of' or "consisting of' .

[0038] “A,” “an,” or “a(n)”, is an indefinite article when used in reference to a group of substituents or “substituent group” herein, mean at least one.

[0039] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of therange. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3. In some embodiments, reference to about a value or parameter includes a description of that value or parameter per se. For example, reference to about 20 molar equivalents includes and describes 20 molar equivalents per se.

[0040] “Administering” refers to administration of the composition of the present disclosure to a subject.

[0041] “Composition” or “Pharmaceutical Composition” as used herein is intended to encompass a product comprising the specified active product ingredient (API), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined throughout the originally filed disclosure, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein.

[0042] “Patient” or “subject” refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but is not limited to humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, horse, and other mammalian animals and the like. In some embodiments, the patient is human.

[0043] The term “pharmaceutically acceptable” indicates that the carrier(s), diluent(s) or excipient(s) must be compatible with the other components or ingredients of the compositions of the present disclosure, i.e., that which is useful, safe, non-toxic, and acceptable for pharmaceutical use. In accordance with the present disclosure pharmaceutically acceptable means approved or approvable as is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0044] “Partial” or “hemi” hydrochloride salts refer to salts having a substoichiometric amount of hydrochloride. For example, a partial or hemi hydrochloride salt can have from about 0.1 to about 0.9 molar equivalents of hydrogen chloride associated with the compound of Formula (I). Representative, non-limiting partial or hemi hydrochloride salts, include, but are not limited to 0.2, 0.3, 0.4, 0.5 0.6 and 0.7 equivalents HC1 associated with the compound of Formula (I).

[0045] “Free base” refers to a compound (e.g., the compound of Formula (I)) in a salt-free form.

[0046] Compositions or pharmaceutical compositions of the present disclosure may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc. and the like. When the composition is a tablet composition, the tablet may include, but is not limited to different layers. The tablet composition can also include one or more coatings.

[0047] “Solvate” as used herein, means a physical association of the compound of Formula (I) of the present disclosure with one or more solvent molecules. This physical association involves varying degrees of bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation. The term “solvate” is intended to encompass both solutionphase and isolatable solvates. Non-limiting examples of suitable solvates include hydrates.

[0048] “Therapeutically effective amount” refers to an amount of a compound (i.e., a compound of Formula (I), Form A or a compound of Formula (I), Form B) or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount” further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient’s general health, the patient’s age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0049] As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent, e.g., a compound of Formula (I), Form A or a compound of Formula (I), Form B, (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof, where the purpose of the application or administration is to cure,heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, its symptoms. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0050] As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0051] Abbreviation, “(w / w)” refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition. For example, a 2% (w / w) solution can indicate 2 grams of solute is dissolved in 100 grams of solution.

[0052] Systemic routes of administration as conventionally understood in the medicinal or pharmaceutical arts, refer to or are defined as a route of administration of drug, a pharmaceutical composition or formulation, or other substance into the circulatory system so that various body tissues and organs are exposed to the drug, formulation or other substance. As conventionally understood in the art, administration can take place orally (where drug or oral preparations are taken by mouth, and absorbed via the gastrointestinal tract), via enteral administration (absorption of the drug also occurs through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation, etc.

[0053] Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is impacted by the properties of the dosage form, which depend partly on its design and manufacture.

[0054] “Digestive tract tissue” as used herein refers to all the tissues that comprise the organs of the alimentary canal. For example only, and without limitation, “digestive tract tissue” includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, and anus.Crystalline Forms

[0055] Provided herein are crystalline forms of a compound of Formula (I), Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3-Pal]-Sarc-NH2([Pen]* -[Pen]* form disulfide bond)

[0056] The compound of Formula (I) has an amino acid string of Ac-[Pen]*-N-T-[W(7- Me)] - [Lys(Ac)] - [Pen] * -Phe[4-(2-aminoethoxy)] - [2-Nal] - [THP] -E-N- [3 -Pal] -Sarc-NEE (* [Pen] - [Pen]* form a disulfide bond), wherein all amino acid residues are in L configuration. Structures of non- naturally occurring amino acids present in the compound of Formula (I) are provided in Table 1.Table 1:

[0057] Crystalline forms of a compound of Formula (I) were obtained and isolated.

[0058] The crystalline forms disclosed herein are suitable for use in pharmaceutical formulations. As such, crystalline forms of the compound of Formula (I) may be uniquely advantageous as the corresponding amorphous forms are often unsuitable for formulating, such as tableting.

[0059] In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD)patern comprising at least two peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.3° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.4° 20.

[0060] In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD) patern comprising peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.2° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.3° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form A characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.6°, 9.9°, 17.7°, and 19.7° 20 ± 0.4° 20.

[0061] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.4° 20.

[0062] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.4° 20.

[0063] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.4° 20.

[0064] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.4° 20.

[0065] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising one or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.4° 20.

[0066] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising two or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), FormA is characterized as having an XRPD pattern further comprising two or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 26 ± 0.4° 20.

[0067] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising three or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.4° 20.

[0068] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising four or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising four or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern further comprising four or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 20 ± 0.4° 20.

[0069] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.4° 20.

[0070] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound ofFormula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.4° 20.

[0071] An additional crystalline form of a compound of Formula (I), designated as Form B, was obtained and isolated. This crystalline form disclosed herein is suitable for use in pharmaceutical formulations.

[0072] In some embodiments, the compound of Formula (I) designated as Form B is a free base.

[0073] In some embodiments, the crystalline form designated as Form B is characterized as having a XRPD pattern substantially as shown in FIG. 6.

[0074] In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at 7.4°, 9.8°, 11.4°, and 16.6° 20 ± 0.2° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at 7.4°, 9.8°, 11.4°, and 16.6° ° 20 ± 0.3° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at 7.4°, 9.8°, 11.4°, and 16.6° 20 ± 0.4° 20.

[0075] In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.4°, 9.8°, 11.4°, and 16.6° 20 ± 0.2° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.4°, 9.8°, 11.4°, and 16.6° ° 20 ± 0.3° 20. In some embodiments, the present disclosure provides a crystalline form of a compound of Formula (I), Form B characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.4°, 9.8°, 11.4°, and 16.6° 20 ± 0.4° 20.

[0076] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.4° 20.

[0077] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.4° 20.

[0078] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.9°, 10.1°, 12.5°, and 15.7° 20 ± 0.4° 20.

[0079] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising one or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.4° 20.

[0080] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.4°, 7.9°,9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising two or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.4° 20.

[0081] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.4°, 7.9°,9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising three or more peaks at 7.4°, 7.9°,9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.4° 20.

[0082] In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.3° 20. In some embodiments, the crystalline form of the compound of Formula (I), Form B is characterized as having an XRPD pattern further comprising peaks at 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.4° 20.

[0083] In some embodiments, the crystalline form of the compound of Formula (I) is a crystalline free base form of the compound of Formula (I). In some embodiments, the crystalline free base form of the compound of Formula (I) is in the form of a solvate. In some embodiments, the crystalline free base form of the compound of Formula (I) is in the form of a hydrate.

[0084] In some embodiments, the crystalline form of the compound of Formula (I) is characterized as having an XRPD pattern substantially as set forth in FIG. 1.

[0085] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having an endotherm peak at about 75.78 °C, as determined by differential scanning calorimetry (DSC). In some embodiments, the crystalline form of the compound ofFormula (I), Form A is characterized as having an endotherm peak at about 211.56 °C, as determined by DSC. In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having endotherm peaks at about 75.78 °C and about 211.56 °C, as determined by DSC.

[0086] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having a DSC thermogram substantially as shown in FIG. 3.

[0087] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having a weight loss of about 10.9% from about 25 °C to about 150 °C, as determined by thermogravimetric analysis (TGA).

[0088] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having a TGA thermogram substantially as shown in FIG. 4.

[0089] In some embodiments, the crystalline form of the compound of Formula (I), Form A is characterized as having a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 5.

[0090] In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least 98%, or at least about 99% as determined by ultra-performance liquid chromatography (UPLC), high-performance liquid chromatography (HPLC), or other appropriate methods. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of between about 90% and 100%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof. In other embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of between about 95.0% and 99.9%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 95%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 96%.In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 97%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 98%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 99%. In some embodiments, the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B has a purity level of at least 99.5%.

[0091] In some embodiments, the crystalline form of a compound of Formula (I), Form A or the compound of Formula (I), Form B has a moisture content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight. In some embodiments, the crystalline form of a compound of Formula (I), Form A or the compound of Formula (I), Form B has a moisture content level of about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight. In some embodiments, the crystalline form of a compound of Formula (I), Form A or the compound of Formula (I), Form B has a moisture content level of greater than about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5% by weight. In some embodiments, the crystalline form of a compound of Formula (I), Form A or the compound of Formula (I), Form B has a moisture content level of lower than about 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight.Pharmaceutical Compositions

[0092] The present disclosure further provides pharmaceutical compositions comprising the crystalline forms of the compound of Formula (I), as described herein (e.g., a crystalline free base forms of the compound of Formula (I)), and one or more pharmaceutically acceptable excipients.

[0093] In some embodiments, the amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B in the composition is in the range of about 0.1% to about 65%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight. In some embodiments, theamount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B in the composition is in the range of about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B in the composition is in the range of about 2% to about 65%, about 2% to about 60%, about 2% to about 55%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, or about 2% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B in the composition is in the range of about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B in the composition is in the range of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% by weight.

[0094] In general, pharmaceutical compositions of the present disclosure may be formed into different dosage forms prepared using conventional materials and techniques known in the pharmaceutical and formulary arts, which may include, but is not limited to techniques, such as mixing, blending and the like and as set forth throughout the instant disclosure. Moreover, pharmaceutical composition used to form dosage forms may also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, solid or liquid dosage forms, which may include, but are not limited to tablets, capsules, powders, solutions, suspensions, or emulsions and the like, etc. In accordance with the present disclosure, solid unit dosage forms may be other conventional types known in the art.

[0095] Suitable compositions of the present disclosure may be in different forms, including, but are not limited to a liquid, a tablet, a capsule, etc. and the like. In some embodiments, the composition may be a tablet composition or a capsule composition.

[0096] Further, excipients suitable for use in the pharmaceutical compositions of the present disclosure include, but are not limited to, water, saline, aqueous dextrose and related sugar solutions, glycols such as propylene glycol or polyethylene glycol, buffered solutions and the like. Such vehicles are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0097] The compositions of the present disclosure may include a variety of other pharmaceutically acceptable components or excipients, such as a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like.

[0098] In accordance with the present disclosure, compositions as described herein may include at least one filler. In some embodiments, a composition of the present disclosure may comprise a filler including, but is not limited to, one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate and the like. In some embodiments, a composition of the present disclosure may include mannitol. In other embodiments, a composition of the present disclosure may include sorbitol.

[0099] Representative fillers for use in the compositions of the present disclosure may include, but are not limited to, starch, lactitol, lactose, an inorganic calcium salt, microcrystalline cellulose, sucrose, combinations thereof and the like. Additional fillers or diluents for use in the compositions of the present disclosure, may include, but are not limited to fillers or diluents conventionally known in the art, i.e., which are typically used in formulation of pharmaceutical compounds. Examples of such fillers or diluents for use in accordance with the present disclosure may include, but are not limited to sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In some embodiments, such fillers or diluents suitable for use in the present disclosure may include, but are not limited to lactose, microcrystalline cellulose, combinations thereof and the like.

[0100] Moreover, in other embodiments, a filler for use in the present disclosure may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w / w) of a composition as defined in the instant specification. Moreover, such a filler may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, which may include any fractional amount in between those as defined.

[0101] In some embodiments, the filler is present in an amount from about 10% to about 95% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 25% to about 95% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 30% to about 90% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 10% to about 50% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 10% to about 40% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 10% to about 30% (w / w) of the composition. In some embodiments, the filler is present in an amount from about 10% to about 20% (w / w) of the composition. In certain embodiments, the filler is present in an amount from about 10% to about 15% (w / w). In certain embodiments, the filler is present in an amount of about 12% (w / w).

[0102] In some aspects, the composition may further include microcrystalline cellulose. Several types of microcrystalline cellulose may be suitable for use in compositions described herein, for example, microcrystalline cellulose may be selected from but is not limited to MICROCEL® or AVICEL®types: PH101, PH102, PH103, PH105, PH 112, PHI 13, PH200, PH301, and the like, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In some embodiments, a composition for use in the present disclosure may include microcrystalline cellulose (AVICEL PHI 02). In other embodiments, a composition suitable for use in the present disclosure may include microcrystalline cellulose (AVICEL PH101).

[0103] In some embodiments, microcrystalline cellulose may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w / w) of the composition. In some embodiments, microcrystalline cellulose may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, which may include anyfractional amount in between those as defined. In some embodiments, microcrystalline cellulose may also be present in an amount of from about 3% to about 5% (w / w) of a composition.

[0104] In some embodiments, the composition may further include a silicified microcrystalline cellulose. In some embodiments, silicified microcrystalline cellulose may be, but is not limited to SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM and the like. In some embodiments, silicified microcrystalline cellulose may be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM. The silicified microcrystalline cellulose may be present in any suitable amount for use in the present disclosure. For example, the SMCC can be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 10% to about 50%, or from about 20% to about 50%, or from about 25% to about 45%, or from about 30% to about 40%, or from about 35% to about 37% (w / w) of the composition. In some embodiments, the amount of the silicified microcrystalline cellulose is from about 30% to about 70% (w / w) of the composition. In some embodiments, the amount of the silicified microcrystalline cellulose is from about 65% to about 85% (w / w) of the composition. In some embodiments, the amount of the silicified microcrystalline cellulose is from about 66.5% to about 81.3% (w / w) of the composition. In some embodiments, the amount of the silicified microcrystalline cellulose is about 31.3%, about 36.6%, about 37.7%, about 50.9%, about 52%, about 65.2%, about 71.5%, about 79%, or about 80.5% of the composition. The SMCC can be present in an amount of about 30% (w / w) of the composition, or about 31%, 32%, 33%, 34%, 35%, 36%, 36.1%, 36.2%, 36.3%, 36.4%, 36.5%, 36.6%, 36.7%, 36.8%, 36.9%, 37%, 38%, 39%, or about 40% (w / w) of the composition.

[0105] In some embodiments, SMCC is present in an amount of from about 20% to about 90% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 25% to about 85% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 25% to about 45% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 30% to about 40% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 65% to about 90% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 70% to about 85% (w / w), whichincludes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 70% to about 75% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 80% to about 85% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 30%. In some embodiments, SMCC is present in an amount of about 40%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 50%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 60%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 70%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 80%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 90%, which includes, but is not limited to any fractional amount in between.

[0106] In some embodiments, SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0107] In some embodiments, the composition may further include one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate. In some embodiments, the composition may further include mannitol.

[0108] In some embodiments, a composition of the present disclosure may include sorbitol. For example, sorbitol may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w / w) of the composition. In other embodiments, sorbitol can be present in an amount of about 5% (w / w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition. In some embodiments, the composition also includes sorbitol in an amount of from about 5% to about 15% (w / w) of the composition. In some embodiments, the amount of the sorbitol is from about 10% to about 15% (w / w) of the composition. In some embodiments, the composition includes sorbitol in an amount of about 10.7% (w / w) of the composition.

[0109] In some embodiments, a composition of the present disclosure may include mannitol. For example, mannitol may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w / w) of the composition. In another embodiment, mannitol can be present in an amount of about 5% (w / w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition, which includes, but is not limited to any fractional amount in between. In some embodiments, the composition also includes mannitol in an amount of from about 5% to about 15% (w / w) of the composition. In some embodiments, the amount of the mannitol is from about 10% to about 15% (w / w) of the composition. In some embodiments, the composition includes mannitol in an amount of about 10.7% (w / w) of the composition.

[0110] In some embodiments, a sugar alcohol can be present in range from about 1% to about 50% (w / w) of the composition, or from about 5% to about 50%, or from about 5% to about 30%, or from about 10% to about 30% (w / w) of the composition. In some embodiments, the amount of the sugar alcohol can be present in an amount of about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some embodiments, the amount of the sugar alcohol can be present in an amount higher than about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some embodiments, the amount of the sugar alcohol can be present in an amount lower than about 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition.

[0111] In some embodiments, the pharmaceutical composition described herein does not include a sugar alcohol. In some embodiments, the pharmaceutical composition described herein does not include sorbitol. In some embodiments, the pharmaceutical composition described herein does not include mannitol.

[0112] The composition of the disclosure may include at least one disintegrant in an effective therapeutic amount. Representative disintegrants for use in the present disclosure, include, but are not limited to, starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like. Additional representative disintegrants for use in the present disclosure, may include, but are not limited to microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone,cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.

[0113] In some embodiments, the disintegrant is a cross-linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, a silicate, or a soy polysaccharide. In some embodiments, the disintegrant is croscarmellose sodium or crospovidone. In some embodiments, disintegrants for use in the present disclosure may include, but are not limited to, croscarmellose sodium. In some embodiments, a disintegrant for use in the present disclosure can include crospovidone. In some embodiments, a disintegrant may be present in an amount of from about 1% to about 99% (w / w) of a composition of the present disclosure, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w / w) of the composition. Disintegrants for use in the present disclosure may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w / w) of the composition, which include, but is not limited to any fractional amount in between. In some embodiments, an amount of the disintegrant may be present in from about 1% to about 10% (w / w) of a composition of the present disclosure. In some embodiments, an amount of the disintegrant may be present in from about 8% to about 12% (w / w) of a composition of the present disclosure. In some embodiments, an amount of the disintegrant may be present in from about 3% to about 8% (w / w) of a composition of the present disclosure.

[0114] In other embodiments, a composition of the present disclosure may also include silica. In some embodiments, the silica is Aerosil 200, having a specific surface area of about 200 m2 / g. Alternatives to silica may include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, combinations thereof and the like.

[0115] In some embodiments, a composition of the present disclosure may further comprise a silica. In some embodiments, silica may be present in compositions of the present disclosure in an amount of from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1.25%, or from about 0.5% to about 1.5%, or from about 1.0% to about 1.25%, or from about 0.1% to about 1%, or from about 0.3% to about 0.7% (w / w) of the composition of thepresent disclosure. For example, silica as used in the present disclosure may be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or about 1.5% (w / w) of the composition, including any fraction amount in between as defined. In other embodiments, a composition of the present disclosure may further include an amount of silica in from about 0.1% to about 1.5% (w / w) of the composition. In other embodiments, a composition of the present disclosure may further include an amount of silica in from about 0.5% to about 2% (w / w) of the composition. In other embodiments, a composition of the present disclosure may further include an amount of silica in from about 0.3% to about 0.7% (w / w) of the composition. In other embodiments, a composition of the present disclosure may further include an amount of silica in about 0.5% (w / w) of the composition. In other embodiments, the composition further may comprise silica in an amount of about 1% (w / w) of the composition. Examples of suitable silica materials include, but are not limited to colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, silicon dioxide fumed, colloidal anhydrous silica, colloidal silicon dioxide, and the like. In some embodiments, the silica is colloidal silica.

[0116] The composition can also include a binder. Binders for use in the compositions of the present disclosure include binders commonly used in the formulation of pharmaceuticals. Examples of binders for use in the present disclosure include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and sodium carboxymethyl cellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, targacanth, guar, alginates and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like.

[0117] In some embodiments, the binder is hydroxypropyl methylcellulose (HPMC).In some embodiments, binders for use in the present disclosure may also be present in an amount of about 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w / w) of the composition, which include, but is not limited to any fractional amount in between.

[0118] The compositions of the present disclosure may further include a lubricant in any suitable amount. Examples of suitable lubricants for use in the present disclosure include, but are not limited to, magnesium carbonate, magnesium lauryl sulphate, calcium silicate, talc, fumed silicon dioxide, combinations thereof, and the like. Other useful suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate,polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like.

[0119] In some embodiments, the lubricant is magnesium stearate. In some embodiments, an amount of the lubricant can be present in from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2.5%, or from about 0.1% to about 1%, or from about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, an amount of the lubricant can be present in from about 0.5% to about 2.5% or about 0.5% to about 2.0% (w / w) of the composition. In some embodiments, an amount of the lubricant can be present in from about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, the amount of the lubricant is from about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the amount of the lubricant is about 0.5% (w / w) of the composition. The lubricant can also be present in an amount of about 0.10% (w / w) of the composition, or about 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or about 0.30% (w / w) of the composition. The lubricant can also be present in an amount of about 0.5% (w / w) of the composition, or about 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, or about 2.5% (w / w) of the composition. In some embodiments, the lubricant may be present in an amount of about 0.25% (w / w).

[0120] The composition described herein may include a variety of other pharmaceutically acceptable components or excipients, such as a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like.

[0121] The compositions described herein can include at least one disintegrant in any suitable amount in accordance with the present disclosure. Representative disintegrants for use in the present disclosure, may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like. In some embodiments, the disintegrant may include croscarmellose sodium. In some embodiments, the disintegrant may include crospovidone. Insome embodiments, suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any fractional amount in between as defined in the present disclosure. In other embodiments of the present disclosure, the disintegrant may be, but is not limited to being, present in an amount of about 1 to 10% (w / w) of the composition. In some embodiments, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0122] In some embodiments, the microcrystalline cellulose can be present in an amount of from about 1% to about 10% (w / w) of the composition. In some embodiments, the microcrystalline cellulose can be present in an amount of about 3.9% (w / w) of the composition.

[0123] In some embodiments, the composition further may comprise silica. In some embodiments, the composition further may comprise silica in an amount of from about 0.1% to about 1.5% (w / w) of the composition. For example, the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w / w) of the composition, including any fraction amount in between as defined herein. In some embodiments, the composition further may comprise silica in an amount of from about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition further may comprise silica in an amount of from about 0.5% to about 2% (w / w) of the composition. In some embodiments, the composition further may comprise silica in an amount of about 0.5% (w / w) of the composition.

[0124] In some embodiments, the composition of the present disclosure may further comprise at least one of: a disintegrant in an amount from about 1% to about 10% (w / w) of the composition, a microcrystalline cellulose in an amount from about 1% to about 10% (w / w) of the composition, a silica in an amount from about 0.1% to about 1.5% (w / w) of the composition, or sorbitol in an amount from about 5% to about 15% (w / w) of the composition.

[0125] In other embodiments, the composition further may comprise: a disintegrant in an amount from about 1% to about 10% (w / w) of the composition; a microcrystalline cellulose in an amount from about 1% to about 10% (w / w) of the composition; a silica in an amount from about 0.1% to about 1.5% (w / w) of the composition; and sorbitol in an amount from about 5% to about 15% (w / w) of the composition.

[0126] In some embodiments, the compositions of the present disclosure further may comprise at least one of: a microcrystalline cellulose in an amount of about 3.9% (w / w); sorbitolin an amount of about 10.7% (w / w); a disintegrant in an amount of about 5.0% (w / w); and a silica in an amount of about 0.5% (w / w).

[0127] In some embodiments, the compositions further may comprise: a microcrystalline cellulose in an amount of about 3.9% (w / w); sorbitol in an amount of about 10.7% (w / w); a disintegrant in an amount of about 5.0% (w / w); and a silica in an amount of about 0.5% (w / w).

[0128] In some embodiments, the compositions further may comprise: Avicel PHI 01 in an amount of about 3.9% (w / w); sorbitol in an amount of about 10.7% (w / w); croscarmellose sodium in an amount of about 5.0% (w / w); and Aerosil 200 in an amount of about 0.5% (w / w).

[0129] The microcrystalline cellulose can include any microcrystalline cellulose known in the art. In some embodiments, the microcrystalline cellulose may comprise a silicified microcrystalline cellulose (SMCC).

[0130] In some embodiments, the microcrystalline cellulose may be a silicified microcrystalline cellulose (SMCC) and may have any particle size. In some embodiments, the composition includes silicified microcrystalline cellulose in an amount of from about 25% to about 45% (w / w) of the composition. In some embodiments, the composition includes silicified microcrystalline cellulose in an amount of about 36.6% (w / w) of the composition.

[0131] The composition can include at least one disintegrant in any suitable amount in accordance with the present disclosure. Representative disintegrants for use in the present disclosure, may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like. In some embodiments, the disintegrant may include croscarmellose sodium. In some embodiments, the disintegrant may include crospovidone. The disintegrant for use in the present disclosure, may be, but is not limited to being present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w / w) of the composition. In some embodiments, a suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any fractional amount in between as defined in the present disclosure. In other embodiments of the presentdisclosure, the disintegrant may be, but is not limited to being present in an amount of about 1% to about 10% (w / w) of the composition. In other embodiments, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0132] In other embodiments, the composition may also include silica in any amount in accordance with the present disclosure. Silica is exemplified by Aerosil 200, having a specific surface area of about 200 m2 / g. Alternatives to silica include, without limitation, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof and the like. Silica (e.g., Aerosil 200) may be present in the compositions in an amount of from about 0.1 to 10% (w / w) of the composition, or from about 0.1 to 5%, or from about 0.1 to 2%, or from about 0.1 to 1.5%, or from about 0.1 to 1%, or from about 0.3 to 0.7% (w / w) of the composition. For example, the Aerosil 200 silica can be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or 1.5% (w / w) of the composition, including any fraction amount in between.

[0133] In some embodiments, the composition further may comprise silica (e.g., Aerosil 200). In some embodiments, the composition further may comprise silica (e.g., Aerosil 200) in in an amount of from about 0.1% to about 1.5% (w / w) of the composition. For example, the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w / w) of the composition, including any fraction amount in between as defined herein. In some embodiments, the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.5% to about 2% (w / w) of the composition. In some embodiments, the composition further may comprise silica in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition further may comprise silica (e.g., Aerosil 200) in an amount of about 1% (w / w) of the composition.

[0134] In some embodiments, the compositions disclosed herein can further comprise at least one of: a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount from about 1% to about 10% by weight of the composition, or a silica (e.g., Aerosil 200) in an amount from about 0.1% to about 1.5% by weight of the composition.Dosage Forms

[0135] In accordance with the present disclosure, pharmaceutical compositions are comprised of an active principal ingredient (i.e., a crystalline form of the compound of Formula (I)) and at least one or more additional pharmaceutically acceptable ingredients.

[0136] The percentage or amount of active principal ingredient (API) in compositions of the present disclosure, which may of course, be varied as amount of active compound in such therapeutically useful compositions is such that a suitable dosage for administration in a subject or patient will be obtained. It will be appreciated that the actual preferred dosages of API being used in the compositions of this disclosure will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated.

[0137] In some embodiments, the tablet compositions of the present disclosure may have a bioavailability of from about 1% to about 10% (w / w). In some embodiments, the tablet compositions of the present disclosure may have a bioavailability of from about 10% to about 50%. For example, bioavailability may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability can be measured using area under curve (AUC) for oral dosing versus AUC by intravenous dosing.

[0138] In some embodiments, the tablet compositions of the present disclosure may have a bioavailability of from about 0.01% to about 10% (w / w). In some embodiments, the tablet compositions of the present disclosure may have a bioavailability of from about 0.1% to about 1% (w / w). For example, bioavailability may be about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability can be measured using area under curve (AUC) for oral dosing versus AUC by intravenous dosing.

[0139] A dose of a composition described herein may be administered according to a method and / or use of the present disclosure herein. In some embodiments, a dose of a composition of the present disclosure can be administered once daily, twice daily, or three times daily. In some embodiments, a dose of a composition of the present disclosure can be administered once daily. In some embodiments, a dose of a composition of the present disclosure can be administered twice daily. In some embodiments, a dose of a composition of the present disclosure can be administered three times daily.Methods of Treatment and / or Uses

[0140] The present disclosure further provides methods for treating a subject afflicted with a condition or indication associated with IL-23 or IL-23R activity (e.g., activation of the IL-23 / IL- 23R signaling pathway), wherein the method comprises administering to the subject the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein. In some embodiments, the present disclosure provides a method for treating a subject afflicted with a condition or indication characterized by aberrant or dysregulated IL-23 or IL-23R activity or signaling, comprising administering to the subject the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein in an amount sufficient to inhibit (partially or fully) binding of IL-23 to an IL-23R in the subject. The inhibition of IL-23 binding to IL-23R may occur in particular organs or tissues of the subject, e.g., the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts.

[0141] The present disclosure further relates to methods comprising providing the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein to a subject in need thereof. The subject in need thereof may be a subject that has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23 / IL-23R. The subject may be a mammal. The subject may be, in particular, a human.

[0142] The disease or disorder to be treated by treatment with an IL-23R inhibitor of the present disclosure may be an inflammatory disease or disorder, an autoimmune inflammation diseases or disorder, and / or related disorders, including multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular, the disease or disorder may be psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, generalized pustular psoriasis (GPP) or erythrodermic psoriasis), atopic dermatitis, acne ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as inleukocyte adhesion deficiency- 1, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

[0143] The present disclosure provides a method or use of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein for treating an inflammatory disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of the crystalline form or a pharmaceutical composition disclosed herein.

[0144] The present disclosure provides a method or use of the crystalline form of the compound of Formula (I) as described herein for treating an autoimmune disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of the crystalline form or a pharmaceutical composition disclosed herein.

[0145] The present disclosure provides a method or use of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein for treating an autoimmune inflammation disease or disorder in a subject in need thereof that includes administering to the subject a therapeutically effective amount of the crystalline form or a pharmaceutical composition disclosed herein.

[0146] Suitable inflammatory diseases, autoimmune inflammation diseases, and / or related disorders for treatment with the crystalline form or a composition of the present disclosure, may include, but are not limited to inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA) and the like. The inflammatory disease to be treated may be inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. The inflammatory disease to be treated may be selected from psoriasis or psoriatic arthritis. The inflammatory disease to be treated may be psoriasis The inflammatory disease to be treated may be psoriatic arthritis. The inflammatory disease to be treated may be IBD. The inflammatory disease to be treated may be Crohn’s disease. The inflammatory disease to be treated may be ulcerative colitis.

[0147] Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell- independent pathways of intestinal inflammation through effects on T-helper 1 (Thl) and Thl7- associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis. Peptides and methods for specific targeting of the IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.

[0148] Accordingly, the present disclosure also provides a method of treating or preventing inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B or a pharmaceutical composition described herein. In some embodiments, the method is for treating or preventing inflammatory bowel disease (IBD). In some embodiments, the method is for treating or preventing Crohn’s disease (CD). In some embodiments, the method is for treating or preventing ulcerative colitis (UC).

[0149] Psoriasis, a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms. IL-23 is one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin- 17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL- 23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23 -dependent inhibition of psoriasis development in animal models of psoriasis. Orally bioavailable peptide inhibitors of IL-23 may provide both a non-steroidal treatment option for patients with mild to moderate psoriasis and treatment for moderate to severe psoriasis that does not require delivery by infusion.

[0150] Accordingly, the present disclosure also provides a method of treating or preventing psoriasis (PsO) or psoriatic arthritis (PsA) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the crystalline form of the compound of Formula (I) or a pharmaceutical composition described herein. In someembodiments, the method is for treating or preventing psoriasis (PsO). In some embodiments, the method is for treating or preventing psoriatic arthritis (PsA).

[0151] Furthermore, the present disclosure provides a method of treating or preventing generalized pustular psoriasis (GPP) or erythrodermic psoriasis (EP) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B or a pharmaceutical composition described herein. In some embodiments, the method is for treating or preventing generalized pustular psoriasis (GPP) (also known as von Zumbusch psoriasis). In some embodiments, the method is for treating or preventing erythrodermic psoriasis (EP).

[0152] The present disclosure further relates to a method of selectively inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in a subject (e.g., in a subject in need thereof), comprising administering to the subject the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein. In some embodiments, the present disclosure includes and provides a method of selectively inhibiting IL- 23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject the crystalline form of the compound of Formula (I) as described herein by oral administration. The exposure of GI tissues (e.g., small intestine or colon) to the administered peptide inhibitor may be at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold greater than the exposure (level) in the blood. In particular embodiments, the present disclosure includes a method of selectively inhibiting IL23 or IL23R signaling (or the binding of IL23 to IL23R) in the GI tract of a subject (e.g., a subject in need thereof), comprising providing to the subject the crystalline form of the compound of Formula (I) as described herein. In a further related embodiment, the present disclosure provides a method of inhibiting GI inflammation and / or neutrophil infiltration to the GI, comprising providing to a subject in need thereof the crystalline form of the compound of Formula (I) as described herein. In some embodiments, methods of the present disclosure comprise providing the crystalline form of the compound of Formula (I), Form A or the compound of Formula (I), Form B as described herein to a subject (e.g., a subject in need thereof) in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject before and / or simultaneously with and / or after thepeptide inhibitor is administered to the subject. In particular embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory drug, steroid, or immune modulating agent. In certain embodiments, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

[0153] In some embodiments, the present disclosure relates to methods and / or uses for inhibiting IL-23 receptor in a digestive tract tissue for treatment of autoimmune inflammation and related diseases and disorders, that include administering a crystalline form of the compound of Formula (I) or a pharmaceutical composition thereof to a subject in need thereof.

[0154] In some embodiments of the methods and / or uses of the present disclosure, the digestive tract tissue is selected from mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. In some embodiments, the digestive tract tissue is mouth. In some embodiments, the digestive tract tissue is esophagus. In some embodiments, the digestive tract tissue is stomach. In some embodiments, the digestive tract tissue is small intestine. In some embodiments, the digestive tract tissue is large intestine. In some embodiments, the digestive tract tissue is duodenum. In some embodiments, the digestive tract tissue is anus.

[0155] The present disclosure also relates to methods of inhibiting IL-23 binding to an IL- 23R on a cell, comprising contacting the IL-23R with the crystalline form of the compound of Formula (I) as described herein. The cell may be a mammalian cell. The method may be performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.

[0156] The present disclosure further relates to methods of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23R with the crystalline form of the compound of Formula (I) as described herein. In certain embodiments, the cell is a mammalian cell. In particular embodiments, the method is performed in vitro or in vivo. In particular embodiments, the inhibition of IL-23 signaling may be determined by measuring changes in phospho-STAT3 levels in the cell.

[0157] Each embodiment of the present disclosure defined in this or in any other section may incorporate definitions and limitations, such as those set forth throughout the originally filed disclosure, specification, and claims.ExamplesExample 1: Preparation of a Crystalline Free Base of a Compound of Formula (I), Form A

[0158] Seeding material: The seeding material used was a crystalline free base form of the compound of Formula (I), Form A having the following XRPD peaks: 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20.

[0159] Crystallization protocol: IM phosphate buffer (pH 8; 23.34 mL) was added to Reactor A (an EasyMax 102 reactor) under stirring at 20 °C. To this solution was added 50 mg of seeding material (crystalline free base form of the compound of Formula (I), Form A). In another reactor (Reactor B; a second EasyMax 102 reactor), the partial hydrochloric salt of the compound of Formula (I) (5 g) was dissolved under stirring at 20 °C in a solution of 21.125 mL water and 3.89 mL IM HC1. The solution of Reactor B was then dosed over 18 hours to the solution of Reactor A at a temperature of 20 °C. The resulting slurry was stirred for at least 24 hours at 20 °C. The solid was isolated by vacuum filtration and washed two times with 5 mL water before transferring to Reactor C (a third EasyMax 102 reactor). Water (58.3 mL) was added to Reactor C, and the resulting slurry was stirred for at least 24 hours at 20 °C. The solid was isolated by vacuum filtration and washed twice with 5 mL water. The solid was then dried atmospherically.

[0160] Characterization: An XRPD pattern of the solid confirmed its crystallinity (FIG. 1). The following major peaks were observed: 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20. A list of selected peaks observed is shown in Table 2.

[0161] Differential scanning calorimetry (DSC) showed two endothermic events in the profile of the isolated crystalline free base of the compound of Formula (I), Form A. The first endothermic event showed a maximum at 75.78 °C, and the second endothermic event showed a maximum at 211.56 °C (FIG. 3). Thermogravimetric analysis (TGA) of the isolated crystalline free base of the compound of Formula (I), Form A showed 10.86% weight loss when heated to about 150°C (FIG. 4). A dynamic vapor sorption curve (DVS) of the isolated crystalline free base of the compound of Formula (I), Form A indicated a hygroscopic material (FIG. 5). XRPD analysis of the crystalline compound after DVS analysis showed a decrease in crystallinity as compared to the material prior to DVS (FIG. 5).Table 2. - Compound of Formula (I), Form A: Selected peak positions and intensitiesExample 2: Preparation of a Crystalline Free Base of a Compound of Formula (I), Form B

[0162] Seeding material. The seeding material used was a crystalline free base form of the compound of Formula (I), Form B having the following XRPD peaks: 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20.

[0163] Crystallization protocol.

[0164] Method 1 : To compound of Formula (I), (amorphous) was added a stir bar and 5 vol. of 70 % water / MeOH (v / v) at room temperature. This mixture was heated at 50 °C with stirring at 350 rpm. After 5 minutes a clear solution was observed and after 10 minutes a thick slurry was observed. To this mixture was added compound of Formula (I), Form A. After 4 days at 50 °C, a sample was analyzed by XRPD and found to be amorphous. After 5 days at 50 °C a small amount of compound of Formula (I), Form A was added. After 6 days an aliquot of the reaction mixture was analyzed by XRPD and revealed compound of Formula (I), Form B.

[0165] Method 2: A compound of Formula (I), Form A was heated to 75 °C or above or at low relative humidity (30 %RH (relative humidity) or less) to provide compound of Formula (I), Form B.

[0166] Method 3: A compound of Formula (I), Form A was subjected to an atmospheric environment of 30 %RH to provide compound of Formula (I), Form B.

[0167] Method 4: IM phosphate buffer (pH 8; 23.34 mL) was added to Reactor A (an EasyMax 102 reactor) under stirring at 20 °C. To this solution was added 50 mg of seeding material (crystalline free base form of the compound of Formula (I), Form B). In another reactor(Reactor B; a second EasyMax 102 reactor), the partial hydrochloric salt of the compound of Formula (I) (5 g) was dissolved under stirring at 20 °C in a solution of 21.125 mL water and 3.89 mL IM HC1. The solution of Reactor B was then dosed over 18 hours to the solution of Reactor A at a temperature of 20 °C. The resulting slurry was stirred for at least 24 hours at 20 °C. The solid was isolated by vacuum filtration and washed two times with 5 mL water before transferring to Reactor C (a third EasyMax 102 reactor). Water (58.3 mL) was added to Reactor C, and the resulting slurry was stirred for at least 24 hours at 20 °C. The solid was isolated by vacuum filtration and washed twice with 5 mL water. The solid was then dried atmospherically.

[0168] Characterization: An XRPD pattern of the solid confirmed its crystallinity (FIG. 6). The following major peaks were observed: 7.4°, 7.9°, 9.8, 10.1°, 11.4°, 12.5°, 15.7°, and 16.6° 20 ± 0.2° 20.Table 3 Compound of Formula (I), Form B: Selected peak positions and intensities

[0169] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications can be practiced within the scope of the appended claims. It is to be understood that the present disclosure is not limited to the aspects and embodiments illustrated herein above and the right is reserved to the illustrated aspects and all modifications coming within the scope of the claims.

Claims

CLAIMS1. A crystalline form of a compound of Formula (I), Form A having the structure:characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.6°, 9.9°, 17.7°, and 19.7° 26 ± 0.2° 20.

2. The crystalline form of claim 1 , characterized as having an XRPD pattern further comprising one or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20.

3. The crystalline form of claim 1 or claim 2, characterized as having an XRPD pattern further comprising three or more peaks at 7.2°, 10.3°, 10.9°, 11.4°, 13.3°, and 20.8° 20 ± 0.2° 20.

4. The crystalline form of any one of claims 1-3, characterized as having an XRPD pattern comprising peaks at 4.6°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 13.3°, 17.7°, 19.7°, and 20.8° 20 ± 0.2° 20.

5. The crystalline form of any one of claims 1-4, characterized as having an XRPD pattern further comprising one or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 26 ± 0.2° 26.

6. The crystalline form of any one of claims 1-5, characterized as having an XRPD pattern further comprising three or more peaks at 5.5°, 12.2°, 14.6°, 15.0°, 16.6°, 16.9°, 18.8°, and 23.5° 26 ± 0.2° 26.

7. The crystalline form of any one of claims 1-6, characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20.

8. The crystalline form of any one of claims 1-7, characterized as having an XRPD pattern comprising peaks at 4.6°, 5.5°, 7.2°, 7.5°, 9.9°, 10.3°, 10.9°, 11.4°, 12.2°, 12.4°, 13.3°, 14.6°, 15.0°, 16.6°, 16.9°, 17.7°, 17.9°, 18.8°, 19.7°, 20.8°, and 23.5° 20 ± 0.2° 20.

9. The crystalline form of any one of claims 1-8, wherein the compound of Formula (I), Form A is a free base.

10. The crystalline form of any one of claims 1-9, characterized as having a XRPD pattern substantially as shown in FIG. 1.

11. The crystalline form of any one of claims 1-10, characterized as having an endotherm peak at about 75.78 °C, as determined by differential scanning calorimetry (DSC).

12. The crystalline form of any one of claims 1-11, characterized as having an endotherm peak at about 211.56 °C, as determined by DSC.

13. The crystalline form of any one of claims 1-12, characterized as having a DSC thermogram substantially as shown in FIG. 2.

14. The crystalline form of any one of claims 1-13, characterized as having a weight loss of about 10.9% from about 25 °C to about 150 °C, as determined by thermogravimetric analysis (TGA).

15. The crystalline form of any one of claims 1-14, characterized as having a TGA thermogram substantially as shown in FIG. 3.

16. The crystalline form of any one of claims 1-15, characterized as having a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4.

17. A pharmaceutical composition comprising the crystalline form of any one of claims 1-16 and one or more pharmaceutically acceptable excipients.

18. A method for treating a disease or disorder associated with Interleukin 23 (IL-23 ) / Interleukin 23 Receptor (IL-23R), comprising administering to a subject in need thereof the pharmaceutical composition of claim 17.

19. The method of claim 18, wherein the disease or disorder is selected from multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases(IBDs), juvenile IBD, adolescent IBD, Crohn’s disease, ulcerative colitis, Celiac disease (nontropical Sprue), microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency- 1, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo- Plantar Pustulosis, psoriasis vulgaris, or erythrodermic psoriasis), atopic dermatitis, acne ectopica, enteropathy associated with seronegative arthropathies, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich Syndrome, pouchitis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

20. The method of claim 18, wherein the disease or disorder is selected from ulcerative colitis (UC), Crohn’s disease (CD), psoriasis (PsO), or psoriatic arthritis (PsA).