Peptide inhibitors of interleukin-23 receptor and pharmaceutical compositions thereof

Abstract

The present invention relates to peptide inhibitors of the interleukin-23 receptor (IL-23R), or salts, solvates or forms thereof, corresponding pharmaceutical compositions, methods and / or uses, for the treatment of autoimmune inflammatory diseases and related disorders.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 305,631, filed February 1, 2022, which is incorporated by reference in its entirety.

[0002] (Sequence Listing) The contents of the electronic sequence listing (242272001440SEQLIST.xml; size: 5,358 bytes, and creation date: January 26, 2023) are incorporated herein by reference in their entirety.

[0003] FIELD OF THEINVENTION The present invention relates to peptide inhibitors of the interleukin-23 receptor (IL-23R), or salts, solvates or forms thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders. [Background technology]

[0004] Interleukin-23 (IL-23) cytokine has been implicated as playing an important role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), e.g., ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed a key role for IL-23R and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. Gene expression and protein levels of IL-23R have been found to be increased at the intestinal mucosal surface in IBD patients. IL-23 inhibits pathogenic CD4 T cells that produce IL-6, IL-17, and tumor necrosis factor (TNF). + It is thought to mediate this effect by promoting the development of T cell populations.

[0005] IL-23 is produced in abundance in the intestine, where it is believed to play a key role in suppressing regulatory T cell responses in the intestine in favor of inflammation, in addition to controlling the balance between tolerance and immunity via T cell-dependent and T cell-independent pathways of intestinal inflammation by influencing T-helper 1 (Th1) and Th17-associated cytokines. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing a key role for the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis (PsO), a chronic skin disease affecting approximately 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 that is reportedly a key player in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation through 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 psoriasis patients, and antibodies neutralizing IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0007] IL-23 binds to a unique p19 subunit and to the interferon-γ (IFN-γ)-producing T helper 1 (T Helper 1) subunit. H 1) It is a heterodimer composed of a shared p40 subunit with IL-12, a cytokine involved in cell development. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are prone to inflammatory autoimmune diseases, whereas IL-23-deficient animals are prone to inflammatory autoimmune diseases, possibly due to the CD4+ subunits that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. + Resistance is due to a reduction in the number of T cells. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. IL-23 binding to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, but compared to IL-12, activation of Stat4 is substantially weaker and a different DNA-binding Stat complex is formed in response to IL-23. IL-23R constitutively associates with Jak2 and ligand-dependently associates with Stat3. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 acts preferentially on memory CD4(+) T cells.

[0008] Attempts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for use in treating IL-23-related diseases and disorders. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, an antibody that binds to the p40 subunit of IL-23, which has been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn's disease, and moderate to severe active ulcerative colitis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, e.g., U.S. Patent Application Publication No. 2013 / 0029907). Clinical trials of briakinumab (which also targets the common p40 subunit), as well as tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) in Crohn's disease or psoriasis have revealed the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases. Although these findings are promising, challenges remain regarding the successful delivery of such drugs to the target. Effective delivery could improve the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related disorders.

[0009] An inhibitor of IL-23R is described as peptide #104 in PCT Publication No. WO 2021 / 146441 and U.S. Patent Application Publication No. 2021 / 0261622, the disclosures of which are incorporated by reference in their entireties into this specification.

[0010] There remains a need in the art to develop effective pharmaceutical vehicles, such as pharmaceutical compositions, for delivering therapeutic agents to treat and prevent IL-23 and / or IL-23R related diseases, particularly diseases associated with autoimmune inflammation, such as in the intestinal tract, which may include, but are not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's Disease (CD), psoriasis, or psoriatic arthritis.

[0011] The present invention addresses these needs by providing pharmaceutical compositions of peptide inhibitors or pharma- ceutical acceptable salt or solvate forms thereof that bind to IL-23R and inhibit IL-23 binding, IL-23 signaling via the IL-23 receptor and / or IL-23 pathway, for the treatment of the aforementioned inflammatory diseases or disorders, including but not limited to those that are moderate to severe in severity and may be suitable for oral administration (i.e., may include but are not limited to, for example, psoriasis, psoriatic arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, etc.). In addition, pharmaceutical compositions for specific targeting of IL-23R from the luminal side of the intestine, as well as corresponding methods and / or uses, may provide therapeutic benefit to IBD patients suffering from local inflammation of intestinal tissue. Summary of the Invention [Means for solving the problem]

[0012] Provided herein are crystalline forms of peptide inhibitors of interleukin-23 receptor (IL-23R), as well as pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders. Crystalline forms have advantageous properties, such as ease of isolation, improved purity, and greater physical and chemical stability, compared to the analogous amorphous forms. These attributes may be particularly important for pharmaceutical agents where large-scale production, reproducibility, and compound purity are required. Crystalline forms of peptides may be uniquely advantageous, as the corresponding amorphous forms are often not suitable for formulation, such as tableting.

[0013] In general, the present invention relates to peptide inhibitors of the interleukin-23 receptor (IL-23R), or hydrochloride salts, solvates or forms thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders.

[0014] In particular, the present invention relates to pharmaceutical compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R), or hydrochloride salts, solvates or forms thereof, corresponding methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders.

[0015] In particular, the present invention relates to pharmaceutical compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R), or pharma- ceutically acceptable salts, solvates or forms thereof, corresponding methods and / or uses, for the treatment of autoimmune inflammation and related diseases and disorders.

[0016] The present invention relates to a pharmaceutical composition as described herein, comprising a peptide of SEQ ID NO:1 having the structure of formula (I): Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (wherein, [Pen] * -[Pen] * (wherein x forms a disulfide bond), or a pharma- ceutically acceptable salt, or a crystalline form of a solvate of the foregoing.

[0017] [ka]

[0018] In particular, the present invention relates to compounds of formula (I) having the following structure:

[0019] [ka] A crystalline hydrochloride salt form of the solvate is provided.

[0020] The present invention also provides a crystalline form of a peptide of SEQ ID NO: 1, or a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing. Pharmaceutically acceptable salts of the peptides of SEQ ID NO: 1 provided herein include hydrochloride, bishydrochloride, acetate, fumarate, glutarate, glycolate, mesylate, sulfate, and citrate salts.

[0021] The present invention also provides a crystalline form of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing. Pharmaceutically acceptable salts of the compound of formula (I) provided herein include hydrochloride, bishydrochloride, acetate, fumarate, glutarate, glycolate, mesylate, sulfate, and citrate salts.

[0022] Further provided herein are crystalline forms of the free base of the peptide compound of formula (I) or a solvate thereof.

[0023] Additionally provided herein are crystalline forms of the free base of the compound of formula (I) or a solvate thereof.

[0024] The present invention further provides a pharmaceutical composition comprising the hydrochloride salt form of a peptide of the compound of formula (I) or a solvate thereof, wherein the hydrochloride salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 1.

[0025] The present invention further provides a pharmaceutical composition comprising the hydrochloride salt form of the compound of formula (I) or a solvate thereof, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1, and a pharma- ceutically acceptable excipient.

[0026] The present invention further provides a pharmaceutical composition comprising the hydrochloride salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the hydrochloride salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in FIG.

[0027] The present invention further provides a pharmaceutical composition comprising the hydrochloride salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the hydrochloride salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in FIG.

[0028] The present invention further provides a pharmaceutical composition comprising the acetate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the acetate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in FIG.

[0029] The present invention further provides a pharmaceutical composition comprising the fumarate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the fumarate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 15.

[0030] The present invention further provides a pharmaceutical composition comprising the glutarate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the glutarate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 18.

[0031] The present invention further provides a pharmaceutical composition comprising the glycolate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the glycolate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 21.

[0032] The present invention further provides a pharmaceutical composition comprising the mesylate form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the mesylate form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 24.

[0033] The present invention further provides a pharmaceutical composition comprising the sulfate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the sulfate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 26.

[0034] The present invention further provides a pharmaceutical composition comprising a citrate salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the citrate salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 28.

[0035] The present invention further provides a pharmaceutical composition comprising the bishydrochloride salt form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the bishydrochloride salt form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 29.

[0036] The present invention further provides a pharmaceutical composition comprising the free base form of a peptide of SEQ ID NO:1 or a solvate thereof, and one or more pharma- ceutically acceptable excipients, wherein the free base form of the peptide of SEQ ID NO:1 is characterized by an XRPD pattern substantially as shown in Figure 11.

[0037] The present invention further provides a pharmaceutical composition comprising the hydrochloride salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the hydrochloride salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 3.

[0038] The present invention further provides a pharmaceutical composition comprising the acetate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the acetate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 7.

[0039] The present invention further provides a pharmaceutical composition comprising the fumarate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the fumarate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 15.

[0040] The present invention further provides a pharmaceutical composition comprising the glutarate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the glutarate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 18.

[0041] The present invention further provides a pharmaceutical composition comprising the glycolate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the glycolate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 21.

[0042] The present invention further provides a pharmaceutical composition comprising the mesylate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the mesylate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 24.

[0043] The present invention further provides a pharmaceutical composition comprising the sulfate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the sulfate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 26.

[0044] The present invention further provides a pharmaceutical composition comprising the citrate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the citrate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 28.

[0045] The present invention further provides a pharmaceutical composition comprising the bishydrochloride salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the bishydrochloride salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 28.

[0046] The present invention further provides a pharmaceutical composition comprising the glycolate salt form of the compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the glycolate salt form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 21.

[0047] The present invention further provides a pharmaceutical composition comprising the free base form of a compound of formula (I) or a solvate thereof, and a pharma- ceutically acceptable excipient, wherein the free base form of the compound of formula (I) is characterized by an XRPD pattern substantially as shown in Figure 11.

[0048] Also provided herein are compositions comprising the hydrochloride form of a peptide or solvate thereof of a compound of formula (I) in an amount of about 0.1% to about 15% (w / w) of the composition, and one or more pharma- ceutically acceptable excipients.

[0049] Further provided herein are compositions comprising a crystalline form of a peptide of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing, in an amount of about 0.1% to about 60% (w / w) of the composition, and one or more pharma- ceutically acceptable excipients.

[0050] Further provided herein is a composition comprising the hydrochloride form of a peptide or solvate thereof of a compound of formula (I) in an amount of about 0.1% to about 15% (w / w) of the composition, an absorption enhancer in an amount of about 5% to about 50% (w / w) of the composition, and one or more pharma- ceutically acceptable excipients.

[0051] Also provided herein is a composition comprising a crystalline form of a peptide of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing, in an amount of about 0.1% to about 60% (w / w) of the composition; an absorption enhancer in an amount of about 5% to about 65% (w / w) of the composition; and one or more pharma- ceutically acceptable excipients.

[0052] Provided herein is a method comprising forming a mixture comprising a hydrochloride form of a peptide of a compound of formula (I) or a solvate thereof, silicified microcrystalline cellulose, sorbitol, crospovidone, and silica (e.g., Aerosil 200), adding magnesium stearate to the mixture, compressing the mixture, and applying a subcoating to the mixture to form a tablet.

[0053] Also provided herein is a method, comprising forming a mixture comprising the hydrochloride form of a peptide of the compound of formula (I) or a solvate thereof, sodium caprate, microcrystalline cellulose, sorbitol, silica (e.g., Aerosil 200), silicified microcrystalline cellulose, and crospovidone to form a core tablet, applying a subcoating over the core tablet, and applying an enteric coating over the subcoating to form a tablet.

[0054] Further provided is a tablet formed by the methods described herein.

[0055] The present invention provides a method of treating an inflammatory disease, comprising administering to a subject or patient in need of such treatment a therapeutically effective amount of a composition of the present invention as described herein.

[0056] The present invention provides a method of treating inflammatory bowel disease (IBD), comprising administering to a subject or patient in need of such treatment a therapeutically effective amount of a composition of the present invention.

[0057] The invention provides the use of a composition of the invention in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

[0058] The invention provides a method of treating psoriasis or psoriatic arthritis in a subject, comprising administering to the subject a therapeutically effective amount of a composition of the invention described herein.

[0059] The invention provides the use of a composition of the invention in the manufacture of a medicament for treating psoriasis or psoriatic arthritis. [Brief description of the drawings]

[0060] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of a crystalline form of the hydrochloride salt of compound of formula (I). [Diagram 2] 1 shows the XRPD pattern of the crystalline form of the hydrochloride salt of compound of formula (I). [Diagram 3] 1 shows the XRPD pattern of the crystalline form of the hydrochloride salt of compound of formula (I). [Figure 4] 1 shows a thermogravimetric analysis (TGA) graph of the crystalline form of the hydrochloride salt of compound of formula (I). [Diagram 5] 1 shows a differential scanning calorimetry (DSC) graph of the crystalline form of the hydrochloride salt of the peptide of the compound of formula (I). [Figure 6] 1 shows the dynamic vapor sorption (DVS) curve of the crystalline form of the hydrochloride salt of the peptide of the compound of formula (I). [Figure 7] 1 shows the XRPD pattern of the crystalline form of the acetate salt of the peptide compound of formula (I). [Figure 8] 1 shows a TGA graph of a crystalline form of the acetate salt of the compound of formula (I). [Figure 9] 1 shows a DSC graph of a crystalline form of the acetate salt of the compound of formula (I). [Figure 10]1 shows the DVS curve of the crystalline form of the acetate salt of the compound of formula (I). [Figure 11] 1 shows the XRPD pattern of the crystalline form of the free base of compound of formula (I). [Figure 12] 1 shows a TGA graph of the crystalline form of the free base of the compound of formula (I). [Figure 13] 1 shows a DSC graph of the crystalline form of the free base of the compound of formula (I). [Figure 14] 1 shows the DVS curve of the crystalline form of the free base of the compound of formula (I). [Figure 15] 1 shows the XRPD pattern of the crystalline form of the fumarate salt of peptide mesylate of SEQ ID NO:1. [Figure 16] 1 shows a TGA graph of a crystalline form of the fumarate salt of the compound of formula (I). [Figure 17] 1 shows a DSC graph of a crystalline form of the fumarate salt of the compound of formula (I). [Figure 18] 1 shows an XRPD pattern of a crystalline form of the glutarate salt of compound of formula (I). [Figure 19] 1 shows a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the glutarate salt of compound of formula (I). [Figure 20] 1 shows the DVS curve of the crystalline form of the glutarate salt of compound of formula (I). [Figure 21] 1 shows the XRPD pattern of a crystalline form of the glycolic acid salt of compound of formula (I). [Figure 22] 1 shows a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the glycolic acid salt of compound of formula (I). [Diagram 23] 1 shows the DVS curve of the crystalline form of the glycolic acid salt of compound of formula (I). [Figure 24] 1 shows an XRPD pattern of a crystalline form of the mesylate salt of compound of formula (I). [Diagram 25] 1 shows a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the mesylate salt of the compound of formula (I). [Figure 26]1 shows an XRPD pattern of a crystalline form of the sulfate salt of compound of formula (I). [Figure 27] 1 shows a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the sulfate salt of the compound of formula (I). [Figure 28] 1 shows an XRPD pattern of a crystalline form of the citrate salt of the compound of formula (I). [Figure 29] 1 shows the XRPD pattern of the crystalline form of the bis-hydrochloride salt of compound of formula (I). [Diagram 30] 1 shows a TGA graph of the crystalline form of the bis-hydrochloride salt of compound of formula (I). [Diagram 31] 1 shows a DSC graph of the crystalline form of the bis-hydrochloride salt of the compound of formula (I). [Diagram 32] 1 shows the DVS curve of the crystalline form of the bis-hydrochloride salt of compound of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] I. Overview The present invention relates to peptide inhibitors of the interleukin-23 receptor (IL-23R) or pharma- ceutically acceptable salts or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders. In particular, the present invention relates to crystalline forms of peptide inhibitors of IL-234R and pharma- ceutical acceptable compositions thereof.

[0062] In general, the present invention relates to hydrochloride salt compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods, and / or uses for the treatment of autoimmune inflammation and related diseases and disorders.

[0063] II. Definition "A," "an," or "a(n)," when used herein with respect to a group of substituents or a "substituent group," are indefinite articles meaning at least one.

[0064] "About" when referring to a value includes the recited value + / - 10% of the recited value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to + / - 10% of the recited value at each upper and lower limit of the recited range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range of 0.9 to 3.3. In some embodiments, reference to a value or parameter includes reference to that value or parameter per se. For example, reference to about 20 molar equivalents includes and describes 20 molar equivalents per se.

[0065] "Absorption enhancer" refers to a component that improves or facilitates mucosal absorption of a drug in the gastrointestinal tract, e.g., a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer (PE) is an agent that aims to improve oral delivery of therapeutic agents with poor bioavailability. PEs can increase paracellular and / or transcellular passage of drugs. Pharmaceutical excipients that can increase permeation are referred to as "absorption modifying excipients" (AMEs). AMEs can be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogol glycerides), and can be included in compositions, particularly as PEs, to improve bioavailability. PEs can be classified with respect to how they alter barrier integrity via paracellular or transcellular routes.

[0066] "Intestinal Permeation Enhancer (IPE)" refers to a component that improves the bioavailability of a component. Representative IPEs suitable for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium chain glycerides, steroid detergents, acylcarnitines and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, an IPE suitable for use in the present invention may be sodium caprate.

[0067] "Administering" refers to administration of a composition of the invention to a subject.

[0068] A "composition" or "pharmaceutical composition" as used herein is intended to encompass an invention or product comprising a specific Active Product Ingredient (API), which may result from a combination of specific components, such as specific ingredients in specific amounts as described herein, e.g., in specific amounts defined throughout the originally filed disclosure, and may include pharma- ceutical acceptable excipients, carriers, or diluents as described herein.

[0069] A "granulated mixture" refers to a mixture of two or more drugs, made by mixing the two or more drugs and granulating the two or more drugs together in particulate form. Such a mixture provides a particulate material composed of two or more drugs. For example, in the present invention, a composition may include, but is not limited to, a granulated mixture of the hydrochloride form of a peptide of SEQ ID NO: 1 or a solvate thereof and an absorption enhancer or permeation enhancer, such as sodium caprate. Such a granulated mixture is formed into a particle or tablet form containing the hydrochloride form of the compound of formula (I) or a solvate thereof and sodium caprate. In some embodiments, the composition may include a granulated mixture containing sodium caprate.

[0070] "Disintegrant" refers to a pharmaceutical excipient incorporated into a composition to facilitate the disintegration of the composition when the composition comes into contact with liquid. For example, a disintegrant is a pharma- ceutically acceptable agent used in the preparation of tablets that causes the tablet to disintegrate and release medicinal substances when it comes into contact with moisture. Examples of disintegrants include, but are not limited to, cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), and cross-linked polymers, including modified starch sodium starch glycolate. Representative disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clays, other algins, other celluloses, gums (such as gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof. In some embodiments, disintegrants for use in the present invention may include, but are not limited to, croscarmellose sodium. Additional representative disintegrants for use in the present invention 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. Representative disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates, and gums, as well as cross-linked starches, celluloses, and polymers, combinations thereof, and the like.

[0071] "Disposed on" refers to the placement of one phase or coating on top of another phase or coating. Such placement can conform to the shape of the underlying phase or coating, such that the layering of the phases and coatings does not leave substantial gaps between the phases and coatings.

[0072] "Enteric coating" refers to any of the commonly applied polymeric coatings used for delayed release of active ingredients. As conventionally understood in the art, enteric coating is generally a polymeric barrier applied to oral drugs that prevents dissolution or disintegration of oral drugs in the stomach environment. This serves either by protecting the drug from stomach acidity, protecting the stomach from adverse effects of the drug, or releasing the drug after the stomach (usually in the upper intestinal tract). Some drugs are unstable at the pH of stomach acid and need to be protected from degradation. Enteric coating is also an effective method to obtain drug targeting (such as gastro-resistant drugs). Such delayed release is typically pH-dependent, allowing further release of active ingredients in the intestinal tract where the pH is different from that in the stomach. Generally, suitable materials used for enteric coatings may include, but are not limited to, fatty acids, waxes, shellac, plastics, and vegetable fibers, and such enteric materials may include, but are not limited to, cellulose acetate phthalate, polyvinyl alcohol phthalate, shellac, zein, hydroxypropyl methylcellulose phthalate, cellulose acetate trimalate, and film resins, etc. Additional examples of enteric coatings for use in the present invention may include, but are not limited to, those based on esters of aleurtic acid, cellulose acetate phthalate (Cellulose Acetate Phthalate, CAP), poly(methacrylic acid-co-methyl methacrylate), poly(vinyl acetate phthalate, PVAP), cellulose acetate trimellitate (Cellulose Acetate Trimellitate, CAT), and hydroxypropyl methylcellulose phthalate (HpMCP), etc.Other suitable materials for use in the enteric coating may also include, but are not limited to, methacrylic acid copolymers, poly(ethyl methacrylate acrylate) 1:1, poly(methyl methacrylate methacrylate) 1:2, poly(ethyl methacrylate acrylate) (L100D-55), methyl acrylate, methyl methacrylate, hydroxypropyl methylcellulose (HPMC), a combination of methacrylic acid (FS30D), Eudragit®, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and L-, M-, or H-type HPMC-AS. In some embodiments, the enteric coating is disposed over the subcoating.

[0073] "Lubricant" refers to a substance added to a powder to improve the flow and / or lubricity of the powder. Examples of lubricants can include, but are not limited to, magnesium stearate, fumed silica, starch, talc, etc.

[0074] "Silica" refers to a pharmaceutical excipient that can be used in solid product forms as a flow agent (anti-caking), adsorbent, and desiccant. Hydrophilic silica can also be used to increase the mechanical stability and disintegration rate of the composition. The silica can be fumed, i.e., this refers to the production of silica by a pyrogenic process to produce fine particles of silica. The size of the particles of fumed silica can vary, such as 5 nm to 100 nm or 5 to 50 nm. The particles can be non-porous and can be 50 to 1,000 m. 2 / g or 50~600m 2 An example of silica has a surface area of ​​about 200 m 2Aerosil 200 having a specific surface area of ​​1000 nm / g is also included. The silica can be hydrophilic. Examples of suitable silica materials include, but are not limited to, SiO2, colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, fumed silicon dioxide, colloidal anhydrous silica, colloidal silicon dioxide, and the like.

[0075] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds that function as lubricants can also have lubricant properties. Examples of lubricants can include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0076] "Microcrystalline cellulose" or "MCC" refers to pharmaceutical grade cellulose produced from refined wood pulp. MCC can be unmodified or chemically modified, for example, silicified microcrystalline cellulose (SMCC). MCC can act as a bulking agent and can aid in tablet formation due to the favorable compressibility characteristics of MCC.

[0077] "Patient" or "subject" refers to a living organism, including, but not limited to, a human subject suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples can include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other mammals. In some aspects, the patient is a human.

[0078] By "pharmaceutical acceptable" it is meant that the carrier, diluent or excipient must be compatible with other components or ingredients of the compositions of the present invention, i.e., useful, safe, non-toxic and acceptable for pharmaceutical use. According to the present invention, pharmacopoeia means approved or approvable as described in the US Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, and particularly in humans.

[0079] "Hemi" hydrochloride refers to a salt having a substoichiometric amount of hydrochloride. For example, a hemi hydrochloride can have about 0.1 to about 0.9 molar equivalents of hydrogen chloride associated with the peptide of SEQ ID NO:1. Representative non-limiting hemi hydrochloride salts include, but are not limited to, 0.2, 0.3, 0.4, 0.5 0.6, and 0.7 equivalents of HCl associated with the peptide of SEQ ID NO:1. In the context of the present invention, the term "hemi" hydrochloride is not to be distinguished from the term "partial" hydrochloride. In some embodiments, "hemi" refers to other pharma- ceutically acceptable salt forms of the peptide of SEQ ID NO:1, such as the acetate salt of the peptide of SEQ ID NO:1, the fumarate salt of the peptide of SEQ ID NO:1, the glutarate salt of the peptide of SEQ ID NO:1, the glycolate salt of the peptide of SEQ ID NO:1, the mesylate salt of the peptide of SEQ ID NO:1, the bishydrochloride salt of the peptide of SEQ ID NO:1, the citrate salt of the peptide of SEQ ID NO:1, or the sulfate salt of the peptide of SEQ ID NO:1.

[0080] "Free base" refers to the salt-free form of the compound having the following structure:

[0081] [ka] It refers to the peptide of SEQ ID NO:1 having the following structure:

[0082] "Crystalline salt" refers to a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I), which may include, but is not limited to, a crystalline acetate salt of the compound of formula (I), a crystalline hydrochloride salt of the compound of formula (I), a crystalline fumarate salt of the compound of formula (I), a crystalline glutarate salt of the compound of formula (I), a crystalline glycolate salt of the compound of formula (I), a crystalline mesylate salt of the compound of formula (I), a crystalline citrate salt of the compound of formula (I), a crystalline bishydrochloride salt of the compound of formula (I), or a crystalline sulfate salt of the compound of formula (I).

[0083] The composition or pharmaceutical composition of the present invention may be in different pharma- ceutical acceptable forms, which may include, but are not limited to, liquid compositions, tablet or matrix compositions, and capsule compositions.When the composition is a tablet composition, the tablet may include, but are not limited to, different layers.The tablet composition may also include, but are not limited to, one or more coatings.

[0084] "Siliconized microcrystalline cellulose" or "SMCC" refers to a particulate aggregate of co-processed microcrystalline cellulose and silicon dioxide. SMCC suitable for use in the present invention may contain silicon dioxide in an amount of about 0.1% to about 20% by weight of the microcrystalline cellulose, but is not limited thereto, and the silicon dioxide may have a particle size of about 1 nanometer (nm) to about 100 micrometers (μm) based on the average primary particle size. For example, the silicon dioxide may contain about 0.5% to about 10% of the silicified microcrystalline cellulose, or about 1.25% to about 5% by weight of the microcrystalline cellulose. Furthermore, the silicon dioxide may have a particle size of about 5 nm to about 40 μm or about 5 nm to about 50 μm. The silicon dioxide may have a particle size of about 10 nm to about 50 μm. 2 / g~about 500m 2 / g, or about 50m 2 / g~about 500m 2 / g, or about 175m 2 / g~about 350m 2 / g surface area. Silica-treated microcrystalline cellulose is commercially available from several sources known to those skilled in the art, including Penwest Pharmaceuticals, Inc. under the trademark PROSOLV®. PROSOLV® is available in several grades, including, for example, PROSOLV® SMCC 50, PROSOLV® SMCC 90, and PROSOLV® HD. Other products include, but are not limited to, SMCC 50LD, SMCC HD90, and SMCC 90LM.

[0085] "Sodium caprate" or "NaC10" has the molecular formula C 10 H 19 It refers to NaO2 and the IUPAC compound sodium decanoate, which has the following structural formula:

[0086] [ka]

[0087] In some embodiments, sodium caprate functions as either an absorption enhancer or an excipient in tablet formulations. Sodium caprate is approved by the European Union and the Food and Drug Administration (FDA) as a direct food additive for human consumption.

[0088] As used herein, "solvate" refers to the physical association of the peptide of SEQ ID NO:1 of the present invention with one or more solvent molecules. This physical association involves varying degrees of bonding, including hydrogen bonding. In certain cases, the solvate is isolable. The term "solvate" is intended to include both solution-phase solvates and isolable solvates. Non-limiting examples of suitable solvates include hydrates.

[0089] "Sorbitol" refers to the sugar alcohol D-glucitol, which can function as a binder to promote adhesion of ingredients in a tablet composition.

[0090] As used herein, "sugar alcohol" refers to a compound derived from sugar and containing one or more hydroxyl groups. Sugar alcohols may contain multiple -OH groups and may be classified as polyols. Examples of sugar alcohols include, but are not limited to, sorbitol, mannitol, and xylitol.

[0091] "Subcoating" refers to any number of film layers disposed over a core tablet, where the film layers can provide one or more benefits, such as providing a smooth tablet surface to facilitate swallowing of the composition, including coloring to aid in pill identification, providing a moisture barrier, and providing a high tensile strength outer layer for the tablet. Such subcoatings can include, but are not limited to, graft copolymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG). Commercially available products that provide subcoatings include product lines under trade names such as OPADRY® and OPAGLOS®. The subcoatings can be further covered by one or more additional coatings.

[0092] In some embodiments, subcoating refers to any number of film layers disposed on the core tablet. Examples of suitable materials for cosmetic subcoating include polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers (e.g., OPADRY® QX). Other coatings include, but are not limited to, HPMC, HPC, PVA, Eudragit E-based coatings, and the like.

[0093] In some embodiments, the subcoating may be further covered by one or more additional coatings, such as an enteric coating or a functional coating. In certain embodiments, the subcoating comprises one or more of a plasticizer, an anti-blocking agent, a colorant, HPMC, HPC, PVA, and a Eudragit E-based coating. In some embodiments, the subcoating is covered with one or more additional coatings. In certain embodiments, the one or more additional coatings on the subcoating are enteric coatings. In other embodiments, the one or more additional coatings on the subcoating are functional coatings.

[0094] In some aspects, the subcoating is not covered by one or more additional coatings and is referred to as a cosmetic subcoating. For example, in certain embodiments, the core tablet is covered by a cosmetic coating, and the cosmetic coating is not further covered by an enteric coating or a functional coating. In some embodiments, the cosmetic coating can serve as a lubricious surface to aid in swallowing the tablet. In some embodiments, the cosmetic coating can provide a vehicle for coloring for tablet identification. It serves as a lubricious surface to aid in swallowing the tablet.

[0095] "Core tablet" refers to a mixture of components of the core tablet. In some embodiments, the components are one or more of a crystalline form of the peptide of SEQ ID NO: 1, a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing, and suitable excipients. In some embodiments, the suitable excipients are one or more of the following, but are not limited to: fillers, disintegrants, glidants, lubricants, and absorption enhancers. A subcoating, a cosmetic coating, an enteric coating, or any combination thereof may be disposed on the core tablet.

[0096] "Therapeutically effective amount" refers to an amount of a compound (i.e., a peptide of SEQ ID NO: 1) or pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of a particular drug, which refers to an amount sufficient to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on factors such as, for example, the patient's general health, the patient's age, and the like. The exact amount will depend on the purpose of the treatment, and can be ascertained 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).

[0097] "Treate", "treating", and "treatment" refer to any indication of success in treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, such as remission, remission, reducing symptoms or making the injury, pathology, or condition more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation.

[0098] The abbreviation "(V / V)" refers to the phrase "volume for volume," i.e., the proportion of a particular substance in a mixture as measured by the volume or amount by volume of a component of the compositions disclosed herein relative to the total volume of the composition. Thus, the amount is unitless and represents the volume percentage amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that there are 2 mL of one solvent in 100 mL of the solvent mixture.

[0099] The abbreviation "(w / w)" refers to the phrase "weight for weight," i.e., the proportion of a particular substance in a mixture as measured by the weight or mass or amount of weight of a component of the composition relative to the amount of the total weight of the compositions disclosed herein. Thus, the amounts are unitless and represent the weight percentage amount of the component relative to the total weight of the composition. For example, a 2% (w / w) solution may indicate that 2 grams of solute are dissolved in 100 grams of solution.

[0100] A systemic route of administration, as conventionally understood in the medical or pharmaceutical arts, refers to or is defined as a route of administration in which a drug, pharmaceutical composition or formulation, or other substance enters the circulatory system, thereby exposing various body tissues and organs to the drug, formulation, or other substance. As conventionally understood in the art, administration can be oral (wherein a drug or oral preparation is taken by mouth and absorbed through the gastrointestinal tract), enteral (wherein drug absorption also occurs across the gastrointestinal tract), or parenteral (generally, by injection, infusion, or implantation, etc.).

[0101] "Systemically active" peptide pharmacotherapy in the context of the present invention generally refers to treatment with a pharmaceutical composition comprising a peptide active ingredient, where the peptide resists immediate metabolism and / or excretion, resulting in exposure of the peptide in various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous, or immune systems.

[0102] Systemic drug activity in the present invention also refers to treatments using substances that travel throughout the bloodstream to reach and affect cells in various body tissues and organs. Systemically active drugs are transported to their site of action and act throughout the body to attack the physiological processes that cause inflammatory diseases.

[0103] Bioavailability refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby gains access to the site of action. The bioavailability of a drug is influenced by the properties of the dosage form, which in turn depend in part on the design and manufacture of the dosage form.

[0104] As used herein, "gastrointestinal tissue" refers to all tissues comprising the organs of the gastrointestinal tract. By way of example only, "gastrointestinal tissue" includes, but is not limited to, tissues of the mouth, esophagus, stomach, small intestine, large intestine, and anus.

[0105] III. Crystalline form Crystalline forms of peptide inhibitors of interleukin-23 receptor (IL-23R) are provided herein. Crystalline forms of the compound of formula (I) have been obtained and isolated unexpectedly. Crystalline forms of pharma-ceutically acceptable salts of the compound of formula (I) have been prepared, isolated, and found to be suitable for use in pharmaceutical formulations.Thus, crystalline forms of peptides can be uniquely advantageous, since the corresponding amorphous forms are often not suitable for formulation, such as tableting.

[0106] In one aspect, the present invention provides a compound of formula (I):

[0107] [ka] The present invention relates to pharmaceutical compositions of crystalline salts of pharma- ceutically acceptable salts thereof, or solvates of the foregoing.

[0108] In another aspect, the invention relates to a crystalline free base form of the compound of formula (I).

[0109] In one aspect, the invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO:1.

[0110] In one aspect, the invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (I).

[0111] In another aspect, the present invention relates to a pharmaceutical composition of the crystalline form of the hydrochloride salt of the peptide of SEQ ID NO:1.

[0112] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharma- ceutically acceptable salt of a peptide of SEQ ID NO: 1. The crystalline form of a pharma- ceutically acceptable salt of a peptide of SEQ ID NO: 1 can be a crystalline hydrochloride, a crystalline acetate, a crystalline fumarate, a crystalline glycolate, a crystalline glutarate, a crystalline mesylate, a crystalline sulfate, a crystalline bishydrochloride, and a crystalline citrate of a peptide of SEQ ID NO: 1.

[0113] In another aspect, the present invention relates to a pharmaceutical composition of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0114] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I). The crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) can be a crystalline hydrochloride, a crystalline acetate, a crystalline fumarate, a crystalline glycolate, a crystalline glutarate, a crystalline mesylate, a crystalline sulfate, a crystalline bishydrochloride, and a crystalline citrate of the compound of formula (I).

[0115] In some embodiments, the crystalline hydrochloride salt form of the compound of formula (I) has the structure:

[0116] [ka] It has a solvate thereof.

[0117] In other aspects, the crystalline hydrochloride salt form of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some aspects, the crystalline hydrochloride salt form or solvate thereof is a hemihydrochloride salt. In some embodiments, the crystalline hydrochloride salt form of the compound of Formula (I) is characterized by an XRPD pattern substantially as shown in Figure 1 or Figure 2.

[0118] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline hydrochloride salt or solvate thereof described herein and one or more pharma- ceutically acceptable excipients.

[0119] In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline salt or solvate thereof described herein and one or more pharma- ceutically acceptable excipients.

[0120] Free Base Form In some embodiments, the compound of formula (I) is a free base of the compound of formula (I). In some embodiments, the free base of the compound of formula (I) is crystalline. In some embodiments, the free base of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the free base of the compound of formula (I) is a hydrate. In some other embodiments, the free base of the compound of formula (I) is crystalline and in the form of a solvate.

[0121] In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.2 degrees 2 theta. In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.3 degrees 2 theta. In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.4 degrees 2 theta.

[0122] In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees 2-theta.

[0123] In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees 2-theta.

[0124] In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees 2-theta.

[0125] In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees 2-theta. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline free base salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 11.

[0126] In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 71.0° C. and / or about 130.2° C. as determined by DSC. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having a DSC curve substantially as shown in FIG.

[0127] In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 3.7% from about 26.5° C. to about 70.0° C. and a weight loss of about 2.7% from 70.0° C. to about 170.0° C. as determined by TGA. In certain embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having a TGA graph substantially as shown in Figure 12. In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in Figure 14.

[0128] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline free base of a compound of formula (I) or a solvate thereof as described herein, and one or more pharma- ceutically acceptable excipients.

[0129] Salt ratio In some embodiments, the compound of formula (I) is in the form of a pharma- ceutically acceptable salt. In certain embodiments, the pharma-ceutically acceptable salt of the compound of formula (I) is crystalline. In some embodiments, the crystalline pharma-ceutically acceptable salt of the compound of formula (I) comprises the cationic form of the compound of formula (I) and a pharma-ceutically acceptable anion. For example, the crystalline hydrochloride salt of the compound of formula (I) comprises the compound of formula (I) in its cationic form and a chloride anion. The salt compositions described herein comprise the salt of the compound of formula (I), wherein the salt is a pharma-ceutically acceptable salt selected from acetate, fumarate, glycolate, glutarate, mesylate, sulfate, citrate, bishydrochloride, and the like.

[0130] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a hydrochloride salt, and the anion is chloride. In some embodiments, the salt of the compound of formula (I) is an acetate salt, and the anion is acetate. In some embodiments, the salt of the compound of formula (I) is a fumarate salt, and the anion is fumaric acid. In some embodiments, the salt of the compound of formula (I) is a glutarate salt, and the anion is glutaric acid. In some embodiments, the salt of the compound of formula (I) is a glycolate salt, and the anion is glycolic acid. In some embodiments, the salt of the compound of formula (I) is a mesylate salt, and the anion is mesylic acid. In some embodiments, the salt of the compound of formula (I) is a sulfate salt, and the anion is sulfate. In some embodiments, the salt of the compound of formula (I) is a citrate salt, and the anion is citrate. In some embodiments, the salt of the compound of formula (I) is a bishydrochloride salt, and the anion is chloride.

[0131] In some embodiments, the molar equivalent of the anion of the crystalline salt of the compound of Formula (I) to 1 mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the anion of the salt of the compound of Formula (I) to 1 mole of the compound of Formula (I) is about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0, including any amount therebetween and any subportion therebetween.

[0132] In some embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.5 to about 1.0. In certain embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.6 to about 0.7.

[0133] In some embodiments, the molar equivalent of acetate anion of the crystalline acetate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of acetate anion of the crystalline acetate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of acetate anion of the crystalline acetate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.5 to about 1.0. In certain embodiments, the molar equivalent of acetic acid of the crystalline acetate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.6 to about 0.7. In certain embodiments, the molar equivalent of acetic acid of the crystalline acetate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.65.

[0134] In some embodiments, the molar equivalent of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.5 to about 1.0. In other embodiments, the molar equivalent of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.0 to about 1.5. In other embodiments, the molar equivalent of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 2.0.

[0135] In some embodiments, the molar equivalent of the glutaric acid anion of the crystalline glutarate salt of the compound of formula (I) to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the glutaric acid anion of the crystalline glutarate salt of the compound of formula (I) to 1 mole of the compound of formula (I) is about 0.2 to about 1.0. In other embodiments, the molar equivalent of the glutaric acid anion of the crystalline glutarate salt of the compound of formula (I) to 1 mole of the compound of formula (I) is about 0.3 to about 0.6. In certain embodiments, the molar equivalent of the glutaric acid anion of the crystalline glutarate salt of the compound of formula (I) to 1 mole of the compound of formula (I) is about 0.5.

[0136] In some embodiments, the molar equivalent of the glycolate anion of the crystalline glycolate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the glycolate anion of the crystalline glycolate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 1.0. In other embodiments, the molar equivalent of the glycolate anion of the crystalline glycolate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.3 to about 0.6. In certain embodiments, the molar equivalent of the glycolate anion of the crystalline glycolate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.5.

[0137] In some embodiments, the molar equivalent of mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalent of mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 2.0. In other embodiments, the molar equivalent of mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.8 to about 1.9. In certain embodiments, the molar equivalent of mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.8.

[0138] In some embodiments, the molar equivalent of sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalent of sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 2.0. In other embodiments, the molar equivalent of sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 1.7. In certain embodiments, the molar equivalent of sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.6.

[0139] In some embodiments, the molar equivalent of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.5 to about 1.0. In other embodiments, the molar equivalent of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.0 to about 1.5. In other embodiments, the molar equivalent of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 2.0.

[0140] In some embodiments, the molar equivalent of the chloride anion of the crystalline bis-hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the chloride anion of the crystalline bis-hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalent of the chloride anion of the crystalline bis-hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.5 to about 2.0. In certain embodiments, the molar equivalent of the chloride anion of the crystalline bis-hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 1.9 to about 2.0. In certain embodiments, the molar equivalent of the chloride anion of the crystalline bis-hydrochloride salt of the compound of formula (I) relative to 1 mole of the compound of formula (I) is about 2.0.

[0141] Salt Form Hydrochloride In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. In some embodiments, the hydrochloride salt of the compound of formula (I) is crystalline. In some embodiments, the hydrochloride salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride salt of the compound of formula (I) is a hydrate. In some other embodiments, the hydrochloride salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0142] In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. In some embodiments, the hydrochloride salt of the compound of formula (I) is crystalline. In some embodiments, the hydrochloride salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride salt of the compound of formula (I) is a hydrate. In some other embodiments, the hydrochloride salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0143] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0144] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of SEQ ID NO: 1 or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0145] In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees 2-theta. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees 2-theta. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees 2-theta.

[0146] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 1. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 2.

[0147] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2-theta.

[0148] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 3.

[0149] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in FIG. 1, FIG. 2, or FIG.

[0150] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 81.4° C. as determined by differential scanning calorimetry (DSC). In certain embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a DSC curve substantially as shown in FIG.

[0151] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 5.6% at about 26.5° C. to about 160.0° C. as determined by thermogravimetric analysis (TGA). In certain embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a TGA graph substantially as shown in FIG. 4. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in FIG. 6.

[0152] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof as described herein, and one or more pharma- ceutically acceptable excipients.

[0153] Acetate In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is an acetate salt. In some embodiments, the acetate salt of the compound of formula (I) is crystalline. In some embodiments, the acetate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the acetate salt of the compound of formula (I) is a hydrate. In some other embodiments, the acetate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0154] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2 theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2 theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2 theta.

[0155] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0156] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0157] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees 2-theta.

[0158] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least three diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO:1 or a solvate thereof is characterized by having an XRPD pattern having at least three diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least three diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees 2-theta.

[0159] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of a peptide of a compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees 2-theta.

[0160] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 3 theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.3 degrees 2 theta. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO:1 or a solvate thereof is characterized by having an XRPD pattern having at least three diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees 2-theta.

[0161] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees 2-theta.

[0162] In some embodiments, the crystalline acetate salt of a peptide of a compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in FIG.

[0163] In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 80.7° C. and / or about 240.7° C. as determined by DSC. In certain embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having a DSC curve substantially as shown in FIG.

[0164] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof is characterized by having a weight loss of about 5.8% as determined by TGA from about 26.5° C. to about 150.0° C. In certain embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof is characterized by having a TGA graph substantially as shown in Figure 8. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in Figure 10.

[0165] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline acetate salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutically acceptable excipient.

[0166] Fumarate In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a fumarate salt. In some embodiments, the fumarate salt of the compound of formula (I) is crystalline. In some embodiments, the fumarate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the fumarate salt of the compound of formula (I) is a hydrate. In some other embodiments, the fumarate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0167] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0168] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0169] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0170] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.4 degrees 2-theta.

[0171] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7, 17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 15.

[0172] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 65.3° C. as determined by DSC. In certain embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having a DSC curve substantially as shown in FIG. 17. In some embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 4.4% at about 26.5° C. to about 110.0° C. as determined by TGA. In certain embodiments, the crystalline fumarate salt of the compound of formula (I) or a solvate thereof is characterized by having a TGA graph substantially as shown in FIG. 16.

[0173] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline fumarate salt of the compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutical acceptable excipient.

[0174] Glutarate In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a glutarate salt. In some embodiments, the glutarate salt of the compound of formula (I) is crystalline. In some embodiments, the glutarate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate salt of the glutarate salt of the compound of formula (I) is a hydrate. In some other embodiments, the glutarate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0175] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0176] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0177] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0178] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.4 degrees 2-theta.

[0179] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 18.

[0180] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 224.0° C. as determined by simultaneous thermal analysis (SDT). In certain embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG. 19. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 6.4% from about 26.5° C. to about 125.0° C. as determined by SDT. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in FIG. 20.

[0181] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline glutarate salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutical acceptable excipient.

[0182] Glycolic acid salt of peptide of SEQ ID NO:1 In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a glycolate salt. In some embodiments, the glycolate salt of the compound of formula (I) is crystalline. In some embodiments, the glycolate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the glycolate salt of the compound of formula (I) is a hydrate. In some other embodiments, the glycolate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0183] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0184] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0185] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0186] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.4 degrees 2-theta.

[0187] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 21.

[0188] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an endothermic peak, as determined by SDT, at about 237.0° C. In certain embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG.

[0189] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having a weight loss of about 5.1% from about 26.5° C. to about 100.0° C. as determined by SDT. In certain embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG. 22. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in FIG.

[0190] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline glycolate salt of the compound of formula (I) or a solvate thereof as described herein, and one or more pharma- ceutically acceptable excipients.

[0191] Sulfate of peptide of SEQ ID NO:1 In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a sulfate salt. In some embodiments, the sulfate salt of the compound of formula (I) is crystalline. In some embodiments, the sulfate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the sulfate salt of the compound of formula (I) is a hydrate. In some other embodiments, the sulfate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0192] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2 theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2 theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2 theta.

[0193] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2-theta.

[0194] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.4 degrees 2-theta.

[0195] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 26.

[0196] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an endothermic peak, as determined by SDT, at about 255.0° C. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG.

[0197] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having a weight loss, as determined by SDT, of about 4.4% from about 26.5° C. to about 80.0° C. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG.

[0198] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline sulfate salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutical acceptable excipient.

[0199] Mesylate of peptide of SEQ ID NO:1 In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a mesylate salt. In some embodiments, the mesylate salt of the compound of formula (I) is crystalline. In some embodiments, the mesylate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the mesylate salt of the compound of formula (I) is a hydrate. In some other embodiments, the mesylate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0200] In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0201] In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2-theta.

[0202] In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.2 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.3 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.4 degrees 2-theta.

[0203] In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.2 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.3 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8, and 27.8 degrees 2-theta + / - 0.4 degrees 2-theta. In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 24.

[0204] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an endothermic peak at about 242.1° C. as determined by SDT. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG. 25. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having a weight loss of about 5.4% at about 26.5° C. to about 80.0° C. as determined by SDT. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an SDT thermogram substantially as shown in FIG. 25.

[0205] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline mesylate salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutically acceptable excipient.

[0206] Citrate salt of peptide of SEQ ID NO:1 In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a citrate salt. In some embodiments, the citrate salt of the compound of formula (I) is crystalline. In some embodiments, the citrate salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the citrate salt of the compound of formula (I) is a hydrate. In some other embodiments, the citrate salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0207] In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2-theta.

[0208] In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2-theta.

[0209] In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.4 degrees 2-theta.

[0210] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1, 13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in FIG.

[0211] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline citrate salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutical acceptable excipient.

[0212] Bishydrochloride salt of peptide of SEQ ID NO:1 In some embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is a bishydrochloride salt. In some embodiments, the bishydrochloride salt of the compound of formula (I) is crystalline. In some embodiments, the bishydrochloride salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the bishydrochloride salt of the compound of formula (I) is a hydrate. In some other embodiments, the bishydrochloride salt of the compound of formula (I) is crystalline and in the form of a solvate.

[0213] In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2 theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2 theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2 theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2 theta.

[0214] In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with two or more diffraction peaks at 2-theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0215] In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline bishydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees 2-theta.

[0216] In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at 2-theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.4 degrees 2-theta.

[0217] In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an XRPD pattern with diffraction peaks at 2-theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.4 degrees 2-theta. In some embodiments, the crystalline bis hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by an XRPD pattern substantially as shown in Figure 29.

[0218] In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 79.5° C. and / or about 235.3° C. as determined by DSC. In certain embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a DSC curve substantially as shown in FIG.

[0219] In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 11.3% as determined by TGA from about 26.5° C. to about 190.0° C. In certain embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a TGA graph substantially as shown in FIG.

[0220] In some embodiments, the crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a DVS graph substantially as shown in FIG.

[0221] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline bis-hydrochloride salt of a compound of formula (I) or a solvate thereof as described herein, and a pharma- ceutical acceptable excipient.

[0222] purity In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof produced by the methods described herein 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 suitable methods. In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-100%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate 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 and portions therebetween. In other embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of about 95.0% to 99.9%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of at least 95%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of at least 96%. In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof has a purity level of at least 97%. In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof has a purity level of at least 98%. In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof has a purity level of at least 99%. In some embodiments, the crystalline salt of the compound of formula (I) or a solvate thereof has a purity level of at least 99.5%.

[0223] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof 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 and portions therebetween. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof has a purity level of about 99.0% to 99.5%. In certain embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof has a purity level of at least 99.0%.

[0224] In some embodiments, the crystalline acetate salt of the compound of formula (I) or its solvate 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 and portions therebetween. In certain embodiments, the crystalline acetate salt of the compound of formula (I) or its solvate has a purity level of at least 99.0%. In other embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of about 99.0% to 99.5%.

[0225] In some embodiments, the crystalline fumarate salt of the compound of formula (I) or its solvate has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount and portions therebetween. In other embodiments, the crystalline fumarate salt of the compound of formula (I) or its solvate has a purity level of about 86%-90%. In other embodiments, the crystalline fumarate salt of the compound of formula (I) or its solvate has a purity level of about 86%-87%. In certain embodiments, the crystalline fumarate salt of the compound of formula (I) or its solvate has a purity level of at least 86%.

[0226] In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof 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 99.3%, including any amount and portions therebetween. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of about 85%-90%. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-95%. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of about 95%-99%. In some embodiments, the crystalline glutaric acid salt of the compound of formula (I) or a solvate thereof has a purity level of about 99.0% to 99.5%. In some embodiments, the crystalline glutaric acid salt of the compound of formula (I) or a solvate thereof has a purity level of at least 99.0%.

[0227] In some embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount and portions therebetween. In other embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-95%. In other embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof has a purity level of about 95%-99%. In other embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-92%. In certain embodiments, the crystalline mesylate salt of the compound of formula (I) or a solvate thereof has a purity level of at least 90%.

[0228] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount and portion therebetween. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-95%. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof has a purity level of about 95%-99%. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof has a purity level of about 90%-92%. In certain embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof has a purity level of at least 91%.

[0229] In some embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof 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 and portions therebetween. In other embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof has a purity level of about 99.0% to 99.9%. In certain embodiments, the crystalline citrate salt of the compound of formula (I) or a solvate thereof has a purity level of at least 99.5%.

[0230] In some embodiments, the crystalline free base of the compound of formula (I) or its solvate 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 99.3%, including any amount and part therebetween. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 97.0%. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 98.0%. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 99.0%. In another embodiment, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of about 97.0% to 98.0%. In another embodiment, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of between about 98.0%. In another embodiment, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of between about 99.0%.

[0231] IV. Pharmaceutical Compositions In general, the present invention relates to pharmaceutical hydrochloride salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0232] Furthermore, the present invention relates to pharmaceutical crystalline salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0233] In one aspect, the present invention provides a compound of formula (I): Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen]* -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (wherein ([Pen] * -[Pen] * forms a disulfide bond), and has the chemical structure shown below,

[0234] [ka] It relates to pharmaceutical compositions of the hydrochloride salt of the corresponding solvate.

[0235] In some embodiments, the monocyclic peptide comprises the amino acid sequence Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2, wherein the monocyclic peptide is cyclized via a Pen-Pen disulfide bond, or a pharma- ceutically acceptable salt thereof. In any of the foregoing embodiments, one or more amino acids are in the L-configuration. In certain embodiments, all amino acids are in the L-configuration.

[0236] In some embodiments, the crystalline form of the compound of formula (I) or a solvate thereof has a water content ranging from 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 the compound of formula (I) or a solvate thereof has a water 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 the compound of formula (I) or a solvate thereof has a water 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 the compound of formula (I) or a solvate thereof has a water content level of less 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.

[0237] In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 0.1% to about 65% by weight, about 0.1% to about 60% by weight, about 0.1% to about 55% by weight, about 0.1% to about 50% by weight, about 0.1% to about 45% by weight, about 0.1% to about 40% by weight, about 0.1% to about 35% by weight, about 0.1% to about 30% by weight, about 0.1% to about 25% by weight, about 0.1% to about 20% by weight, about 0.1% to about 15% by weight, about 0.1% to about 10% by weight, or about 0.1% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 1% to about 65% by weight, about 1% to about 60% by weight, about 1% to about 55% by weight, about 1% to about 50% by weight, about 1% to about 45% by weight, about 1% to about 40% by weight, about 1% to about 35% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, or about 1% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 2% to about 65% by weight, about 2% to about 60% by weight, about 2% to about 55% by weight, about 2% to about 50% by weight, about 2% to about 45% by weight, about 2% to about 40% by weight, about 2% to about 35% by weight, about 2% to about 30% by weight, about 2% to about 25% by weight, about 2% to about 20% by weight, about 2% to about 15% by weight, about 2% to about 10% by weight, or about 2% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 5% to about 65% by weight, about 5% to about 60% by weight, about 5% to about 55% by weight, about 5% to about 50% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, or about 5% to about 10% by weight.In some embodiments, the amount of crystalline form of the compound of formula (I) or a solvate thereof 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.

[0238] In another embodiment, the hydrochloride of the compound of formula (I) or its corresponding solvate can be in any form, such as a hydrate or other solvate. In some embodiments, the hydrochloride of the compound of formula (I) or its solvate can be provided in crystalline, amorphous, or semi-crystalline form. In some embodiments, the hydrochloride of the compound of formula (I) or its solvate is in crystalline form. In some embodiments, the hydrochloride of the compound of formula (I) or its solvate is in amorphous form. In some embodiments, the hydrochloride of the compound of formula (I) or its solvate is in semi-crystalline form.

[0239] In one embodiment, the composition of the hydrochloride salt of the compound of formula (I) or a solvate thereof is a hemihydrochloride salt. In some embodiments, the hemihydrochloride salt has about 0.1 to about 0.9, for example, about 0.2 to about 0.8 or about 0.3 to about 0.7 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemihydrochloride salt has about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or about 0.9 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemihydrochloride salt has about 0.5 molar equivalents of hydrogen chloride compared to the compound of formula (I).

[0240] In some embodiments, the hydrochloride form of the compound of formula (I) or a solvate thereof may be a hydrate. In some embodiments, the hydrate of the hydrochloride of the compound of formula (I) has about 0.2 to about 100 molar equivalents of water relative to the compound of formula (I). In another embodiment, the hydrate may be present in the range of about 2% w / w to about 10% w / w of water relative to the hydrochloride of the compound of formula (I). The present invention relates to the hydrochloride composition of the present invention, which may be in a liquid or solid composition.

[0241] In some embodiments, the hydrochloride form of the compound of formula (I) or a solvate thereof has a water content ranging from 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 hydrochloride form of the compound of formula (I) or a solvate thereof has a water 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 hydrochloride salt form of the compound of formula (I) or a solvate thereof has a water 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 hydrochloride salt form of the compound of formula (I) or a solvate thereof has a water content level of less 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.

[0242] The hydrochloride salt compositions of the present invention may be administered to a subject or patient by any means according to a therapeutic administration that achieves the intended purpose or pharmaceutical efficacy. Examples include administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular routes. In some embodiments, administration of the hydrochloride salt compositions of the present invention is adapted for oral administration.

[0243] In another aspect, the present invention provides a composition comprising the hydrochloride salt of a compound of formula (I) or a solvate thereof, in an amount of about 0.1% to about 15% (w / w) of the composition, and one or more pharma- ceutically acceptable excipients.

[0244] In another aspect, the present invention provides a composition comprising the hydrochloride salt of a compound of formula (I) or a solvate thereof, and about 50 mM aqueous phosphate buffer at pH 7.4.

[0245] In another aspect, the invention relates to a composition comprising the hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, an absorption enhancer in an amount of about 10% to about 60% (w / w), and one or more pharma- ceutically acceptable excipients.

[0246] In some embodiments, the amount of the hydrochloride salt of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 0.1% to about 65% by weight, about 0.1% to about 60% by weight, about 0.1% to about 55% by weight, about 0.1% to about 50% by weight, about 0.1% to about 45% by weight, about 0.1% to about 40% by weight, about 0.1% to about 35% by weight, about 0.1% to about 30% by weight, about 0.1% to about 25% by weight, about 0.1% to about 20% by weight, about 0.1% to about 15% by weight, about 0.1% to about 10% by weight, or about 0.1% to about 5% by weight. In some embodiments, the amount of the hydrochloride salt of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 1% to about 65% by weight, about 1% to about 60% by weight, about 1% to about 55% by weight, about 1% to about 50% by weight, about 1% to about 45% by weight, about 1% to about 40% by weight, about 1% to about 35% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, or about 1% to about 5% by weight. In some embodiments, the amount of the hydrochloride salt of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 2% to about 65% by weight, about 2% to about 60% by weight, about 2% to about 55% by weight, about 2% to about 50% by weight, about 2% to about 45% by weight, about 2% to about 40% by weight, about 2% to about 35% by weight, about 2% to about 30% by weight, about 2% to about 25% by weight, about 2% to about 20% by weight, about 2% to about 15% by weight, about 2% to about 10% by weight, or about 2% to about 5% by weight. In some embodiments, the amount of the hydrochloride salt of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 5% to about 65% by weight, about 5% to about 60% by weight, about 5% to about 55% by weight, about 5% to about 50% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, or about 5% to about 10% by weight.In some embodiments, the amount of the hydrochloride salt of the compound of formula (I) or a solvate thereof 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.

[0247] In another aspect, the present invention provides a composition comprising the hydrochloride salt of a compound of formula (I) or a solvate thereof, in an amount of about 0.1% to about 15% (w / w) of the composition; sodium caprate, in an amount of about 20% to about 45% (w / w) of the composition; and microcrystalline cellulose.

[0248] In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in any amount of about 0.1% to about 15% (w / w) of the composition. For example, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 0.5% to about 15% (w / w), or about 1% to about 10%, or about 0.5% to about 5%, or about 0.5% to about 3%, or about 1% to about 3%, or about 1.5% to about 2.5%, or about 1.5% to about 2.0% (w / w) of the composition. In another embodiment, the hydrochloride of the compound of formula (I) or its solvate is present in an amount of about 1% to about 5% (w / w).

[0249] In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 1 to about 5% (w / w). For example, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount including about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition, and any fractional amount therebetween. In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 1.8% (w / w).

[0250] In another embodiment, the hydrochloride of the compound of formula (I) or a solvate thereof may be present in any amount, for example, about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. In another embodiment, the amount of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 1 mg to about 1000 mg. In another embodiment, the amount of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 5 mg to about 300 mg. In another embodiment, the amount of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 25 mg to about 150 mg. In another embodiment, the amount of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 25 mg to about 100 mg. In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 1 mg to about 100 mg. In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 20 mg to about 40 mg. In another embodiment, the hydrochloride of the compound of formula (I) or its solvate may be present in an amount of about 20 mg to about 30 mg.

[0251] In yet another embodiment, the hydrochloride salt of the compound of formula (I) or its solvate may be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg, including any amount therebetween and portions thereof. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 5 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 10 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 25 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 50 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 75 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 100 mg. In another embodiment, the amount of the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present at about 150 mg.

[0252] In another embodiment, the amount of the crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof can be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg, including any amount therebetween and any subportion therebetween.

[0253] Generally, the pharmaceutical composition of the present invention can be formed into different dosage forms prepared using conventional materials and techniques known in the pharmaceutical and formulation fields, including but not limited to techniques such as mixing, blending, and the like, and as described throughout this disclosure. In addition, the pharmaceutical composition used to form the dosage form can also include, but is not limited to, suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form, such as solid or liquid dosage forms, including but not limited to tablets, capsules, powders, solutions, suspensions, or emulsions, and the like. According to the present invention, the solid unit dosage form can be of other conventional types known in the art.

[0254] Suitable compositions of the present invention may be in different forms, including but not limited to liquids, tablets, capsules, etc. In some aspects, the composition may be a tablet composition or a capsule composition.

[0255] Additionally, solutions are suitable for use in the present invention and can be in, for example, but not limited to, water, saline, aqueous dextrose and related sugar solutions, and glycol buffers such as propylene glycol or polyethylene glycol buffers, which 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.

[0256] The compositions of the present invention may contain a variety of other pharma- ceutically acceptable components or excipients, including, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients, such as those described herein.

[0257] According to the present invention, the compositions described herein may include at least one filler. In some embodiments, the compositions of the present invention may include fillers, including, but 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. In some embodiments, the compositions of the present invention may include mannitol. In other embodiments, the compositions of the present invention may include sorbitol.

[0258] Representative fillers for use in the compositions of the present invention may include, but are not limited to, starch, lactitol, lactose, inorganic calcium salts, microcrystalline cellulose, sucrose, and combinations thereof. Additional fillers or diluents for use in the compositions of the present invention may include, but are not limited to, fillers or diluents that are typically used in the formulation of pharmaceutical compounds and are conventionally known in the art. Examples of such fillers or diluents for use according to the present invention may include, but are not limited to, sugars, such as lactose, dextrose, glucose, sucrose, cellulose, starch, and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, and combinations thereof. In some aspects, such fillers or diluents suitable for use in the present invention may include, but are not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0259] Further, in some embodiments, bulking agents for use in the present invention may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 3% to about 5% (w / w) of the composition, as defined herein. Further, such bulking agents 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, and amounts may include any subdivision therebetween as defined herein.

[0260] In some embodiments, the filler, as defined herein, is present in an amount of about 10% to about 95% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 25% to about 95% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 30% to about 90% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 10% to about 50% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 10% to about 40% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 10% to about 30% (w / w) of the composition. In some embodiments, the filler, as defined herein, is present in an amount of about 10% to about 20% (w / w) of the composition. In certain embodiments, the filler, as defined herein, is present in an amount of about 10% to about 15% (w / w). In certain embodiments, the filler is present in an amount of about 12% (w / w).

[0261] In some embodiments, the composition can further comprise microcrystalline cellulose. Several types of microcrystalline cellulose are suitable for use in the compositions described herein, for example, the microcrystalline cellulose can be selected from, but not limited to, MICROCEL® or AVICEL® types PH101, PH102, PH103, PH105, PH112, PH113, PH200, and PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one embodiment, the filler for use in the present invention can comprise microcrystalline cellulose (AVICEL PH102). In another embodiment, the composition suitable for use in the present invention can comprise microcrystalline cellulose (AVICEL PH101).

[0262] In another embodiment, the microcrystalline cellulose may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50% (w / w) of the composition, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 3% to about 5% (w / w) of the composition, as defined herein. In some embodiments, the 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, and the amount may include any fractional amount therebetween as defined. In some embodiments, the microcrystalline cellulose may also be present in an amount of about 3% to about 5% (w / w) of the composition.

[0263] In some embodiments, the composition can further comprise silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose can be, but is not limited to, SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. In some embodiments, the silicified microcrystalline cellulose can be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. Without being bound by theory, it is understood that the silicified microcrystalline cellulose protects the enteric coating from premature erosion by sodium caprate present in the composition. The silicified microcrystalline cellulose can be present in any amount suitable for use in the present invention. For example, SMCC can be present in an amount of about 1% to about 99% (w / w) of the composition, or about 10% to about 50%, or about 20% to about 50%, or about 25% to about 45%, or about 30% to about 40%, or about 35% to about 37% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is about 30% to about 70% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is about 65% to about 85% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is about 66.5% to about 81.3% (w / w) of the composition. In some embodiments, the amount of 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. 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.

[0264] In some embodiments, SMCC is present in an amount of about 20% to about 90% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 25% to about 85% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 25% to about 45% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 30% to about 40% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 65% to about 90% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 70% to about 85% (w / w), including but not limited to any fraction therebetween. In some embodiments, SMCC is present in an amount of about 70% to about 75% (w / w), including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 80% to about 85% (w / w), including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 30%. In some embodiments, SMCC is present in an amount of about 40%, including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 50%, including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 60%, including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 70%, including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 80%, including but not limited to any fractional amounts therebetween. In some embodiments, SMCC is present in an amount of about 90%, including but not limited to any amount subdivision therebetween.

[0265] In some embodiments, the SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0266] In some embodiments, the composition can further comprise 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 can further comprise mannitol.

[0267] In some embodiments, the compositions of the present invention may include sorbitol. For example, for use in the present invention, sorbitol may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50% of the composition, or about 1% to about 25%, or about 5% to about 25%, or about 5% to about 20%, or about 5 to about 15%, or about 8 to about 12% (w / w). In another embodiment, sorbitol may 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 comprises sorbitol in an amount of about 5% to about 15% (w / w) of the composition. In some embodiments, the amount of sorbitol is about 10% to about 15% (w / w) of the composition. In some embodiments, the composition comprises sorbitol in an amount of about 10.7% (w / w) of the composition.

[0268] In some embodiments, the compositions of the present invention may include mannitol. For example, for use in the present invention, mannitol may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50% of the composition, or about 1% to about 25%, or about 5% to about 25%, or about 5% to about 20%, or about 5 to about 15%, or about 8 to about 12% (w / w). In another embodiment, mannitol may 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, including, but not limited to, any subdivision therebetween. In some embodiments, the composition also comprises mannitol in an amount of about 5% to about 15% (w / w) of the composition. In some embodiments, the amount of mannitol is about 10% to about 15% (w / w) of the composition. In some embodiments, the composition comprises mannitol in an amount of about 10.7% (w / w) of the composition.

[0269] In one embodiment, the amount of sugar alcohol can be present in the range of about 1% to about 50% (w / w) of the composition, or about 5% to about 50%, or about 5% to about 30%, or about 10% to about 30% (w / w) of the composition. In some aspects, the amount of 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 aspects, the amount of sugar alcohol can be present in an amount of more than about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some aspects, the amount of sugar alcohol may be present in an amount less than about 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition.

[0270] In some embodiments, the pharmaceutical compositions described herein do not contain a sugar alcohol. In some embodiments, the pharmaceutical compositions described herein do not contain sorbitol. In some embodiments, the pharmaceutical compositions described herein do not contain mannitol.

[0271] The composition of the present invention may comprise at least one disintegrant in an effective therapeutic amount for use as determined by the present invention, but is not limited thereto.Exemplary disintegrants for use in the present invention include, but are not limited to, starch, clay, cellulose, alginate, and gum, as well as cross-linked starch, cellulose, and polymer, combinations thereof, and the like.Additional exemplary disintegrants for use in the present invention 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.

[0272] In some embodiments, the disintegrant is cross-linked carboxymethylcellulose (croscarmellose), starch glycolate, polyvinylpyrrolidone, sago starch, psyllium husk, silicate, or soy polysaccharide. In some embodiments, the disintegrant is croscarmellose sodium or crospovidone. In some embodiments, the disintegrant for use in the present invention can include, but is not limited to, croscarmellose sodium. In some embodiments, the disintegrant for use in the present invention can include crospovidone. In some embodiments, the disintegrant can be present in an amount of about 1% to about 99% (w / w) of the composition of the present invention, or about 1% to about 50%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 4% to about 6% (w / w) of the composition. Disintegrants for use in the present invention 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, including, but not limited to, any subdivision therebetween. In some embodiments, the amount of disintegrant may be present in an amount of about 1% to about 10% (w / w) of the composition of the present invention. In some embodiments, the amount of disintegrant may be present in an amount of about 8% to about 12% (w / w) of the composition of the present invention. In some embodiments, the amount of disintegrant may be present in an amount of about 3% to about 8% (w / w) of the composition of the present invention.

[0273] In another embodiment, the composition of the present invention may also contain any amount of silica for purposes of the present invention, but is not limited thereto. In particular, the silica may be in an amount of about 200 ml. 2 exemplified by Aerosil 200, which has a specific surface area of ​​1000 nm / 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.

[0274] In some embodiments, the composition of the present invention may further comprise silica. In one embodiment, silica may be present in the composition of the present invention in an amount of about 0.1% to about 10% (w / w) of the composition, or about 0.1% to about 5%, or about 0.1% to about 2%, or about 0.1% to about 1.5%, or about 0.1% to about 1.25%, or about 0.5% to about 1.5%, or about 1.0% to about 1.25%, or about 0.1% to about 1%, or about 0.3% to about 0.7% (w / w) of the composition of the present invention. For example, silica as used in the present invention 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 subdivision therebetween as defined. In another embodiment, the composition of the present invention may further comprise silica in an amount of about 0.1% to about 1.5% (w / w) of the composition. In another embodiment, the composition of the present invention may further comprise silica in an amount of about 0.5% to about 2% (w / w) of the composition. In another embodiment, the composition of the present invention may further comprise silica in an amount of about 0.3% to about 0.7% (w / w) of the composition. In a further embodiment, the composition of the present invention may further comprise silica in an amount of about 0.5% (w / w) of the composition. In some aspects, the composition may further 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, fumed silicon dioxide, colloidal anhydrous silica, colloidal silicon dioxide, etc. In some embodiments, the silica is colloidal silica.

[0275] The composition can also include a binder.The binder for use in the composition of the present invention includes binders commonly used in pharmaceutical preparations.The examples of binders for use in the present invention include, but are not limited to, cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and sodium carboxymethylcellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginate and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof, etc.

[0276] In some embodiments, the binder is hydroxypropylmethylcellulose (HPMC). In some embodiments, the disintegrant for use in the present invention 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, including, but not limited to, any subdivision therebetween.

[0277] In the present invention, the composition may contain any suitable amount of lubricant for use as described herein.Examples of lubricants suitable for use in the present invention may include, but are not limited to, magnesium carbonate, magnesium lauryl sulfate, calcium silicate, talc, fumed silicon dioxide, combinations thereof, etc.Other useful suitable lubricants may include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, etc.

[0278] In some embodiments, the lubricant may include, but is not limited to, magnesium stearate. In one embodiment, the amount of the lubricant may be present at about 0.1% to about 10% (w / w) of the composition, or about 0.1% to about 5%, or about 0.1% to about 2.5%, or about 0.1% to about 1%, or about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, the amount of the lubricant may be present at about 0.5% to about 2.5% or about 0.5% to about 2.0% (w / w) of the composition. In some embodiments, the amount of the lubricant may be present at about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, the amount of the lubricant is 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 may 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 may 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).

[0279] In some embodiments, the composition comprises (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.2% to about 15% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 66.5% to about 81.3% (w / w) of the composition, (iii) sorbitol in an amount of about 12.5% ​​(w / w) of the composition, (iv) a disintegrant in an amount of about 5% (w / w) of the composition, (v) silica in an amount of about 0.5% (w / w) of the composition, and (vi) a lubricant in an amount of about 0.5% (w / w) of the composition.

[0280] In some embodiments, the pharmaceutical composition comprises (i) a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 60% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 40% to about 85% (w / w) of the composition, (iii) a disintegrant in an amount of about 5% to about 10% (w / w) of the composition, (iv) silica in an amount of about 0.1% to about 1.0% (w / w) of the composition, and (v) a lubricant in an amount of about 0.5% to about 1.5% (w / w) of the composition.

[0281] In some embodiments, the pharmaceutical composition comprises (i) a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 10% to about 20% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 85% (w / w) of the composition, (iii) crospovidone in an amount of about 5% (w / w) of the composition, (iv) silica in an amount of about 0.2% (w / w) of the composition, and (v) magnesium stearate in an amount of about 0.5% of the composition.

[0282] In some embodiments, the pharmaceutical composition comprises (i) an absorption enhancer in an amount of about 5% to about 65% (w / w) of the composition, (ii) a crystalline form of a pharma- ceutically acceptable salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, and (iii) silicified microcrystalline cellulose in an amount of about 10% to about 50% (w / w) of the composition.

[0283] In some embodiments, the pharmaceutical composition comprises (i) an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition, (ii) a disintegrant in an amount of about 5% to about 10% (w / w) of the composition, and (iii) a crystalline form of a pharma- ceutically acceptable salt of a compound of formula (I) or a solvate thereof in an amount of about 0.5% to about 15% (w / w) of the composition, (iv) silicified microcrystalline cellulose in an amount of about 30% to about 40% (w / w) of the composition, (v) silica in an amount of about 0.2% to about 1.5% (w / w) of the composition, (vi) a disintegrant in an amount of about 5% to about 10% (w / w) of the composition, (vii) a filler in an amount of about 7.5% to about 15% (w / w) of the composition, and (viii) a lubricant in an amount of about 0.2% to about 1.5% (w / w) of the composition.

[0284] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof in an amount of about 10% to about 20% (w / w) of the composition; (ii) an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; (iii) a disintegrant in an amount of about 0.5% to about 1.0% (w / w) of the composition; (iv) crospovidone in an amount of about 5% (w / w) of the composition; (vi) a crystalline form of a pharma- ceutical acceptable salt of the compound of formula (I) or a solvate thereof in an amount of about 10% to about 20% (w / w) of the composition; (ii) an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; (iii) a disintegrant in an amount of about 0.5% to about 1.0% (w / w) of the composition; (iv) crospovidone in an amount of about 5% (w / w) of the composition; (w / w) of the composition, (vii) silicified microcrystalline cellulose in an amount of about 34.8% to about 39.7% (w / w) of the composition, (viii) mannitol in an amount of about 10.7% (w / w) of the composition, (ix) crospovidone in an amount of about 5% (w / w) of the composition, (x) silica in an amount of about 1.0% (w / w) of the composition, and (xi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0285] In some embodiments, the pharmaceutical composition comprises (i) sodium caprate in an amount of about 38.5% (w / w) of the composition, (ii) hydroxypropyl methylcellulose in an amount of about 0.8% (w / w) of the composition, (iii) a crystalline form of a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof in an amount from about 3.9% (w / w) of the composition, (iv) silicified microcrystalline cellulose in an amount of about 39.7% (w / w) of the composition, (v) mannitol in an amount of about 10.7% (w / w) of the composition, (vi) crospovidone in an amount of about 5% to about 7.5% (w / w) of the composition, (vii) silica in an amount of about 0.5% to about 1.0% (w / w) of the composition, and (viii) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0286] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharma- ceutical acceptable salt of the compound of formula (I) or a solvate thereof in an amount of about 10% to about 20% (w / w) of the composition; (ii) an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; (iii) a disintegrant in an amount of about 0.5% to about 1.0% (w / w) of the composition; (iv) crospovidone in an amount of about 5% (w / w) of the composition; (v) a crystalline form of a pharma- ceutical acceptable salt of the compound of formula (I) or a solvate thereof in an amount of about 10% to about 20% (w / w) of the composition; (vi) an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; (vii) a disintegrant in an amount of about 0.5% to about 1.0% (w / w) of the composition; (viii) a disintegrant in an amount of about 0.5% to about 1.0% (w / w) of the composition; (viiii ... (w / w) of the composition, (vi) silicified microcrystalline cellulose in an amount of about 34.8% to about 39.7% (w / w) of the composition, (vii) mannitol in an amount of about 10.7% (w / w) of the composition, (viii) crospovidone in an amount of about 5% (w / w) of the composition, (ix) silica in an amount of about 1.0% (w / w) of the composition, and (x) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0287] In some embodiments, the composition comprises (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 1% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 80.5% (w / w) of the composition, (iii) sorbitol in an amount of about 12.5% ​​(w / w) of the composition, (iv) crospovidone in an amount of about 5% (w / w) of the composition, (v) silica in an amount of about 0.5% (w / w) of the composition, and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0288] In some embodiments, the composition comprises (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 2.5% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 79% (w / w) of the composition, (iii) sorbitol in an amount of about 12.5% ​​(w / w) of the composition, (iv) crospovidone in an amount of about 5% (w / w) of the composition, (v) silica in an amount of about 0.5% (w / w) of the composition, and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0289] In some embodiments, the composition comprises (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof in an amount of about 10% (w / w) of the composition, (ii) silicified microcrystalline cellulose in an amount of about 71.5% (w / w) of the composition, (iii) sorbitol in an amount of about 12.5% ​​(w / w) of the composition, (iv) crospovidone in an amount of about 5% (w / w) of the composition, (v) silica in an amount of about 0.5% (w / w) of the composition, and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition. The tablet composition may also include one or more coatings.

[0290] The compositions described herein may contain a variety of other pharma- ceutically acceptable components or excipients, including, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients.

[0291] The compositions described herein may include at least one disintegrant in any suitable amount according to the present invention. Representative disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one embodiment, the disintegrant may include croscarmellose sodium. In one embodiment, the disintegrant may include crospovidone. In another embodiment, the suitable disintegrant may be 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, but is not limited thereto, and the amount includes any subdivision therebetween as defined in the present invention. In another embodiment of the present invention, the disintegrant may be present in an amount of about 1-10% (w / w) of the composition, but is not limited thereto. In another embodiment, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0292] In some embodiments, the microcrystalline cellulose may be present in an amount of about 1% to about 10% (w / w) of the composition. In some embodiments, the microcrystalline cellulose may be present in an amount of about 3.9% (w / w) of the composition.

[0293] In some embodiments, the composition may further comprise silica. In some embodiments, the composition may further comprise silica in an amount of about 0.1% to about 1.5% (w / w) of the composition. For example, silica may 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 subdivision therebetween as defined herein. In some embodiments, the composition may further comprise silica in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition may further comprise silica in an amount of about 0.5% to about 2% (w / w) of the composition. In some embodiments, the composition may further comprise silica in an amount of about 0.5% (w / w) of the composition.

[0294] In another embodiment, the compositions of the present invention may further comprise at least one of a disintegrant in an amount of about 1% to about 10% (w / w) of the composition, microcrystalline cellulose in an amount of about 1% to about 10% (w / w) of the composition, silica in an amount of about 0.1% to about 1.5% (w / w) of the composition, or sorbitol in an amount of about 5% to about 15% (w / w) of the composition.

[0295] In yet another embodiment, the composition may further comprise a disintegrant in an amount of about 1% to about 10% (w / w) of the composition, microcrystalline cellulose in an amount of about 1% to about 10% (w / w) of the composition, silica in an amount of about 0.1% to about 1.5% (w / w) of the composition, and sorbitol in an amount of about 5% to about 15% (w / w) of the composition.

[0296] In some embodiments, the compositions of the present invention may further comprise at least one of 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 silica in an amount of about 0.5% (w / w).

[0297] In some embodiments, the composition may further comprise 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 silica in an amount of about 0.5% (w / w).

[0298] In some embodiments, the composition may further comprise Avicel PH101 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).

[0299] The microcrystalline cellulose can include any microcrystalline cellulose known in the art. In some embodiments, the microcrystalline cellulose can include silicified microcrystalline cellulose (SMCC).

[0300] In some embodiments, for use in the present invention, the microcrystalline cellulose may be silicified microcrystalline cellulose (SMCC) and may have any particle size. In some embodiments, the composition comprises silicified microcrystalline cellulose in an amount of about 25% to about 45% (w / w) of the composition. In some embodiments, the composition comprises silicified microcrystalline cellulose in an amount of about 36.6% (w / w) of the composition.

[0301] The composition may include at least one disintegrant in any suitable amount according to the present invention. Exemplary disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one embodiment, the disintegrant may include croscarmellose sodium. In one embodiment, the disintegrant may include crospovidone. The disintegrant for use in the present invention may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 4% to about 6% (w / w) of the composition, but is not limited thereto. In another embodiment, a suitable disintegrant may be 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, but is not limited thereto, including any subdivision therebetween as defined herein. In another embodiment of the present invention, the disintegrant may be present in an amount of about 1% to about 10% (w / w) of the composition, but is not limited thereto. In another embodiment, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0302] In another embodiment, the composition may also include any amount of silica according to the present invention. 2Silica is exemplified by Aerosil 200, which has a specific surface area of ​​1000 nm / g. Substitutes for silica 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. Silica (e.g., Aerosil 200) may be present in the composition in an amount of about 0.1-10% (w / w) of the composition, or about 0.1-5%, or about 0.1-2%, or about 0.1-1.5%, or about 0.1-1%, or about 0.3-0.7% (w / w) of the composition. For example, 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 subamounts therebetween.

[0303] In some embodiments, the composition may further comprise silica (e.g., Aerosil 200). In some embodiments, the composition may further comprise silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% (w / w) of the composition. For example, the silica may 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 subdivision therebetween as defined herein. In some embodiments, the composition may further comprise silica (e.g., Aerosil 200) in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition may further comprise silica (e.g., Aerosil 200) in an amount of about 0.5% to about 2% (w / w) of the composition. In some embodiments, the composition may further comprise silica (e.g., Aerosil 200) in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition may further comprise silica (e.g., Aerosil 200) in an amount of about 1% (w / w) of the composition.

[0304] The compositions described herein may include various other pharmaceutical excipients or components, including, but not limited to, lubricants, disintegrants, binders, desiccants, fillers, and other components. For use in the present invention, the disintegrant may be present in the composition in an amount of about 0.1% to about 10% (w / w) of the composition, or about 0.1% to about 5%, or about 0.1% to about 2%, or about 0.1% to about 1.5%, or about 0.1% to about 1%, or about 0.1% to about 0.4% (w / w) of the composition. In some embodiments, the composition may further include a disintegrant. In some embodiments, the composition may further include silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% (w / w) of the composition. In some embodiments, the composition may further include a disintegrant in an amount of about 0.25% (w / w) of the composition.

[0305] In some embodiments, the compositions disclosed herein may further comprise at least one of a lubricant in an amount of about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount of about 1% to about 10% by weight of the composition, or silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% by weight of the composition.

[0306] In some embodiments, the composition may further comprise a lubricant in an amount of about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount of about 1% to about 10% by weight of the composition, and silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% by weight of the composition.

[0307] In some embodiments, the compositions disclosed herein may further comprise at least one of a disintegrant in an amount of about 5.0% (w / w), a silica (e.g., Aerosil 200) in an amount of about 0.5% (w / w), and a lubricant in an amount of about 0.25% (w / w).

[0308] In some embodiments, the composition comprises silicified microcrystalline cellulose in an amount of about 36.6% (w / w), a disintegrant in an amount of about 5.0% (w / w), silica (e.g., Aerosil 200) in an amount of about 0.5% (w / w), and a lubricant in an amount of about 0.25% (w / w).

[0309] In some embodiments, the composition comprises SMCC HD90 in an amount of about 36.6% (w / w), croscarmellose sodium in an amount of about 5.0% (w / w), Aerosil 200 in an amount of about 0.5% (w / w), and magnesium stearate in an amount of about 0.25% (w / w).

[0310] In some embodiments, the compositions of the present invention may not include or may exclude the use of an absorption enhancer, depending on the intended delivery or use of the absorption enhancer and / or for the treatment of a particular indication as defined herein.

[0311] In some embodiments described herein, e.g., with respect to pharmaceutical compositions, tablets, methods, processes, etc., absorption enhancers are excluded. In some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., absorption enhancers are included.

[0312] In other aspects, preferred compositions of the present invention may exhibit improved bioavailability when administered with an absorption enhancer.

[0313] In some aspects, the composition of the present invention may include an absorption enhancer. When present, the absorption enhancer may be zwitterionic, cationic, anionic, or nonionic. In one aspect, the absorption enhancer is an intestinal permeation enhancer. In some aspects, the absorption enhancer may be selected from, but is not limited to, medium chain saturated fatty acids such as caprate, caprylate, myristate, palmitate, or stearate, including salt forms such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate.

[0314] Other absorption enhancers include citric acid or citrates, e.g., sodium citrate, tartaric acid or tartrates, salicylic acid or its derivatives or salicylates, fatty acid acylated amino acids, alkyl saccharides, C8-o-alkyl polysaccharides, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono- dodecanoate, sucrose mono-tridecanoate, sucrose monotetradecanoate, coco-glucoside, cyclodextrin, alkanoyl carnitines such as lauroyl carnitine, myristoyl carnitine or palmitoyl carnitine, lauroyl carnitine chloride, myristoyl carnitine chloride or palmitoyl carnitine chloride, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate , N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutamate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate , N-dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl propionate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate,N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartate, N-decanoyl-L-aspartic acid, sodium capric sine Steinate, N-Decanoyl-L-Cysteine, Sodium Capric Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Capric Glutaminate, N-Decanoyl-L-Glutamine, Sodium Capric Glycinate, N-Decanoyl-L-Glycine, Sodium Capric Histidinate, N-Decanoyl-L-Histidine, Sodium Capric Isoleucinate, N-Decanoyl-L-Isoleucine, Sodium Capric leucinate, N-decanoyl-L-leucine, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric propionate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophan, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decyl leucine, sodium stearoyl glutamate (e.g., from Amisoft HS-1 1P), sodium myristoyl glutamate (e.g., Amisoft MS-1 1), sodium lauroyl glutamate (e.g., Amisoft LS-1 1), sodium cocoyl glutamate (e.g., Amisoft CS-1 1), sodium cocoyl glycinate (e.g., Am lite GCS-1 1), sodium N-decyl leucine, sodium cocoyl glycine,fatty acid acylated amino acids, and pharma- ceutically acceptable salts of any of the foregoing compounds; or alkanoyl sarcosinates (e.g., lauroyl sarcosinate, such as sodium lauroyl sarcosine), or C 20 one of the 20 standard proteinogenic alpha-amino acids acylated with an alkyl saccharide (e.g., C1-C such as Multitrope™ 1620-LQ-(MV) 20 Alkyl saccharides; or n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose monotridecanoate, sucrose mono-tetradecanoate, coco-glucoside, alkyl saccharides , cyclodextrin (e.g., alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino]caprylic acid, N-[8-(2-hydroxybenzoyl)amino]caprylate, Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, "SNAC (Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate), calcium chelating compounds (e.g., Ethylenediaminetetraacetic Acid (EDTA), cremophor EL (also known as "Kolliphor EL", CAS number 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, or alkanols (e.g., ethanol, decanol), caprylocaproyl polyoxylglycerides (e.g., caprylocaproyl polyoxyl-8 glycerides, available as LABRASOL® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C8-C20 Alkylamines, C8-C 20 These may include, but are not limited to, alkenylamines (e.g., oleylamine), phosphatidylcholines, poloxamers, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbates (e.g., polysorbate 80), cholic acid (or cholate salts, e.g., sodium cholate), deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, or decyldimethylammoniopropanesulfonate.

[0315] In some embodiments, absorption enhancers may include, but are not limited to, sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium chain triglycerides of capric and caprylic acids (e.g., LABRASOL®, available from Gattefosse, USA), sucrose laurate, or lauroyl-L-carnitine (LC, e.g., PEPTELLIGENCE®, available from Enteris BioPharma, NJ, USA), and the like. In some embodiments, the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium chain triglycerides of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).

[0316] The absorption enhancer may be present in the composition in an amount of about 1% to about 99% (w / w) of the composition, or about 5% to about 50% (w / w), or about 10% to about 50% (w / w), or about 20% to about 50% (w / w), or about 30% to about 50% (w / w), or about 30% to about 40% (w / w), or about 32% to about 38% (w / w), or about 35% to about 36% (w / w). In some embodiments, the amount of the absorption enhancer is present in an amount of about 5% to about 50% (w / w). In some embodiments, the amount of the absorption enhancer is present in an amount of about 5% to about 40% (w / w). In some embodiments, the amount of the absorption enhancer is present in an amount of about 30% to about 40% (w / w). For example, the absorption enhancer can be present in an amount of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40% (w / w) of the composition, including any subdivision therebetween. In some embodiments, the absorption enhancer is present in an amount of about 30% to about 40% (w / w). In some embodiments, the absorption enhancer can be present in an amount of about 32% to about 38% (w / w). In some embodiments, the absorption enhancer can be present in an amount of about 35.7% (w / w).

[0317] In some aspects, the absorption enhancer used in the compositions of the present invention may be sodium caprate.

[0318] Sodium caprate can be present in the composition in an amount of about 1% to about 99% (w / w) of the composition, or about 5% to about 50% (w / w), or about 10% to about 50% (w / w), or about 20% to about 50% (w / w), or about 30% to about 50% (w / w), or about 30% to about 40% (w / w), or about 32% to about 38% (w / w), or about 35% to about 36% (w / w). In some embodiments, sodium caprate is present in an amount of about 5% to about 50% (w / w). In some embodiments, sodium caprate is present in an amount of about 5% to about 40% (w / w). In some embodiments, sodium caprate is present in an amount of about 30% to about 40% (w / w). For example, sodium caprate can be present in an amount of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40% (w / w) of the composition, including any subdivision therebetween. In some embodiments, sodium caprate is present in an amount of about 30% to about 40% (w / w). In some embodiments, sodium caprate can be present in an amount of about 32% to about 38% (w / w). In some embodiments, sodium caprate can be present in an amount of about 35.7% (w / w).

[0319] In one embodiment, sodium caprate for use in the compositions of the present invention may have a purity of at least about 98%, 98.2%, 98.4%, 98.6%, 98.8%, 99.0%, 99.5%, or at least about 99.9%. Without being bound by any theory, a higher purity of sodium caprate may provide improved bioavailability compared to lower technical grade sodium caprate, e.g., sodium caprate of about 90% or about 95% purity. In some embodiments, sodium caprate for use in the present invention has a purity of at least about 98% for use in the present invention.

[0320] In another embodiment, for use in the present invention, sodium caprate may have an average particle size of about 10 nm to about 150 micrometers, and sodium caprate may be of various particle sizes. In some embodiments, sodium caprate particles suitable for use in the present invention may have an average diameter of about 1 micrometer to about 150 micrometers. In some embodiments, such sodium caprate particles may have an average diameter of about 50 micrometers to about 150 micrometers. In other embodiments, sodium caprate particles may have an average diameter of about 10 nm to about 5 micrometers. In some embodiments, sodium caprate particles may have an average diameter of about 50 nm to about 1 micrometer. In some embodiments, sodium caprate particles may have an average diameter of about 100 nm to about 800 nm.

[0321] In another embodiment, sodium caprate can be present in crystalline, amorphous, or semi-crystalline form. In some embodiments, the use of crystalline sodium caprate can enhance the bioavailability of the hydrochloride salt of the compound of formula (I) or its solvate. In some embodiments, the use of amorphous sodium caprate can enhance the bioavailability of the hydrochloride salt of the compound of formula (I) or its solvate. In some embodiments, the use of semi-crystalline sodium caprate can enhance the bioavailability of the hydrochloride salt of the compound of formula (I) or its solvate.

[0322] In another embodiment, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate may form a mixture or a granulated mixture. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate form a mixture.

[0323] In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate form a granulation mixture. Thus, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate can be mixed to form a granulation mixture. The granulation mixture can be formed from particles having any average diameter suitable for use in the compositions of the present invention. For example, the particles of the granulation mixture can have an average diameter of about 100 nm to about 5 micrometers. The particles can also have an average diameter of about 1 micrometer to about 150 micrometers. In some embodiments, the particles of the granulation mixture of the compositions of the present invention can have an average diameter of about 200 nanometers to about 1 micrometer.

[0324] In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate form a mixture or a granulation mixture.

[0325] In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate form a mixture. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof and sodium caprate form a granulation mixture.

[0326] In other embodiments, the absorption enhancer used may be sodium sulcaprozate. In some embodiments, the absorption enhancer used may include, but is not limited to, polyethylene glycol (PEG)-modified medium chain triglycerides of capric and caprylic acids.

[0327] In some embodiments, the composition may comprise a hydrochloride salt of the compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, an absorption enhancer in an amount of about 5% to about 50% (w / w), and one or more pharma- ceutically acceptable excipients. In some embodiments, the composition may further comprise microcrystalline cellulose.

[0328] In some embodiments, the composition may comprise the hydrochloride salt of the compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, sodium caprate in an amount of about 5% to about 50% (w / w), and one or more pharma- ceutically acceptable excipients. In some embodiments, the composition may further comprise microcrystalline cellulose.

[0329] In another embodiment, the compositions described herein may comprise the hydrochloride salt of the compound of formula (I) or a solvate thereof in an amount of about 1.8% (w / w), and sodium caprate in an amount of about 35.7% (w / w).

[0330] In some aspects, the invention provides a composition comprising a hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 10% (w / w) of the composition, and an absorption enhancer in an amount of about 20% to about 45% (w / w) of the composition.

[0331] In some aspects, the present invention provides a composition comprising the hydrochloride salt of the compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, and the absorption enhancers sodium caprate and silicified microcrystalline cellulose in an amount of about 5% to about 40% (w / w) of the composition.

[0332] In some aspects, the present invention provides a composition comprising the hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 10% (w / w) of the composition, sodium caprate in an amount of about 20% to about 45% (w / w) of the composition, and microcrystalline cellulose.

[0333] In some aspects, the present invention provides a composition comprising: (i) a hydrochloride salt of a compound of formula (I) or a solvate thereof, in an amount of about 0.5% to about 10% (w / w) of the composition; (ii) an absorption enhancer sodium caprate, in an amount of about 5% to about 40% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) a disintegrant, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 30% to about 70% (w / w) of the composition; (viii) a disintegrant, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) a lubricant in an amount of about 0.25% (w / w) of the composition.

[0334] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.7% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 35.7% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 37.7% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0335] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 1.8% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 35.7% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 36.6% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0336] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.7% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 21.4% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 52% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0337] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 1.8% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 21.4% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 50.9% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0338] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 7.1% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 35.7% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 31.3% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0339] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 1.8% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 7.1% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 65.2% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0340] In some aspects, the present invention provides a composition comprising: (i) the hydrochloride salt of the compound of formula (I) or a solvate thereof, in an amount of about 1.8% (w / w) of the composition; (ii) the absorption enhancer sodium caprate, in an amount of about 35.7% (w / w) of the composition; (iii) microcrystalline cellulose, in an amount of about 3.9% (w / w) of the composition; (iv) sorbitol, in an amount of about 10.7% (w / w) of the composition; (v) crospovidone, in an amount of about 5% (w / w) of the composition; and (vi) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition; (vii) silicified microcrystalline cellulose, in an amount of about 36.6% (w / w) of the composition; (viii) crospovidone, in an amount of about 5% (w / w) of the composition; (ix) silica (e.g., Aerosil 200), in an amount of about 0.5% (w / w) of the composition. 200), and (x) magnesium stearate in an amount of about 0.25% (w / w) of the composition.

[0341] In some embodiments, the composition of the present invention may be in a dosage form that may be, but is not limited to, a tablet or capsule dosage form. In some embodiments, the composition may be a tablet or capsule composition. In some embodiments, the composition may be a tablet composition. In some embodiments, such a tablet composition may include a unit dose size amount, and the unit dose size amount may include, but is not limited to, an amount of about 25 mg to about 2000 mg, about 500 mg to about 2000 mg. The compositions of the present invention can be tablets or capsules of any suitable size according to the present invention, for example, but not limited to, doses or amounts such as 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, or 2000 milligram (mg) doses or amounts. In one embodiment, the composition of the present invention can be as a tablet of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1400 mg, respectively, and the tablet can be administered once or twice a day, or as determined by medical need, but is not limited thereto. In some embodiments, the composition can be a unit dose size of about 500 mg to about 2000 mg. In some embodiments, the composition can be a unit dose size of about 1400 mg. In some embodiments, the composition can be a unit dose size of about 1000 mg.

[0342] In some embodiments, such tablet compositions may comprise a unit dosage size of from 500 mg to about 2000 mg. The tablet composition may be of any suitable size according to the present invention, for example, but not limited to, 25, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, or 2000 mg tablets. In some embodiments, the composition is a 1400 mg tablet.

[0343] Tablets formed from the compositions of the invention may be administered in single or multiple doses, depending on the dosing and frequency as required and tolerated by the patient, and such tablets contain a quantity or amount of active agent sufficient to effectively treat a particular disease state. Thus, in one aspect, the invention relates to a composition for oral administration of the hydrochloride salt of a compound of formula (I) or a solvate thereof, which may be taken in a daily dose of about 0.05 to about 30 mg / kg body weight / day. In some embodiments, the dosage may be about 0.1 mg to about 20 mg / kg body weight / day. In another embodiment, the dosage may be about 0.1 mg to about 5 mg / kg body weight / day. In another embodiment, the dosage may be about 0.1 mg to about 1 mg / kg body weight / day.

[0344] coating Cosmetic Subcoating In some embodiments, the composition can further include a subcoating. In some embodiments, the subcoating is a cosmetic subcoating. In some embodiments, the cosmetic subcoating can also function as a physical barrier. The cosmetic coating can include polyethylene glycol-polyvinyl alcohol (PEG-PVA) graft copolymer, polyvinyl alcohol (PVA), hypromellose (HPMC), and hydroxypropyl cellulose (HPC). In some embodiments, the weight of the cosmetic subcoating is compared weight / weight to the weight of the composition before coating. In some embodiments, the cosmetic subcoating can be present in an amount of about 1% to about 10% (w / w). In some embodiments, the cosmetic subcoating is present in an amount of about 1% to about 5% (w / w). For example, the cosmetic subcoating can be present in an amount including about 1%, 1.5%, 2.0%, 2.5%, and about 3%, including any subamount and range therebetween, such as about 2.0% to 3.0%. In some embodiments, the cosmetic subcoating is present in an amount of about 3% (w / w). In some embodiments, the weight of the cosmetic subcoating is compared on a weight / weight basis to the weight of the composition or the weight of the core tablet before coating.

[0345] In other embodiments, the cosmetic subcoating level is given in terms of weight (mg) of cosmetic subcoating per surface area of ​​the core tablet. In some embodiments, the surface area is the surface area of ​​the outermost layer of coating covering the core tablet. For example, in some embodiments, the surface area for calculating the cosmetic subcoating level is the surface area of ​​the core tablet. In other embodiments, the surface area is the surface area of ​​the cosmetic subcoating, subcoating, or enteric coating disposed on the core tablet. For example, in some embodiments, two or more coatings are disposed on the core tablet and the surface area refers to the surface area of ​​the outermost coating.

[0346] In some embodiments, the cosmetic subcoating level is about 6 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the cosmetic subcoating level is about 9 mg / cm 2 ~about 30mg / cm 2 In another embodiment, the cosmetic subcoating level is about 12 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the cosmetic subcoating level is about 17 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the cosmetic subcoating level is about 20 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the cosmetic subcoating level is about 25 mg / cm 2 ~about 30mg / cm 2 For example, a cosmetic subcoating level is about 6 mg / cm 2 , 7 mg / cm 2 , 8 mg / cm 2 , 9 mg / cm 2 , 10 mg / cm 2 , 6 mg / cm 2 , 11 mg / cm 2 , 12 mg / cm 2 , 13 mg / cm 2 , 14 mg / cm 2 , 15mg / cm 2 , 16 mg / cm 2 , 17 mg / cm 2 , 18 mg / cm 2 , 19 mg / cm 2 , 21 mg / cm 2 , 22 mg / cm 2 , 23 mg / cm 2 , 24 mg / cm 2 , 25 mg / cm 2 , 26 mg / cm 2 , 27 mg / cm 2 , 28 mg / cm 2 , 29 mg / cm 2 , or 30 mg / cm2 In some embodiments, the cosmetic subcoating level is about 6 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 7 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 8 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 9 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 10 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 11 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 6 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 12 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 13 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 14 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 15 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 16 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 17 mg / cm 2 In some embodiments, the cosmetic subcoating level is about 18 mg / cm 2 It is.

[0347] Sub-coating In some embodiments, the composition can further comprise a subcoating of PVA-PEG graft copolymer disposed on the composition. In some embodiments, the composition can comprise a subcoating of PVA-PEG graft copolymer disposed on the core tablet. This coating can function as a smooth surface to aid in swallowing of the tablet. The coating can also provide a platform for further layers, which can comprise an enteric coating disposed on the subcoating. In some embodiments, the subcoating can also provide a vehicle for coloring for tablet identification. Other coatings include, but are not limited to, HPMC, HPC, PVA, Eudragit E based coatings, and the like. In some embodiments, the composition can further comprise a subcoating. This coating can function as a barrier between the core tablet components and the enteric or functional coating. The subcoating can comprise an OPADRY® class product and can be present in any desired amount. In some embodiments, the weight of the subcoating is compared to the weight of the composition before coating on a weight / weight basis. In some embodiments, the subcoating can be present in an amount of about 1% to about 10% (w / w). In some embodiments, the subcoating is present in an amount of about 1% to about 5% (w / w). In some embodiments, the subcoating can be present in an amount of about 1% to about 3% (w / w) based on the core tablet before coating. For example, the subcoating can be present in an amount including about 1%, 1.5%, 2.0%, 2.5%, and about 3%, including any subdivision therebetween. In some embodiments, the subcoating is present in an amount of about 3% (w / w). In some embodiments, the weight of the subcoating is compared weight / weight to the weight of the composition or the weight of the core tablet before coating.

[0348] In other embodiments, the subcoating level is determined by the coating weight gain (mg / cm 2In some embodiments, the subcoating level is about 6 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the subcoating level is about 9 mg / cm 2 ~about 30mg / cm 2 In another embodiment, the subcoating level is about 12 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the subcoating level is about 17 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the subcoating level is about 20 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the subcoating level is about 25 mg / cm 2 ~about 30mg / cm 2 For example, the subcoating level is about 6 mg / cm 2 , 7 mg / cm 2 , 8 mg / cm 2 , 9 mg / cm 2 , 10 mg / cm 2 , 6 mg / cm 2 , 11 mg / cm 2 , 12 mg / cm 2 , 13 mg / cm 2 , 14 mg / cm 2 , 15mg / cm 2 , 16 mg / cm 2 , 17 mg / cm 2 , 18 mg / cm 2 , 19 mg / cm 2 , 21 mg / cm 2 , 22 mg / cm 2 , 23 mg / cm 2 , 24 mg / cm 2 , 25 mg / cm 2 , 26 mg / cm 2 , 27 mg / cm 2 , 28 mg / cm 2 , 29 mg / cm 2 , or 30 mg / cm 2In some embodiments, the subcoating level is about 6 mg / cm 2 In some embodiments, the subcoating level is about 7 mg / cm 2 In some embodiments, the subcoating level is about 8 mg / cm 2 In some embodiments, the subcoating level is about 9 mg / cm 2 In some embodiments, the subcoating level is about 10 mg / cm 2 In some embodiments, the subcoating level is about 11 mg / cm 2 In some embodiments, the subcoating level is about 6 mg / cm 2 In some embodiments, the subcoating level is about 12 mg / cm 2 In some embodiments, the subcoating level is about 13 mg / cm 2 In some embodiments, the subcoating level is about 14 mg / cm 2 In some embodiments, the subcoating level is about 15 mg / cm 2 In some embodiments, the subcoating level is about 16 mg / cm 2 In some embodiments, the subcoating level is about 17 mg / cm 2 In some embodiments, the subcoating level is about 18 mg / cm 2 It is.

[0349] Enteric Coating In some embodiments, the composition includes an enteric coating disposed over the subcoating. In some embodiments, the enteric coating is selected to provide release of the tablet contents in a pH range of about 5 to about 8. In some embodiments, the enteric coating is a pH 5.5 enteric coating. The enteric coating can include, but is not limited to, those based on cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), or hydroxypropyl methylcellulose phthalate (HPMCP). In some embodiments, the enteric coating can be a methacrylic acid copolymer.

[0350] In some embodiments, the enteric coating can include, but is not limited to, poly(ethyl methacrylate acrylate) (L100D-55), a combination of methyl acrylate, methyl methacrylate and methacrylic acid (FS30D), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), L-type HPMC-AS, or a copolymer of ethyl methacrylate acrylate (e.g., Acryl-eze®).

[0351] In some embodiments, the weight of the enteric coating is compared to the weight of the composition before coating on a weight / weight basis. In some embodiments, the enteric coating can be present in an amount of about 1% to about 15% (w / w). In some embodiments, the enteric coating can be present in an amount of about 2% to about 15% (w / w). In some embodiments, the enteric coating can comprise about 5% to about 15% (w / w) of the core tablet of the composition. For example, the amount of the enteric coating can be in an amount of about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w / w), including amounts thereof. In some embodiments, the enteric coating can be present in an amount of about 6% (w / w). In some embodiments, the enteric coating can be present in an amount of about 7% (w / w). In some embodiments, the enteric coating can be present in an amount of about 8% (w / w). In some embodiments, the weight of the enteric coating is compared weight / weight to the weight of the core tablet before coating.

[0352] In another embodiment, the enteric coating level is determined by the coating weight gain (mg / cm 2 In some embodiments, the enteric coating level is about 6 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is about 9 mg / cm 2 ~about 30mg / cm 2 In another embodiment, the enteric coating level is about 12 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is about 17 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is about 20 mg / cm 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is about 25 mg / cm 2 ~about 30mg / cm 2For example, the enteric coating level is about 6 mg / cm 2 , 7 mg / cm 2 , 8 mg / cm 2 , 9 mg / cm 2 , 10 mg / cm 2 , 6 mg / cm 2 , 11 mg / cm 2 , 12 mg / cm 2 , 13 mg / cm 2 , 14 mg / cm 2 , 15mg / cm 2 , 16 mg / cm 2 , 17 mg / cm 2 , 18 mg / cm 2 , 19 mg / cm 2 , 21 mg / cm 2 , 22 mg / cm 2 , 23 mg / cm 2 , 24 mg / cm 2 , 25 mg / cm 2 , 26 mg / cm 2 , 27 mg / cm 2 , 28 mg / cm 2 , 29 mg / cm 2 , or 30 mg / cm 2 In some embodiments, the enteric coating level is about 6 mg / cm 2 In some embodiments, the enteric coating level is about 7 mg / cm 2 In some embodiments, the enteric coating level is about 8 mg / cm 2 In some embodiments, the enteric coating level is about 9 mg / cm 2 In some embodiments, the enteric coating level is about 10 mg / cm 2 In some embodiments, the enteric coating level is about 11 mg / cm 2 In some embodiments, the enteric coating level is about 6 mg / cm 2 In some embodiments, the enteric coating level is about 12 mg / cm 2 In some embodiments, the enteric coating level is about 13 mg / cm 2In some embodiments, the enteric coating level is about 14 mg / cm 2 In some embodiments, the enteric coating level is about 15 mg / cm 2 In some embodiments, the enteric coating level is about 16 mg / cm 2 In some embodiments, the enteric coating level is about 17 mg / cm 2 In some embodiments, the enteric coating level is about 18 mg / cm 2 It is.

[0353] In some embodiments, the tablet compositions of the present invention may have a subcoating of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating of Acryl-eze® Yellow in an amount of about 6% (w / w).

[0354] In some embodiments, the tablet compositions of the present invention may have a subcoating of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating of Acryl-eze® Yellow in an amount of about 7% (w / w).

[0355] In some embodiments, the tablet compositions of the present invention may have a subcoating of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating of Acryl-eze® Yellow in an amount of about 8% (w / w).

[0356] Coating Order In some embodiments, the core tablet is covered by one or more of a cosmetic coating, a subcoating, an enteric coating, or any combination thereof. When more than one cosmetic coating, subcoating, and / or enteric coating covers the core tablet, such coatings may be applied in any order, such that any of the cosmetic coatings, subcoatings, and / or enteric coatings may be applied directly to the surface of the core tablet. In such cases, any additional cosmetic coatings, subcoatings, and / or enteric coatings may be applied thereafter in any order.

[0357] In some embodiments, the core tablet is covered by a cosmetic subcoating. In some embodiments, the core tablet is covered by a cosmetic subcoating and then covered by an enteric coating. In some embodiments, the core tablet is covered by a cosmetic subcoating and then covered by a subcoating. In certain embodiments, the core tablet is covered by a cosmetic subcoating, then covered by a subcoating, then covered by an enteric coating. In certain embodiments, the core tablet is covered by a cosmetic subcoating, then covered by an enteric coating, then covered by a subcoating.

[0358] In other embodiments, the core tablet is covered by a subcoating. In some embodiments, the core tablet is covered by a subcoating and then covered by an enteric coating. In some embodiments, the core tablet is covered by a subcoating and then covered by a cosmetic subcoating. In certain embodiments, the core tablet is covered by a subcoating, then covered by an enteric coating, and then covered by a cosmetic subcoating. In certain embodiments, the core tablet is covered by a subcoating, then covered by a cosmetic subcoating, and then covered by an enteric coating.

[0359] In other embodiments, the core tablet is coated with an enteric coating. In other embodiments, the core tablet is coated with an enteric coating and then coated with a subcoating. In certain embodiments, the core tablet is coated with an enteric coating and then coated with a cosmetic subcoating. In other embodiments, the core tablet is coated with an enteric coating, then coated with a subcoating, and then coated with a cosmetic coating. In certain embodiments, the core tablet is coated with an enteric coating, then coated with a cosmetic coating, and then coated with a subcoating.

[0360] In some embodiments, the tablet composition of the present invention may have a bioavailability of about 1% to about 10% (w / w). In some embodiments, the tablet composition of the present invention may have a bioavailability of about 10% to about 50%. For example, the bioavailability may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability may be measured using the Area Under Curve (AUC) for oral administration versus the AUC for intravenous administration.

[0361] In some embodiments, the tablet composition of the present invention may have a bioavailability of about 0.01% to about 10% (w / w). In some embodiments, the tablet composition of the present invention may have a bioavailability of about 0.1% to about 1% (w / w). For example, the bioavailability may be about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability may be measured using the area under the curve (AUC) for oral administration versus the AUC by intravenous administration.

[0362] The dose of the composition described herein can be administered according to the method and / or use of the present invention herein. In some embodiments, the dose of the composition of the present invention can be administered once a day, twice a day, or three times a day. In some embodiments, the dose of the composition of the present invention can be administered once a day. In some embodiments, the dose of the composition of the present invention can be administered twice a day. In some embodiments, the dose of the composition of the present invention can be administered three times a day.

[0363] Some embodiments described herein, e.g., with respect to pharmaceutical compositions, tablets, methods, processes, etc., exclude acetate salts of the compound of formula (I). Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., include acetate salts of the compound of formula (I).

[0364] V. Methods or Processes for Making Tablets or Dosage Forms In accordance with the present invention, a pharmaceutical composition, as defined throughout this disclosure, is comprised of an active principle (i.e., the hydrochloride salt of a compound of formula (I) or a solvate thereof) and at least one or more additional pharma- ceutically acceptable ingredients (i.e., which may include, but are not limited to, absorption enhancers), adjuvants, carriers, excipients, or stabilizers, etc.

[0365] In some embodiments, the active ingredient is a crystalline salt of a compound of formula (I), as described herein, or a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing.

[0366] The percentage or amount of active principal ingredient (API) in the compositions of the present invention may, of course, vary as the amount of active compound in such therapeutically useful compositions, such that a suitable dosage is obtained for administration in a subject or patient. It will be understood that the actual preferred dosage of the API used in the compositions of the present invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration, and the host being treated. Selection of the most appropriate initial dosage for a particular patient is determined by the practitioner using well-known medical principles, including, but not limited to, body weight.

[0367] Furthermore, the oral tablet dosage form of the present invention may have a surface layer coated with an enteric coating, which may be, but is not limited to, the enteric coating described in the definition section of this specification.For example, the oral tablet dosage form may be formulated as a core component, a separate continuous layer, or a combination thereof, and the tablet components such as the core, other layers, etc. may have different release-modifying component properties based on the gastrointestinal environment, pH, or time.Therefore, the oral tablet dosage form of the present invention may also be coated with a pH-sensitive polymer.

[0368] Tablets containing the compositions of the present invention may be prepared using conventional tableting equipment conventionally known in the art, which may use compression, rollers, etc. In some embodiments, the tableting technique is roller compression.

[0369] VI. Methods of Treatment and / or Use In one aspect, the present invention relates to a method and / or use for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof disclosed herein or a composition thereof. In some aspects, the present invention provides a method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof disclosed herein or a composition thereof. Inflammatory diseases suitable for treatment with the compositions of the present invention may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA), etc. In some aspects, the inflammatory disease is moderate to severe in severity.

[0370] In any of the methods of treatment and / or use embodiments detailed herein, it is understood that such methods and uses may include any of the crystalline forms and pharmaceutical compositions of the compound of formula (I) described herein, as if each and every combination were specifically and individually recited. For example, any of the methods of treatment and / or uses may, in some embodiments, include administering to a subject a therapeutically effective amount of a crystalline form of the compound of formula (I), a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing. In some embodiments, the crystalline form is selected from the hydrochloride salt of the compound of formula (I), the acetate salt of the compound of formula (I), the fumarate salt of the compound of formula (I), the glutarate salt of the compound of formula (I), the glycolate salt of the compound of formula (I), the mesylate salt of the compound of formula (I), the bishydrochloride salt of the compound of formula (I), the citrate salt of the compound of formula (I), and the sulfate salt of the compound of formula (I).

[0371] In some aspects, the present invention provides a method and / or use for treating a subject suffering from a condition or indication associated with IL-21 or IL-23R (e.g., activation of the IL-23 / IL-23R signaling pathway), comprising administering to the subject a crystalline hydrochloride salt of a compound of formula (I) of the present invention or a solvate thereof, or a composition thereof. In some aspects, the present invention provides a method and / or use for treating a subject suffering from a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the individual a crystalline hydrochloride salt of a compound of formula (I) of the present invention or a solvate thereof, or a composition thereof, in an amount sufficient to inhibit (partially or fully) binding of IL-23 to IL-23R in the subject. In some embodiments, inhibition of binding of IL-23 to IL-23R occurs in a particular organ or tissue of the subject, such as the stomach, small intestine, large intestine / colon, intestinal mucosa, lamina propria, Peyer's patches, mesenteric lymph nodes, or lymphatic vessels.

[0372] In some embodiments, the method and / or use of the present invention may comprise administering the crystalline hydrochloride salt of the compound of formula (I) or its solvate of the present invention or a composition thereof to a subject in need thereof. In some embodiments, the subject in need thereof has been diagnosed or determined to be at risk of developing a disease or disorder associated with IL-23 / IL-23R. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0373] In some embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, for example, autoimmune inflammation and related diseases and disorders may include, but are not limited to, multiple sclerosis, asthma, rheumatoid arthritis, intestinal inflammation, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, ulcerative colitis, sarcoidosis, systemic lupus erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriasis, or psoriatic arthritis. In some embodiments, the disease or disorder is inflammatory bowel disease (IBD). In some embodiments, the disease or disorder is Crohn's disease. In some embodiments, the disease or disorder is ulcerative colitis. In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is psoriatic arthritis.

[0374] In some embodiments, the disease or disorder is psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, palmoplantar pustulosis, plaque psoriasis, or erythrodermic psoriasis), atopic dermatitis, ectopic acne, ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis / esophagitis, colitis associated with radiation or chemotherapy, colitis associated with disorders of innate immunity such as in leukocyte adhesion deficiency-1. In one embodiment, the present invention is or may be selected from: colitis resulting from rectal colectomy and ileoanal anastomosis, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, pouchitis, pouchitis resulting from proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral associated enteropathy, pericholechiitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease.

[0375] In one aspect, the present invention relates to a method and / or use for the treatment of autoimmune inflammation and related diseases and disorders, which may include, but are not limited to, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), or psoriatic arthritis (PsA). In some aspects, the inflammatory disease is inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, psoriasis, or psoriatic arthritis. In some aspects, the inflammatory disease is inflammatory bowel disease (IBD). In some aspects, the inflammatory disease is Crohn's disease. In some aspects, the inflammatory disease is ulcerative colitis. In some aspects, the inflammatory disease is psoriasis. In some aspects, the inflammatory disease is psoriatic arthritis.

[0376] In some aspects, the present invention relates to a method and / or use for inhibiting IL-23 receptor for the treatment of autoimmune inflammation and related diseases and disorders, comprising administering a crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof or a composition thereof to a subject in need thereof. In some aspects, the IL-23 receptor is inhibited in blood, blood circulation, tissue, skin, or joint. In some aspects, the IL-23 receptor is inhibited in a tissue selected from blood, skin, cartilage, or synovium. In some aspects, the IL-23 receptor is inhibited in blood. In some aspects, the IL-23 receptor is inhibited in skin. In some aspects, the IL-23 receptor is inhibited in cartilage. In some aspects, the IL-23 receptor is inhibited in synovium.

[0377] In some aspects, the present invention relates to a method and / or use for inhibiting IL-23 receptor in gastrointestinal tissue for the treatment of autoimmune inflammation and related diseases and disorders, comprising administering a crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof or a composition thereof to a subject in need thereof.

[0378] In some embodiments of the methods and / or uses of the present invention, the gastrointestinal tissue is selected from the mouth, esophagus, stomach, small intestine, large intestine, duodenum, and anus. In some embodiments, the gastrointestinal tissue is the mouth. In some embodiments, the gastrointestinal tissue is the esophagus. In some embodiments, the gastrointestinal tissue is the stomach. In some embodiments, the gastrointestinal tissue is the small intestine. In some embodiments, the gastrointestinal tissue is the large intestine. In some embodiments, the gastrointestinal tissue is the duodenum. In some embodiments, the gastrointestinal tissue is the anus.

[0379] In some embodiments, the present invention provides a method and / or use for treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a crystalline hydrochloride salt of the compound of formula (I) of the present invention or a solvate thereof or a composition thereof. In some embodiments, the present invention provides a method for treating inflammatory bowel disease (IBD) in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of the compound of formula (I) of the present invention or a solvate thereof or a composition thereof. In some embodiments, the IBD is ulcerative colitis. In some embodiments, the IBD is Crohn's disease.

[0380] In some aspects, the present invention provides a method or use of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof of the present invention, or a composition thereof, in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

[0381] In another aspect, the present invention relates to a method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline hydrochloride salt of the compound of formula (I) or its solvate disclosed herein or a composition thereof. In some aspects, the IBD is Crohn's disease or ulcerative colitis. In some aspects, the IBD is Crohn's disease. In some aspects, the IBD is ulcerative colitis.

[0382] In some aspects, the present invention provides the use of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof disclosed herein, or a composition thereof, in the manufacture of a medicament for treating inflammatory bowel disease (IBD).

[0383] In some embodiments, the present invention relates to a method of treating psoriasis or psoriatic arthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof of the present invention, or a composition thereof. In some embodiments, the present invention relates to a method comprising treating psoriasis. In some embodiments, the present invention relates to a method comprising treating psoriatic arthritis.

[0384] In some embodiments, the present invention provides the use of the crystalline hydrochloride salt of the compound of formula (I) or its solvate disclosed herein or a composition thereof in the manufacture of a medicament for treating psoriasis or psoriatic arthritis. In some embodiments, the present invention provides the use for treating psoriasis. In some embodiments, the present invention provides the use for treating psoriatic arthritis.

[0385] In some embodiments, the methods and / or uses comprise orally administering a crystalline hydrochloride salt of a compound of formula (I) or a solvate thereof of the present invention or a composition thereof.

[0386] In some embodiments, the present invention relates to a method and / or use for treating inflammatory bowel disease (IBD) in a subject, comprising administering a therapeutically effective amount of the crystalline hydrochloride salt of the compound of formula (I) or its solvate or a composition thereof disclosed herein. In some embodiments, the IBD is Crohn's disease or ulcerative colitis. In some embodiments, the method and / or use of the present invention comprises orally administering the crystalline hydrochloride salt of the compound of formula (I) or its solvate or a composition thereof in tablet form once, twice, or three times a day according to the patient's treatment.

[0387] In some embodiments, the present invention relates to a method and / or use for treating psoriasis or psoriatic arthritis in a subject, comprising administering a therapeutically effective amount of the crystalline hydrochloride salt of the compound of formula (I) or its solvate or a composition thereof disclosed herein. In some embodiments, the present invention relates to a method and / or use for treating psoriasis. In some embodiments, the present invention relates to a method and / or use for treating psoriatic arthritis. In some embodiments, the method and / or use of the present invention comprises orally administering the crystalline hydrochloride salt of the compound of formula (I) or its solvate or a composition thereof in tablet form once, twice, or three times a day according to the patient's treatment.

[0388] In some embodiments, the method and / or use of the present invention comprises administering a dose of the crystalline hydrochloride of the compound of formula (I) or a solvate thereof or a composition thereof. In some embodiments, the hydrochloride of the compound of formula (I) or a solvate thereof may be present in any dose range, for example, about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. In another embodiment, the dose range of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 1 mg to about 1000 mg. In another embodiment, the dose range of the hydrochloride of the compound of formula (I) or a solvate thereof may be about 5 mg to about 300 mg. In another embodiment, the dose range of the hydrochloride of the compound of formula (I) or a solvate thereof is about 25 mg to about 150 mg. In another embodiment, the dose range of the compound of formula (I) or the hydrochloride of its solvate may be about 25 mg to about 100 mg. In another embodiment, the compound of formula (I) or the hydrochloride of its solvate may be present in a dose range of about 1 mg to about 100 mg. In another embodiment, the compound of formula (I) or the hydrochloride of its solvate may be present in a dose range of about 20 mg to about 40 mg. In another embodiment, the compound of formula (I) or the hydrochloride of its solvate may be present in a dose range of about 20 mg to about 30 mg.

[0389] In yet another embodiment, the method and / or use of the present invention comprises administering a dose of the crystalline hydrochloride salt of the compound of formula (I) or its solvate or a composition thereof at a dose of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg, including any amount therebetween and any part thereof. In another embodiment, the dose of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 5 mg. In another embodiment, the dose of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 10 mg. In another embodiment, the dose of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 25 mg. In another embodiment, the dose of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 50 mg. In another embodiment, the dose of the hydrochloride salt of the compound of formula (I) or its solvate may be present at about 75 mg. In another embodiment, the dosage of the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present at about 100 mg. In another embodiment, the dosage of the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present at about 150 mg.

[0390] In some embodiments, the method and / or use of the present invention comprises administering a crystalline hydrochloride of the compound of formula (I) or its solvate or a composition thereof at a dose of about 10 mg, about 25 mg, or about 50 mg once a day or twice a day. In some embodiments, the method and / or use of the present invention comprises administering a crystalline hydrochloride of the compound of formula (I) or its solvate or a composition thereof at a dose of about 10 mg twice a day. In some embodiments, the method and / or use of the present invention comprises administering a crystalline hydrochloride of the compound of formula (I) or its solvate or a composition thereof at a dose of about 25 mg twice a day. In some embodiments, the method and / or use of the present invention comprises administering a crystalline hydrochloride of the compound of formula (I) or its solvate or a composition thereof at a dose of about 50 mg twice a day. In some embodiments, the method and / or use of the present invention comprises administering a crystalline hydrochloride of the compound of formula (I) or its solvate or a composition thereof at a dose of about 10 mg once a day. In some embodiments, the methods and / or uses of the invention comprise administering a dose of about 25 mg of the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof or a composition thereof once daily. In some embodiments, the methods and / or uses of the invention comprise administering a dose of about 50 mg of the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof or a composition thereof once daily.

[0391] Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., exclude acetate salts of the compound of formula (I). Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., include acetate salts of the compound of formula (I).

[0392] Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., exclude acetate salts of the compound of formula (I). Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., include acetate salts of the compound of formula (I).

[0393] Each aspect of the invention defined in this section or any other section may incorporate definitions and limitations, such as those set forth throughout the originally filed disclosure, specification, and claims. VII. EXAMPLES

[0394] In describing the present invention, the abbreviations and symbols utilized herein follow common usage of such abbreviations and symbols by those of ordinary skill in the chemical and biological arts. Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0395] List of Standard Chemical Definitions

[0396] [Table 1]

[0397] Example 1. Preparation of a crystalline form of the hydrochloride salt of the peptide of SEQ ID NO:1 Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (wherein, [Pen] * -[Pen] * forms a disulfide bond) (SEQ ID NO:1):

[0398] [ka]

[0399] Synthesis of compounds of formula (I) or pharma- ceutically acceptable salts thereof has been reported, i.e., synthesis includes peptide #104 in U.S. Patent Application Publication No. 2021 / 0261622 ("US '622 Pub."), ​​publication date: August 26, 2021, which corresponds to International Publication No. 2021 / 146441(A1) ("WO '441 Appln."), international publication date: July 22, 2021, each of which is individually incorporated by reference in its entirety herein.

[0400] The hydrochloride salt of compound of formula (I) was prepared using Fmoc solid phase peptide synthesis (SPPS) techniques as described herein in the aforementioned US '622 Pub. or WO '441 Appln. references.

[0401] The peptides were assembled on Rink amide MBHA resin using standard Fmoc-protected synthesis conditions reported in the literature. The assembled peptides were isolated from the resin and protecting groups by cleavage with strong acid followed by precipitation. Oxidation to form disulfide bonds was performed followed by purification.

[0402] During SPPS, sequences of desired compounds (i.e., compounds of formula (I)) were assembled onto a polymeric support by sequential and repetitive addition of selected building blocks. Cross-linked polystyrene resin immobilized the growing peptide chains.

[0403] As building blocks (starting materials) suitably protected amino acid derivatives were used (see Table 1 below). Protection of the reactive α-amino group relied on the Fmoc strategy. Necessary side chain protection was achieved by using other protecting groups that were stable to the reagents used for Fmoc cleavage.

[0404] The peptide chain was assembled from C-terminus to N-terminus by repeated cycles until the resin retained the complete amino acid sequence: (i) N-α-deprotection with 20% (V / V) piperidine in DMF (10 mL / g) to enable the coupling reaction, (ii) coupling of protected building blocks (protected amino acid derivatives) in the presence of DIC and Oxyma as suitable activating reagents (solvent: DMF, 10 mL / g) (Table 2), systematic acetylation (capping) of the remaining free amino groups using acetic anhydride and pyridine (solvent: DMF, 10 mL / g; c: DMF / Ac2O / pyridine 50:1:1). Each step consisted of the following operations: (i) addition of solvent / reagent to the resin, (ii) agitation of the reaction mixture, and (iii) removal of solvent / reagent by filtration and washing (solvent: DMF and / or IPA, 10 mL / g).

[0405] After cleavage of the N-terminal Fmoc group, final acetylation was performed. The peptide resin was then washed alternately with dimethyl formamide (DMF) and isopropanol (IPA) and dried under reduced pressure. Batch size: 30.0 mol, yield (31.5 mol, 105%).

[0406] [Table 2]

[0407] [Table 3]

[0408] Cleavage of the peptide from the resin and simultaneous cleavage of the side chain protecting groups was achieved by treating the peptide resin with TFA (6.30 L / kg resin) in the presence of suitable scavengers: HO (0.175 L / kg resin), ethanedithiol (EDT) (0.175 L / kg resin) and triisopropylsilane (TIS) (0.27 kg / kg resin). The resin was filtered off and washed twice with TFA (total of 2.0 L / kg resin) before the product was precipitated by addition of chilled diisopropyl ether (40 L / kg resin). The product was filtered off, washed three times with diisopropyl ether (3.0 L / kg each) and dried under reduced pressure. Batch size: 5.16 mol, yield: 5.44 mol (105%).

[0409] The crude product was dissolved in aqueous AcOH (H2O / AcOH 70:30, 100 g / L). The resulting peptide solution was treated with aqueous I2 / KI (52 mM I2, 154 mM KI) to assemble disulfide bonds between penicillamine residues by oxidation of the SH moieties. The reaction was quenched by addition of aqueous ascorbic acid (662 mM, 0.106 g ascorbic acid / g crude, 1.35 eq.). The cyclized peptide was purified by preparative HPLC on a reversed-phase column with ACN gradient elution and UV detection at 300 nm.

[0410] Elution was performed using an NH4HCO3 system (eluent NH4HCO3A: 15% ACN in 30 mM NH4HCO3, eluent NH4HCO3B: 50% ACN in 10 mM NH4HCO3). Collected fractions were analyzed by HPLC and pooled accordingly (target: ≥ 97.0%). The pH of the pooled main fraction was adjusted to 7.0 ± 0.2 with aqueous hydrochloric acid (5.5 M).

[0411] One-step preparation of the hydrochloride salt of peptide of SEQ ID NO:1 12.0 kg of compound of formula (I) was cyclized and purified by six preparative HPLC runs. Combination of all main cuts from six purification runs resulted in a volume of compound of formula (I) solution of 202 L. To this solution, 67 L of side cut was added (volume ratio main cut / side cut=3:1) to obtain a total of 269 L. The pH was adjusted to 7.1 by adding 0.25 L of 5.5 N aqueous HCl. The solution was concentrated by evaporation in vacuum at a jacket temperature of 40° C. to a final volume of 60 L. The temperature of the concentrated cloudy product solution was reduced to 23° C. The pH was adjusted to 5.1 with 2.0 L of 1 N aqueous HCl, 12.0 L of IPA was added, and the solution was stirred at 6° C. for 19 hours. Further precipitation occurred during stirring of the solution. The suspension was transferred to a mobile filter dryer, allowed to settle for 10 minutes, and filtered by applying overpressure (initially 0.5 bar, later increased up to 2 bar). A clear mother liquor was observed during filtration. The isolated product was dried in vacuum at 40° C., initially at 65 mbar until solvent distillation ceased. Then, after approximately 8.5 hours, drying continued at full vacuum, but the temperature was reduced to 25° C., since drying was performed over the weekend instead of overnight. After a total drying time of 62 hours at a final vacuum of 6 mbar, the product was removed from the filter dryer.

[0412] Due to the nature of the isolated material (coarse particles with agglomerates), the product was sieved by applying a sieving mill (1.5 mm mesh size). After sieving, a total of 5.24 kg was obtained. The purity (HPLC) was determined to be 97.3% by QC HPLC release method. The chloride content was determined to be 1.3% (theoretical chloride content of the monohydrochloride salt is 1.9%) and the isolated material was readily soluble in water (1 mg / mL) without the need for any pH adjustment.

[0413] Alternative two-step preparation of the crystalline form of the hydrochloride salt of peptide SEQ ID NO:1 Step 1: 7.057 kg of compound of formula (I) was cyclized and purified by four preparative HPLC runs. Combination of all main cuts from the four purification runs resulted in a solution volume of 100 L. The pH was adjusted by adding 0.2 L of 5.5 N aqueous HCl, resulting in a product solution at pH 6.25. The solution was concentrated by evaporation in vacuo at a jacket temperature of 40 °C to a final volume of 35 L (representing a target volume of 10 volume equivalents). The temperature of the suspension was reduced to 26 °C and a pH of 5.1 was determined. After evaporation, the pH of the suspension had already reached the target pH of 5.1, so no further pH adjustment was performed by addition of aqueous HCl. 7.0 L of IPA was added and the suspension was stirred at 5-6 °C for 20 h.

[0414] The suspension was transferred to a mobile filter dryer, allowed to settle for 8 minutes and filtered by applying overpressure (initially 0.5 bar, later increasing up to 2 bar). The isolated product was dried in vacuum at 40° C., initially at 50 mbar, until the end of the solvent distillation. Drying was then continued at full vacuum. After a total drying time of 18 hours at a final vacuum of 3 mbar, the product was removed from the filter dryer.

[0415] The product was sieved by applying a sieving mill (1.5 mm mesh size). After sieving, a total of 2.43 kg of compound of formula (I) was obtained. The chloride content was determined to be 0.5%.

[0416] Step 2: The hydrochloride salt of the compound of formula (I) prepared in the previous step (2.13 kg) was suspended in 43 L of deionized water. A pH of 4.1 was determined for the suspension. The pH was adjusted to 2.90 by adding 1.77 L of 1N aqueous HCl solution. The resulting clear, slightly yellow solution was stirred for 1 hour. The pH of the solution was increased from an initial pH of 2.87 to 5.09 by adding 1.65 L of 1M aqueous NH4HCO3 solution. To the slightly turbid solution, 4.3 L of IPA was added. The resulting suspension was then stirred for 0.5 hours at 25° C. and 19.5 hours at 5° C. (pH 6.09 was determined). The suspension was filtered in a mobile filter dryer and then dried in vacuum at 40° C. for approximately 20 hours (final vacuum of 10 mbar).

[0417] A sample was taken for IPC analysis, especially for determination of residual solvent and loss on drying. Drying was resumed at 25° C. (6.5 h, 3 mbar final vacuum) until IPC results were available. 602 mg / kg residual IPA, 1.57% LOD, 1.0% chloride content, and 99.3% purity (HPLC) were determined. The product was removed from the filter dryer and sieved (1.5 mm mesh). In total, 1.82 kg of regenerated hydrochloride salt of compound of formula (I) was obtained, with a yield of 85.4% (w / w).

[0418] The X-ray powder diffraction (XRPD) pattern of the hydrochloride salt of compound of formula (I) confirmed its crystalline nature (see FIG. 1).

[0419] Example 2 31.3 kg of Rink amide AM resin (substitution: 0.96 mmol / g) was loaded into a 1000 L SPPS reactor and SPPS was performed. Each SPPS cycle consisted of Fmoc cleavage, coupling with each building block, and the required capping. For Fmoc cleavage, the resin was treated with 20% piperidine in DMF (10 ml / g of resin each) for 5±2 min and 10±2 min at 25° C. Coupling was performed with DMF (10 ml / g of resin) as solvent using the building blocks, coupling reagents, and conditions illustrated in Table 3. For capping, the resin was treated with acid anhydride and pyridine in DMF for 20 min (volume ratio DMF / Ac2O / pyridine 50:1:1; DMF:10 ml / g of resin). Diisopropyl carbonate (DIC) was added in two portions, the first portion followed by the second portion approximately 20-30 minutes later.

[0420] [Table 4]

[0421] Final acetylation of the peptide resin was performed with acid anhydride and pyridine in DMF for 20 min (volume ratio DMF / Ac2O / pyridine 10:1:1; DMF:10 ml / g resin). After drying at 25-35°C, 123.7 kg of linear peptide-Rink amide AM resin was obtained.

[0422] TFA cleavage In a jacketed reactor, 100 g of linear peptide-Rink amide AM resin was added to 700 mL of cleavage cocktail consisting of 630 mL of TFA, 35 mL of TIS, 17.5 mL of EDT, and 17.5 mL of water at 20° C. Upon addition of the resin, the temperature rose to 34° C., and the mixture was stirred at 30° C. for another 35 min. The mixture was cooled to 20° C., the resin was filtered off, and washed twice with 100 mL of TFA each. The filtrates were combined and cooled to −17° C. For precipitation, 4.0 L of diisopropyl ether was added within 20 min, while maintaining the temperature of the solution / suspension at 5° C. After complete addition of diisopropyl ether, the temperature was raised to 25° C., and the suspension was stirred for 2.5 h. The suspension was then transferred to a filter dryer and the precipitated crude product was filtered off at ambient temperature. The filter cakes were then washed three times with 300 mL each of diisopropyl ether and dried overnight in vacuum at 30° C. In total, 53.62 g of linear peptide was isolated as the TFA salt.

[0423] Oxidation and purification by preparative HPLC 28 g of the cleaved linear peptide was dissolved in 280 mL of 30% AcOH in water at ambient temperature. 3.71 g of iodine and 7.17 g of potassium iodide were dissolved in 280 mL of water. Both peptide and iodine / iodide solutions were added in parallel to a vigorously stirred mixture of 2.2 L of 30% AcOH in water at ambient temperature within 60 min. After complete addition of both solutions, a red-brown oxidation mixture was obtained. After stirring for 30 min at ambient temperature, IPC showed almost complete conversion of the starting material. 3.5 g of vitamin C was added and the resulting yellow solution was stirred for 10 min. The oxidation mixture was filtered on a fritted glass funnel and then applied to a preparative RP-HPLC column. The chromatographic conditions are shown in Table 4. All fractions were adjusted to pH 7 with 18% HCl in water. The fractions collected during the preparative RP-HPLC were analyzed by UHPLC. Fractions containing >97% product were pooled for subsequent isolation.

[0424] [Table 5]

[0425] Isolation In total, 1.87 g of compound of formula (I) (partial HCl salt) was isolated from the 60 mL product pool, which calculates to 13.1 g of compound of formula (I) from a total product pool of 420 mL. Freeze drying of the mother liquor gave 0.17 g of residue.

[0426] A product pool of 420 mL was obtained after oxidation and preparative HPLC purification. The product concentration of this solution was determined by test lyophilization to be approximately 29 g / L, which corresponds to a theoretical yield of approximately 12.2 g.

[0427] From the total pool volume, 120 mL was transferred to a round-bottom flask and the initial pH of 7.01 was adjusted to pH 2.98 with 4.7 mL of 1 M aqueous HCl. Acetonitrile was evaporated from the product solution in vacuum at 40° C. until water started to evaporate. After evaporation, 84 mL of aqueous product solution remained (pH 2.75), of which 42 mL was transferred to a reactor connected to a heating / cooling system for subsequent isolation.

[0428] The pH of the solution was then adjusted to pH 3.75 by adding 1.1 mL of 0.5 M NH4HCO3 within 60 min. To the clear yellow solution, 1% (w / w) of the compound of formula (I) was added as seeding material, and the thin suspension formed was stirred for 60 min at 25 °C. The pH of the suspension was then adjusted to pH 4.50 by adding 2.6 mL of 0.5 M NH4HCO3 within 120 min. After stirring the suspension for 30 min at 25 °C, the pH dropped to pH 4.35. After stirring for 16 h at 25 °C, a thick suspension was present, which was filtered on a glass Nutsche filter (G4) (1 min filtration time) and washed with 1.74 mL of water (1 volume equivalent; 1 min filtration time) without stirring. The washed filter cake was dried in a vacuum oven at 40 °C in vacuum for 16 h. The dried product was finally removed from the filter.

[0429] In total, 1.87 g of the compound of formula (I) (partial HCl salt) was isolated from the 60 mL product pool, which calculates to 13.1 g of the compound of formula (I) from a total product pool of 420 mL. The isolated material was determined to have a purity of 99.5% (HPLC), a chloride content of 1.6% (titration), and a water content (KF) of 3.2%. XRPD measurements confirmed that the form of the partial HCl obtained was the same as that in Example 1.

[0430] Example 3: Alternative synthesis procedure for the crystalline hydrochloride salt form of the peptide of SEQ ID NO:1 SPPS 18.9 kg of Rink amide AM resin (substitution: 0.95 mmol / g) was loaded into a 1000 L SPPS reactor and SPPS was performed. Each SPPS cycle consisted of Fmoc cleavage, coupling with each building block, and the required capping. For Fmoc cleavage, the resin was treated with 20% piperidine in DMF (10 ml / g of resin each) for 5 ± 2 min and 10 ± 2 min at 25 °C. Coupling was performed with DMF (10 ml / g of resin) as solvent using the building blocks, coupling reagents, and conditions illustrated in Table 5. For capping, the resin was treated with acid anhydride and pyridine in DMF for 20 min (volume ratio DMF / Ac2O / pyridine 50:1:1; DMF:10 ml / g of resin). Diisopropyl carbonate (DIC) was added in two portions, the first portion followed by the second portion approximately 20-30 min later.

[0431] [Table 6]

[0432] Final acetylation of the peptide resin was performed with acid anhydride and pyridine in DMF for 20 min (volume ratio DMF / Ac2O / pyridine 10:1:1; DMF:10 ml / g resin). After drying at 25-35°C, 72.8 kg of linear peptide-Rink amide AM resin was obtained.

[0433] TFA cleavage [In a jacketed reactor, 100 g of PN21235-Rink Amide AM resin (#1000037885; 147841 / 1) was added to a 700 mL cleavage cocktail consisting of 630 mL TFA, 35 mL TIS, 17.5 mL EDT, and 17.5 mL water at 18°C. Upon addition of the resin, the temperature increased to 30°C and the mixture was stirred at 30°C for another 35 min. The mixture was cooled to 20°C, the resin was filtered off and washed twice with 100 mL TFA each. The filtrates were combined and cooled to -15°C. For precipitation, 4.0 L of diisopropyl ether was added within 20 min while maintaining the temperature of the solution / suspension at 7°C. After complete addition of diisopropyl ether, the temperature was increased to 22°C and the suspension was stirred for 2.5 h.

[0434] The suspension was then transferred to a filter drier and the precipitated crude product was filtered off at ambient temperature. The filter cakes were then washed three times with 300 mL of diisopropyl ether each and dried overnight in vacuum at 30° C. to give 52.87 g of the linear peptide as the TFA salt.

[0435] Oxidation and purification by preparative HPLC 28 g of the linear peptide as TFA salt was dissolved in 280 mL of 30% AcOH in water at ambient temperature. 3.71 g of iodine and 7.17 g of potassium iodide were dissolved in 280 mL of water. Both peptide and iodine / iodide solutions were added in parallel to a vigorously stirred mixture of 2.2 L of 30% AcOH in water at ambient temperature within 60 min. After complete addition of both solutions, a brown oxidation mixture was obtained. After stirring for 30 min at ambient temperature, IPC showed almost complete conversion of the starting material. 1.5 h after complete addition of the peptide and iodine solutions, 3.5 g of vitamin C was added. The resulting yellow solution was then stirred for 10 min. The oxidation mixture was filtered on a fritted glass funnel and then applied to a preparative RP-HPLC column. The chromatographic conditions were the same as those used in Example 2. All fractions were adjusted to pH 7 with 18% HCl in water. Fractions collected during preparative RP-HPLC were analyzed by UHPLC. Fractions containing >98% product were pooled for subsequent isolation.

[0436] Isolation A product pool of 420 mL was obtained after oxidation and preparative HPLC purification. The product concentration of this solution was determined by test lyophilization to be approximately 29 g / L, which corresponds to a theoretical yield of approximately 12.2 g.

[0437] From the total pool volume, 120 mL was transferred to a round-bottom flask and the initial pH of 7.51 was adjusted to pH 3.00 with 4.5 mL of 1 M aqueous HCl. Acetonitrile was evaporated from the product solution in vacuum at 40° C. until water started to evaporate. After evaporation, 80 mL of aqueous product solution remained (pH 2.54), of which 40 mL was transferred to a reactor connected to a heating / cooling system for subsequent isolation.

[0438] The pH of the solution was then adjusted to pH 3.75 by adding 1.0 mL of 0.5 M NH4HCO3 within 65 min. 1% (w / w) of the compound of formula (I) was added as seeding material to the clear yellow solution, and the thin suspension formed was stirred for 60 min at 25 ° C. The pH of the suspension was then adjusted to pH 4.50 by adding 2.9 mL of 0.5 M NH4HCO3 within 125 min. After stirring the suspension for 30 min at 25 ° C, the pH had dropped to pH 4.12. The pH was then readjusted to 4.50 by adding 0.2 mL of 0.5 M NH4HCO3. After stirring for 16 h at 25 ° C, a thick suspension was present, which was filtered on a glass Nutsche filter (G4) (1 min filtration time) and washed without stirring with 1.59 mL of water (1 volume equivalent; 1 min filtration time). The washed filter cake was dried in a vacuum oven for 16 hours under vacuum at 25° C. The dried product was finally removed from the filter.

[0439] In total, 1.77 g of compound of formula (I) (partial HCl salt) was isolated from the 60 mL product pool, which calculates to 12.4 g of compound of formula (I) from a total product pool of 420 mL. The isolated material had a purity of 99.4% (HPLC), a chloride content of 1.6% (titration), and a water content of 3.6% (KF).

[0440] The X-ray powder diffraction (XRPD) pattern of the partial hydrochloride salt of compound of formula (I) confirmed its crystalline nature (Figure 2). The following 2-theta peaks were observed: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degrees 2-theta.

[0441] Example 4. Synthetic procedure for seeding of the hydrochloride salt of peptide of SEQ ID NO:1 Seedlings of the hydrochloride salt of compound of formula (I) were prepared using an EasyMax 402 setup (100 mL scale). 3 g of HCl salt was dissolved in 21 mL of MeOH and 9 mL of water at 40° C. 30 mL of H2O was charged to the reactor over 10 hours. After 9 hours of isothermal, the reactor was slowly cooled to 5° C. at a rate of 0.05° C. / min. After 2 hours of isothermal, the reactor was heated to 40° C. at a rate of 1° C. / min, and after 1 hour of isothermal at 40° C., the reactor was cooled to 5° C. The resulting filtrate was washed twice with 3 mL of water and twice with 3 mL of isopropyl alcohol, then air dried.

[0442] Example 5. Synthetic procedure for the crystalline hydrochloride salt of the peptide of SEQ ID NO:1 Crystalline hydrochloride salt of compound of formula (I) prepared according to Example 3 (30 g) was dissolved in 120 mL of methanol and 51.4 mL of water. Dissolution was carried out in an EasyMax 402 with stirring at 40° C. 57.1 mL of sodium chloride 1M was charged to the EasyMax reactor over 1 hour. The solution was then seeded with 300 mg of a seed of the hydrochloride salt of compound of formula (I) prepared according to Example 4. The slurry was then aged for 8 hours with stirring at 40° C. The slurry was cooled to 5° C. at a cooling rate of 0.1 K / min. An additional 114.31 mL of sodium chloride 1M was charged to the EasyMax reactor over 4 hours and the slurry was aged for an additional 5 hours. The solid was isolated by vacuum filtration and washed with 30 mL of water twice and 30 mL of isopropanol twice. The solid was air dried.

[0443] The isolated solid of the crystalline hydrochloride salt form of the compound of formula (I) had a purity of 99.3 area % (UPLC) and a water content (KF) of 6.33 w / w%. The chloride content of the isolated crystalline hydrochloride salt form of the compound of formula (I) was assayed by ion chromatography and found to be 0.64 molar equivalents relative to the compound of formula (I). The XRPD pattern of the crystalline hydrochloride salt form of the compound of formula (I) confirmed its crystalline nature (Figure 3). The following 2 theta peaks were observed: 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees 2 theta + / - 0.2 degrees 2 theta.

[0444] Thermogravimetric analysis (TGA) of the isolated crystalline hydrochloride salt form of compound of formula (I) showed a weight loss of 5.6% when heated to about 160° C., which is attributed to loss of solvent, mainly water (FIG. 4). The first endothermic event in the differential scanning calorimetry (DSC) profile of the isolated crystalline hydrochloride salt form of compound of formula (I), showing a maximum at 81.4° C., corresponds to loss of solvent from the crystalline lattice, while the later event after 225° C. is due to decomposition of the solid (FIG. 5). The dynamic vapor sorption curve (DVS) of the isolated crystalline hydrochloride salt of compound of formula (I) showed a water uptake of about 8.7% at 80% RH, indicative of a hygroscopic material. (FIG. 6).

[0445] Example 6. Synthetic procedure for seeding of acetate salt of peptide of SEQ ID NO:1 The crystalline free base of the compound of formula (I) (900 mg) prepared according to Example 7 (900 mg) was dissolved in 4 mL of water. 1 mL of concentrated acetic acid was added to obtain a pH of 3.5. 5 mL of ammonium acetate 1.6 M was then charged at 0.002 ml / min. After 2 days, the resulting slurry was filtered and the resulting solid was washed with 4 mL of water.

[0446] Example 7. Synthetic procedure for the crystalline acetate salt of peptide of SEQ ID NO:1 The crystalline hydrochloride salt of the compound of formula (I) prepared according to Example 3 (30 g) was dissolved in 120 mL of water and 30 mL of acetic acid was concentrated. Dissolution was carried out in an EasyMax 402 with stirring at 25° C. 150 mL of aqueous ammonium acetate solution (2.4 M) was charged to the EasyMax reactor over a period of 2 hours. The solution was then seeded with a seed of the acetate salt of the compound of formula (I) prepared according to Example 6. The slurry was then aged with stirring at 25° C. for 12 hours. An additional 150 mL of aqueous ammonium acetate solution (2.4 M) was charged to the EasyMax reactor over a period of 4 hours. The slurry was then aged with stirring at 25° C. for an additional 10 hours. The solid was isolated by vacuum filtration and washed with 30 mL of water twice and 30 mL of 2-propanol twice.

[0447] The isolated solid of the crystalline acetate salt form of the compound of formula (I) had a purity of 99.3 area % (UPLC) and a water content (KF) of 6.39 w / w%. The acetate content of the isolated solid of the crystalline acetate salt form of the compound of formula (I) was assayed by ion chromatography and found to be 0.61 molar equivalents relative to the compound of formula (I). The XRPD pattern of the crystalline acetate salt form of the compound of formula (I) confirmed its crystalline nature (Figure 7). The following 2 theta peaks were observed: 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8, 12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 degrees 2 theta + / - 0.2 degrees 2 theta.

[0448] The TGA of the isolated crystalline acetate salt form of the compound of formula (I) shows a weight loss of 5.8% when heated to about 150° C. (FIG. 8). The first endothermic event in the DSC profile of the isolated crystalline acetate salt form of the compound of formula (I), showing a maximum at 80.7° C., corresponds to loss of solvent from the crystalline lattice, while the later event at 240.7 (onset at 228.2° C.) is due to melting / decomposition of the solid (FIG. 9). The dynamic vapor sorption curve (DVS) of the isolated crystalline acetate salt of the compound of formula (I) showed hygroscopic material (FIG. 10).

[0449] Example 8. Synthetic Procedure for the Crystalline Free Base of the Peptide of SEQ ID NO:1 150mL of phosphate buffer pH 8 at 1M concentration was added to an EasyMax 402 reactor with stirring at 25°C. In a separate reactor, the crystalline hydrochloride salt of the compound of formula (I) prepared according to Example 3 (30g) was dissolved in 150mL of water / HCl solution (1.5 molar equivalents of HCl relative to the compound of formula (I)) with stirring at 25°C. The solution was then charged to the EasyMax 402 containing the buffer solution over a period of 50 hours. The solids were isolated by vacuum filtration and placed in a clean EasyMax 402 reactor. 400mL of water was added to the reactor and the slurry was stirred at 25°C for 24 hours. The solids were isolated by vacuum filtration and washed twice with 30mL of water. The solids were allowed to air dry.

[0450] The isolated solid of the crystalline free base of the compound of formula (I) had a purity of 97.9% (UPLC) and a water content (KF) of 12.68 w / w%. The ion content of the isolated crystalline solid was assayed by ion chromatography and found to be <0.02 w / w% chloride and <0.05 w / w% sodium. The XRPD pattern of the crystalline free base of the compound of formula (I) con...

Claims

1. A compound of formula (I) having the following structure: 【Chemistry 1】 A crystalline form of a pharma- ceutically acceptable salt thereof, or a solvate of the foregoing.

2. 2. The crystalline form of claim 1, wherein the crystalline form is a crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof.

3. 3. The crystalline form of claim 2, wherein the crystalline form of the pharma- ceutically acceptable salt or solvate thereof is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2-theta.

4. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline acetate salt of the compound of formula (I) or a solvate thereof.

5. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof.

6. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline glutarate salt of the compound of formula (I) or a solvate thereof.

7. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline glycolate salt of the compound of formula (I) or a solvate thereof.

8. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline bis-hydrochloride salt of the compound of formula (I) or a solvate thereof.

9. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline fumarate salt of the compound of formula (I) or a solvate thereof.

10. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline mesylate salt of the compound of formula (I).

11. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline sulfate salt of the compound of formula (I) or a solvate thereof.

12. 4. The crystalline form of claim 2 or 3, wherein the crystalline form is a crystalline citrate salt of the compound of formula (I) or a solvate thereof.

13. 13. The crystalline form of any one of claims 2-12, characterized in that the crystalline form has an XRPD pattern substantially as shown in Figure 1, Figure 2, Figure 3, Figure 7, Figure 15, Figure 18, Figure 21, Figure 24, Figure 26, Figure 28, or Figure 29.

14. 14. The crystalline form of any one of claims 2 to 11 or 13, characterized in that the crystalline form has a DSC graph or SDT thermogram substantially as shown in Figure 5, Figure 9, Figure 17, Figure 19, Figure 22, Figure 25, or Figure 27.

15. The crystalline form is a. endothermic peaks at about 80.7° C. and / or about 240.7° C. as determined by DSC; b. an endothermic peak at about 81.4° C. as determined by DSC; c. endothermic peaks at about 79.5° C. and / or about 235.3° C. as determined by DSC; d. an endothermic peak at about 65.3° C. as determined by DSC; e. an endothermic peak at about 224.0° C. as determined by SDT; f. an endothermic peak at about 237.0° C. as determined by SDT; g. an endothermic peak at about 242.1° C. as determined by SDT, or h. An endothermic peak at about 255.0° C. as determined by SDT The crystalline form according to any one of claims 2 to 11 or 13 to 14, characterized in that it has

16. 16. The crystalline form of any one of claims 2-11 or 13-15, characterized in that the crystalline form has a TGA graph or SDT thermogram substantially as shown in Figure 4, Figure 8, Figure 16, Figure 19, Figure 22, Figure 25, Figure 27, or Figure 30.

17. The crystalline form is a. about 5.8% weight loss from about 26.5° C. to about 150.0° C. as determined by TGA; b. about 5.6% weight loss from about 26.5° C. to about 160.0° C. as determined by TGA; c. about 11.3% weight loss from about 26.5° C. to about 190.0° C. as determined by TGA; d. about 4.4% weight loss from about 26.5° C. to about 110.0° C. as determined by TGA; e. about 6.4% weight loss from about 26.5° C. to about 125.0° C. as determined by SDT; f. about 5.1% weight loss from about 26.5° C. to about 100.0° C. as determined by SDT; g. about 5.4% weight loss from about 26.5° C. to about 80.0° C. as determined by SDT; or h. About 4.4% weight loss from about 26.5° C. to about 80.0° C. as determined by SDT The crystalline form according to any one of claims 2 to 11 or 13 to 16, characterized in that it has

18. 18. The crystalline form of any one of claims 2-8 or 13-17, wherein the crystalline form has a DVS graph substantially as shown in Figure 6, Figure 10, Figure 20, Figure 23, or Figure 32.

19. 19. The crystalline form of any one of claims 2 to 18, wherein the crystalline form of the pharma- ceutically acceptable salt or solvate thereof of the compound of formula (I) comprises a cation form of the compound of formula (I) and a pharma- ceutically acceptable anion, wherein the molar equivalents of the pharma- ceutically acceptable anion per mole of the compound of formula (I) is from about 0.2 to about 2.

0.

20. 2. The crystalline form of claim 1, wherein the crystalline form is a crystalline form of the free base of the compound of formula (I).

21. 21. The crystalline form of claim 20, characterized in that the crystalline form has an XRPD pattern comprising two or more peaks at angles 2-theta selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees 2-theta.

22. 22. The crystalline form of claim 20 or 21, wherein the crystalline form has an XRPD pattern substantially as shown in Figure 11.

23. 23. The crystalline form of any one of claims 20 to 22, characterized in that the crystalline form has a DSC graph substantially as shown in Figure 13.

24. The crystalline form of any one of claims 20 to 23, characterized in that the crystalline form has an endothermic peak at about 71.0°C and / or about 130.2°C as determined by DSC.

25. 25. The crystalline form of any one of claims 20 to 24, characterized in that the crystalline form has a TGA graph substantially as shown in Figure 12.

26. 26. The crystalline form of any one of claims 20 to 25, characterized in that the crystalline form has a weight loss of about 3.7% from about 26.5°C to about 70.0°C and a weight loss of about 2.7% from 70.0°C to about 170.0°C as determined by TGA.

27. 27. The crystalline form of any one of claims 20 to 26, characterized in that the crystalline form has a DVS graph substantially as shown in Figure 14.

28. A compound of formula (I) having the following structure: 【Chemistry 2】 Crystalline forms of pharma- ceutically acceptable salts thereof, or solvates of the foregoing; one or more pharma- ceutically acceptable excipients; 13. A pharmaceutical composition comprising:

29. 29. The pharmaceutical composition of claim 28, wherein the crystalline form of the compound of formula (I) or its pharma- ceutically acceptable salt or solvate thereof is in an amount of about 0.1% to about 60% (w / w) of the composition.

30. 30. The pharmaceutical composition of claim 28 or 29, wherein the crystalline form of the compound of formula (I) or its pharma- ceutically acceptable salt or solvate thereof is in an amount of about 0.1% to about 30% (w / w) of the composition.

31. 31. The pharmaceutical composition of any one of claims 28 to 30, wherein the crystalline form of the compound of formula (I) or its pharma- ceutically acceptable salt, or solvate thereof, is characterized by having an XRPD pattern comprising peaks at angles 2 of 4.2, 6.9, 7.6, and 9.2 degrees 2-theta + / - 0.2 degrees 2-theta.

32. 32. The pharmaceutical composition of any one of claims 28 to 31, wherein the crystalline form is a pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, wherein the pharma- ceutically acceptable salt is selected from acetate, hydrochloride, fumarate, glutarate, glycolate, mesylate, sulfate, citrate, and bis-hydrochloride.

33. 33. The pharmaceutical composition of claim 32, wherein said pharma- ceutically acceptable salt of the compound of formula (I) comprises the cationic form of said compound of formula (I) and a pharma- ceutically acceptable anion, and the molar equivalents of said pharma- ceutically acceptable anion per mole of said compound of formula (I) are from about 0.2 to about 2.

0.

34. 34. The pharmaceutical composition according to any one of claims 28 to 33, wherein the amount of said crystalline form of said compound of formula (I) or said pharma- ceutically acceptable salt or solvate thereof is in the range of about 1 mg to about 1000 mg.

35. 35. The pharmaceutical composition according to any one of claims 28 to 34, wherein the amount of crystalline pharma- ceutically acceptable salt of said compound of formula (I) or a solvate thereof ranges from about 25 mg to about 300 mg.

36. 36. The pharmaceutical composition of claim 35, wherein the dose of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof is about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

37. The pharmaceutical composition of any one of claims 28 to 36, wherein the composition further comprises a filler.

38. 38. The pharmaceutical composition of claim 37, wherein the filler is silicified microcrystalline cellulose.

39. 39. The pharmaceutical composition of claim 37 or 38, wherein the amount of filler is from about 25% to about 95% (w / w) of the composition, preferably from about 30% to about 90% (w / w) of the composition.

40. 40. The pharmaceutical composition of any one of claims 28-39, wherein the composition further comprises 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.

41. The pharmaceutical composition of any one of claims 28 to 40, wherein the composition further comprises a binder.

42. 42. The pharmaceutical composition of claim 41, wherein the binder is hydroxypropyl methylcellulose.

43. 43. The pharmaceutical composition of claim 41 or 42, wherein the amount of the binder is from about 0.1% to about 85% (w / w) of the composition, preferably from about 0.1% to about 25% (w / w) of the composition.

44. The pharmaceutical composition according to any one of claims 28 to 43, wherein the composition further comprises a disintegrant.

45. 45. The pharmaceutical composition of claim 44, wherein the disintegrant is selected from one or more of cross-linked carboxymethylcellulose (croscarmellose), starch glycolate, polyvinylpyrrolidone, sago starch, psyllium husk, silicates, soy polysaccharides, croscarmellose sodium, or crospovidone.

46. 46. ​​The pharmaceutical composition of claim 44 or 45, wherein the total amount of disintegrant is from about 3% to about 25% (w / w) of the composition, preferably from about 5% to about 15% (w / w) of the composition, and more preferably from about 5% to about 12% (w / w) of the composition.

47. The pharmaceutical composition of any one of claims 28 to 46, wherein the composition further comprises a lubricant.

48. 48. The pharmaceutical composition of claim 47, wherein the amount of said lubricant is from about 0.1% to about 2.5%, preferably from about 0.3% to about 2% (w / w) of said composition.

49. The pharmaceutical composition of any one of claims 28 to 48, wherein the composition further comprises a sugar alcohol.

50. 50. The pharmaceutical composition of claim 49, wherein the amount of sugar alcohol is from about 5% to about 40% (w / w) of the composition, preferably from about 10% to about 30% (w / w) of the composition, and more preferably from about 10% to about 27.5% (w / w) of the composition.

51. The pharmaceutical composition of any one of claims 28 to 50, wherein the composition further comprises silica.

52. 52. The pharmaceutical composition of claim 51, wherein the amount of silica is from about 0.1% to about 1.5% (w / w) of the composition.

53. The pharmaceutical composition according to any one of claims 28 to 52, wherein the composition is a tablet composition or a capsule composition.

54. a. the crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.1% to about 60% (w / w) of the composition; b. silicified microcrystalline cellulose in an amount from about 40% to about 85% (w / w) of said composition; c. a disintegrant in an amount from about 5% to about 10% (w / w) of the composition; d. silica in an amount from about 0.1% to about 1.0% (w / w) of the composition, and e. a lubricant in an amount of about 0.5% to about 1.5% (w / w) of the composition The pharmaceutical composition according to any one of claims 28 to 53, comprising:

55. a. the crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 10% to about 40% (w / w) of the composition; b. the silicified microcrystalline cellulose in an amount ranging from about 60% to about 85% (w / w) of the composition; c. Crospovidone in an amount of about % to about 5% (w / w) of the composition; d. the silica in an amount of about 0.1% to about 1% (w / w) of the composition; and e. magnesium stearate in an amount from about 0.1% to about 1% of the composition The pharmaceutical composition according to any one of claims 28 to 54, comprising:

56. 56. The pharmaceutical composition of any one of claims 28-55, further comprising mannitol, wherein the mannitol is present in an amount of about 10% to about 15% (w / w) of the composition.

57. 57. The pharmaceutical composition of any one of claims 28 to 56, further comprising a cosmetic coating.

58. 58. The pharmaceutical composition of claim 57, wherein the cosmetic coating is a film coating selected from a formulation based on polyethylene glycol-polyvinyl alcohol (PEG-PVA) graft copolymer, polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (HPC), or any combination thereof.

59. a. an absorption enhancer in an amount of about 5% to about 65% (w / w) of the composition; b. the crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.1% to about 15% (w / w) of the composition; and c. silicified microcrystalline cellulose in an amount of about 10% to about 50% (w / w) of the composition. The pharmaceutical composition according to any one of claims 28 to 53, comprising:

60. a. an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; b. a disintegrant in an amount of about 5% to 10% (w / w) of the composition; c. the crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.5% to about 15% (w / w) of the composition; d. silicified microcrystalline cellulose in an amount from about 30% to about 40% (w / w) of the composition; e. silica in an amount from about 0.2% to about 1.5% (w / w) of the composition; f. a disintegrant in an amount from about 5% to about 10% (w / w) of the composition; g. a filler in an amount of about 7.5% to about 15% (w / w) of the composition, and h. a lubricant in an amount of about 0.2% to about 1.5% (w / w) of said composition The pharmaceutical composition according to any one of claims 28 to 53, comprising:

61. a. the absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; b. the disintegrant in an amount of about 5% to about 10% (w / w) of the composition; c. the crystalline form of the pharma- ceutically acceptable salt of the compound of formula (I) or a solvate thereof, in an amount of about 0.5% to about 5% (w / w) of the composition; d. silicified microcrystalline cellulose in an amount from about 35% to about 40% (w / w) of the composition; e. mannitol in an amount from about 5% to about 15% (w / w) of the composition; f. Crospovidone in an amount from about 1% to about 10% (w / w) of the composition; g. silica in an amount from about 0.1% to about 10% (w / w) of the composition, and h. magnesium stearate in an amount from about 0.1% to about 1% (w / w) of the composition; 61. The pharmaceutical composition of claim 60.

62. 60. The pharmaceutical composition of claim 58 or 59, wherein the absorption enhancer is sodium citrate, tartaric acid, a tartrate salt, salicylic acid, sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), polyethylene glycol (PEG)-modified medium chain triglycerides of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).

63. a. sodium caprate in an amount of about 38.5% (w / w) of the composition; b. hydroxypropyl methylcellulose in an amount of about 0.8% (w / w) of the composition; c. the crystalline form of the pharma- ceutically acceptable salt or solvate thereof of the compound of formula (I), in an amount from about 3.9% (w / w) of the composition; d. silicified microcrystalline cellulose in an amount of about 39.7% (w / w) of the composition; e. mannitol in an amount of about 10.7% (w / w) of the composition; f. Crospovidone in an amount from about 5% to about 7.5% (w / w) of the composition; g. silica in an amount from about 0.5% to about 1.0% (w / w) of the composition, and h. magnesium stearate in an amount of about 0.5% (w / w) of the composition; A pharmaceutical composition according to any one of claims 57 to 60.

64. a. a crystalline form of a pharma- ceutically acceptable salt or solvate thereof of the compound of formula (I) in an amount of about 10% to about 20% (w / w) of said composition; b. an absorption enhancer in an amount of about 30% to about 45% (w / w) of the composition; c. a disintegrant in an amount from about 0.5% to about 1.0% (w / w) of the composition; d. Crospovidone in an amount of about 5% (w / w) of the composition; e. microcrystalline cellulose in an amount of about 1.3% (w / w) of the composition; f. silicified microcrystalline cellulose in an amount from about 34.8% to about 39.7% (w / w) of the composition; g. mannitol in an amount of about 10.7% (w / w) of the composition; h. Crospovidone in an amount of about 5% (w / w) of the composition; i. silica in an amount of about 1.0% (w / w) of the composition, and j. magnesium stearate in an amount of about 0.5% (w / w) of the composition The pharmaceutical composition according to any one of claims 28 to 53, comprising:

65. 65. The pharmaceutical composition of any one of claims 59 to 64, further comprising a subcoating.

66. 66. The pharmaceutical composition of claim 65, wherein the subcoating is present in an amount of about 1% to about 5% (w / w).

67. 67. The pharmaceutical composition of claim 65 or 66, further comprising an enteric coating.

68. 68. The pharmaceutical composition of claim 67, wherein the enteric coating is present in an amount of about 2% to about 15% (w / w).

69. 69. The pharmaceutical composition of claim 67 or 68, wherein the enteric coating is present in an amount of about 8% or about 12%.

Images