Methods for preparing crystalline peptide inhibitors of the interleukin-23 receptor

Abstract

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

Description

[Technical Field]

[0001] (Sequence Listing) The contents of the electronic sequence listing (747883-NTT-4258PC_SL.xml, size: 13,484 bytes, and creation date: January 30, 2024) are incorporated herein by reference in their entirety.

[0002] (Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 482,512, filed January 31, 2023, and U.S. Provisional Patent Application No. 63 / 517,307, filed August 2, 2023, the contents of both of which are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present invention relates to a method for preparing crystalline monocyclic peptide compounds, and salts or solvates thereof, which are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystalline monocyclic peptide compounds, and salts or solvates thereof, have favorable rheological (flow) properties, making them suitable for pharmaceutical processing. The peptide inhibitors are useful for the treatment of autoimmune inflammatory diseases and related disorders. [Background technology]

[0004] The 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 the pathogenesis of disease. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are abundant in the intestine. Increased gene expression and protein levels of IL-23R have been found at the intestinal mucosal surface in patients with IBD. 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 abundantly produced in the intestine, where it is thought to play a key role in suppressing intestinal regulatory T cell responses that favor inflammation, as well as controlling the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation by influencing T-helper 1 (Th1) and Th17-associated cytokines. Additionally, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the important role of the IL-23 pathway in intestinal homeostasis.

[0006] Psoriasis (PsO), a chronic skin disease affecting approximately 2% to 3% of the general population, has been shown to be mediated by the body's T cell inflammatory response. IL-23 is one of several interleukins that has been implicated as a key player in the pathogenesis of psoriasis, reportedly by maintaining chronic autoimmune inflammation through the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues from psoriasis patients, and IL-23-neutralizing antibodies have demonstrated IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0007] IL-23 is a unique p19 subunit and a T helper 1 (T) subunit that produces interferon-γ (IFN-γ). H 1) IL-23 is a heterodimer composed of a shared p40 subunit with IL-12, a cytokine involved in the development of IL-12 cells. IL-23 and IL-12 both contain the p40 subunit, but 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 CD4+ TNF-producing cells, possibly due to the lack of CD4+ TNF-producing cells in the CNS of IL-23-deficient animals. + Resistance to IL-23 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. However, compared with IL-12, activation of Stat4 is substantially weaker, and distinct DNA-binding Stat complexes are formed in response to IL-23. IL-23R constitutively associates with Jak2 and with Stat3 in a ligand-dependent manner. In contrast to IL-12, which acts primarily on naive CD4(+) T cells, IL-23 preferentially acts 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. While these findings are promising, challenges remain regarding the successful targeted delivery of such drugs. 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 herein by reference in their entireties.

[0010] Peptide compounds, such as those described in PCT Publication WO 2021 / 146441 and U.S. Patent Application Publication No. 2021 / 0261622, can be produced using solid-phase peptide synthesis (SPPS). In solid-phase peptide synthesis, an amino acid or peptide is attached to a solid support, usually via its C-terminus. A new amino acid is added to the attached amino acid or peptide via a coupling reaction. While solid-phase peptide synthesis has been widely used, the process is tedious and often requires purification of the reaction product by chromatography, resulting in a costly, slow process and difficulty in scaling up.

[0011] Thus, there is a need for alternative methods for synthesizing the peptides described herein, particularly methods that provide improved rheological (flow) properties, particle size, and handling characteristics, such as hygroscopicity, of peptide inhibitors for use as pharmaceutical ingredients.

[0012] There remains a need in the art to develop methods for preparing peptide inhibitors of the interleukin-23 receptor (IL-23R) that provide solid forms of the peptide inhibitors in a form suitable for large-scale commercial development and that have characteristics that improve the handleability of the peptide inhibitors for use as pharmaceutical ingredients. For example, there remains a need to develop methods for preparing and isolating forms of peptide inhibitors of IL-23R that have good rheological properties. The present invention addresses these needs. Summary of the Invention [Means for solving the problem]

[0013] Provided herein are methods for preparing crystalline forms of peptide inhibitors of interleukin-23 receptor (IL-23R). Crystalline forms have advantageous properties compared to the analogous amorphous forms, such as ease of isolation, processability, handling, improved purity, and greater physical and chemical stability. These attributes can be particularly important for pharmaceutical agents where large-scale production, reproducibility, and compound purity are required. Crystalline forms of peptides can be uniquely advantageous because the corresponding amorphous forms are often not suitable for formulations such as tableting.

[0014] Generally, the present invention relates to methods for the preparation of monocyclic peptide compounds or hydrochloride salts, solvates, or forms thereof having rheological (flow) properties suitable for pharmaceutical processing. The methods of the present invention include methods for improving the rheological properties of monocyclic peptide compounds and methods for preparing monocyclic peptide compounds having rheological properties suitable for the manufacture of pharmaceutical compositions.

[0015] In particular, the present invention provides 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 (where [Pen] * -[Pen] * The present invention relates to a process for the preparation of a crystalline form of (wherein the crystalline form forms a disulfide bond), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.

[0016] [ka]

[0017] In particular, the present invention provides a compound having the structure:

[0018] [ka] Compounds of formula (I) having the formula or a process for the preparation of a crystalline hydrochloride salt of a solvate thereof.

[0019] The present invention also provides a peptide of SEQ ID NO: 2 having the structure of a compound of formula (II): Process for the preparation of a crystalline form of Ac-dArg-cyclo[Abu-Gln-Thr-Trp-Gln-Cys]-Phe(2-ae)-2-NaI-Glu-Glu-Asn-Asn-NH or a pharmaceutically acceptable salt thereof or a solvate of the foregoing.

[0020] [ka]

[0021] In another embodiment, the present invention provides a compound having the structure:

[0022] [ka] a compound of formula (II) having the formula or a process for the preparation of a crystalline acetate salt thereof.

[0023] In another embodiment, the present invention provides a peptide of SEQ ID NO: 3 having the structure of a compound of formula (III): Ac-[Pen] * -Asn-Thr-Trp(7Me)-Lys(Ac)-[Pen] * -Tyr(2-ea)-2Nal-αMe-Lys-Lys(Ac)-Asn-D-Leu-NH2(where, [Pen] * -[Pen] * The present invention relates to a process for the preparation of a crystalline form of (wherein the crystalline form forms a disulfide bond), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing.

[0024] [ka]

[0025] The present invention also relates to a compound having the structure:

[0026] [ka] a compound of formula (III) having the formula or a process for the preparation of a crystalline hydrochloride salt of a solvate thereof.

[0027] The present invention also provides methods for the preparation of a crystalline form of a peptide compound of any one of Formulas (I'), (IIa)-(IId), (IIIa)-(IIIf), or (IVa)-(IVd), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, as described herein. Pharmaceutically acceptable salts of the compounds of any one of Formulas (I'), (IIa)-(IId), (IIIa)-(IIIf), or (IVa)-(IVd) provided herein include hydrochloride, bishydrochloride, acetate, fumarate, glutarate, glycolate, mesylate, sulfate, and citrate.

[0028] The present invention also provides a process for the preparation of a crystalline form of the compound of formula (I) or a pharmaceutically 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.

[0029] Further provided herein is a crystalline form of the free base of a compound of formula (I) or a peptide of any one of the compounds of formula (I'), (IIa)-(IId), (IIIa)-(IIIf), (IVa)-(IVd), or a solvate thereof of any of the foregoing, prepared according to the methods of the invention.

[0030] Further provided herein is a crystalline form of the free base of a compound of formula (I), or a compound of any one of formulas (I'), (IIa)-(IId), (IIIa)-(IIIf), (IVa)-(IVd), or a solvate thereof of any of the foregoing, prepared according to the methods of the invention.

[0031] The present invention also provides methods for the preparation of a crystalline form of a peptide compound of any one of Formula (II) or Formula (III) or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, as described herein. Pharmaceutically acceptable salts of compounds of any one of Formula (II) or Formula (III) provided herein can include hydrochloride, bishydrochloride, acetate, fumarate, glutarate, glycolate, mesylate, sulfate, and citrate salts.

[0032] Further provided herein is a crystalline form of the compound of formula (I), or the free base of a compound of any one of formulas (II) or (III), or a solvate thereof of any of the foregoing, prepared according to the methods of the present invention. [Brief explanation of the drawings]

[0033] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 2] 1 shows the XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 3] 1 shows the XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 4] 1 shows a thermogravimetric analysis (TGA) graph of the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 5] 1 shows a differential scanning calorimetry (DSC) graph of the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 6] 1 shows the dynamic vapor sorption (DVS) curve for the crystalline form of the hydrochloride salt of the compound of formula (I). [Figure 7] 1 shows the XRPD pattern of a crystalline form of the acetate salt of the 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 the 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 the 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 a crystalline form of the fumarate salt of compound of formula (I). [Figure 16] 1 shows a TGA graph of the crystalline form of the fumarate salt of the compound of formula (I). [Figure 17] 1 shows a DSC graph of the crystalline form of the fumarate salt of the compound of formula (I). [Figure 18] 1 shows the 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 the 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). [Figure 23] 1 shows the DVS curve of the crystalline form of the glycolate salt of the compound of formula (I). [Figure 24] 1 shows the XRPD pattern of the crystalline form of the mesylate salt of the compound of formula (I). [Figure 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 the XRPD pattern of the crystalline form of the sulfate salt of the 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 the 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 the compound of formula (I). [Figure 30] 1 shows a TGA graph of the crystalline form of the bis-hydrochloride salt of the compound of formula (I). [Figure 31] 1 shows a DSC graph of the crystalline form of the bis-hydrochloride salt of the compound of formula (I). [Figure 32] 1 shows the DVS curve of the crystalline form of the bis-hydrochloride salt of the compound of formula (I). [Figure 33] 1 is a process flow chart for the preparation of a crystalline form of the compound of formula (I). [Figure 34] 1 shows a PLM image of the crystalline form of the hydrochloride salt of compound of formula (II). [Figure 35] 1 shows a PLM image of the crystalline form of the sulfate salt of compound of formula (II). [Figure 36] 1 shows a PLM image of the crystalline form of the acetate salt of compound of formula (II). [Figure 37] 1 shows a PSD data plot comparing material isolated from SPPS, LPPS, and material recovered after tabulation of the crystalline form of the compound of formula (I). [Figure 38]1 shows a PSD data plot comparing statically dried and dynamically dried materials of a crystalline form of the compound of formula (I). [Figure 39] 1 shows a PSD data plot comparing sieved and unsieved material of the crystalline form of the compound of formula (I). [Figure 40] 1 shows a PSD data plot comparing grinding and sieving of a crystalline form of the compound of formula (I) against a control material. DETAILED DESCRIPTION OF THE INVENTION

[0034] I. Overview The present invention relates to a method for preparing a crystalline form of a monocyclic peptide compound, which is a peptide inhibitor of interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The crystalline form of the monocyclic peptide compound, which is a peptide inhibitor of interleukin-23 receptor (IL-23R), or a pharmaceutically acceptable salt thereof, or a solvate thereof has suitable rheological (flow) properties for producing pharmaceutical compositions. The present invention also relates to a crystalline form of the monocyclic peptide compound, which is a peptide inhibitor of IL-23R, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by the method of the present invention.

[0035] The present invention provides a method for the preparation of crystalline forms of monocyclic peptide compounds from monocyclic peptide compounds, such as those obtained by liquid phase peptide synthesis (LPPS). The method of the present invention provides crystalline forms of peptide compounds with improved handleability, rheological properties, and purity suitable for large-scale commercial production without the need for chromatography. The monocyclic peptide compound may be a thixotropic material. The method of the present invention allows for the isolation of crystalline forms of monocyclic peptide compounds that are thixotropic.

[0036] In particular, the present invention provides a compound of formula (I) (SEQ ID NO: 1):

[0037] [ka] The present invention provides a method for the preparation of a crystalline form of the hydrochloride salt of a monocyclic peptide compound having the structure:

[0038] The present invention also relates to a compound of formula (II) (SEQ ID NO: 2):

[0039] [ka] The present invention provides a method for the preparation of a crystalline form of a peptide compound having the structure:

[0040] The present invention relates to a compound of formula (III) (SEQ ID NO: 3):

[0041] [ka] The present invention further provides a process for the preparation of a crystalline form of the hydrochloride salt of a peptide compound having the structure:

[0042] The present invention also provides a method for the preparation of a crystalline form of the acetate salt of a peptide compound having the structure of formula (III).

[0043] II. Definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those skilled in the art.

[0044] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0045] "A," "an," or "a(n)," when used herein in reference to a group of substituents or "substituents," are indefinite articles meaning at least one.

[0046] When referring to a value, "about" includes the stated value + / - 10% of the stated 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 the stated value + / - 10%, respectively, at each upper and lower limit of the stated range. For example, a ratio of about 1 to about 3 (wt / wt) 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.

[0047] As used in this specification and claims, the terms "comprise(s)", "comprising", "include(s)", "having", "has", "can", "contain(s)", and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified features, groups, components, or steps, and do not exclude the presence of other features, groups, components, or steps. For example, the language "a peptide of formula (I') comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I')" means that in addition to amino acids X3 through X16, the peptide may include, but is not limited to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N- or C-terminal capping groups, chemical or biological moieties conjugated to the peptide at any position (e.g., including, but not limited to, lipophilic substituents, antibodies, imaging agents, etc.). The terms "comprise(s)," "comprising," "include(s)," "having," "has," "can," or "contain(s)" can include embodiments encompassed by the terms "consisting essentially of" or "consisting of."

[0048] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and typically refer to molecules comprising a chain of two or more amino acids (e.g., L-amino acids, D-amino acids, modified amino acids, amino acid analogs, amino acid mimetics, etc.).

[0049] Unless otherwise indicated, both naturally occurring L-amino acids and D-amino acids are represented by either the conventional three letter or uppercase single letter amino acid symbols in Table A1. In some embodiments, naturally occurring L-amino acids are represented by either the conventional three letter or uppercase single letter amino acid symbols in Table 1. In some embodiments, D-amino acids are represented by lowercase single letter amino acid symbols corresponding to the single letter symbols in Table A1, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t.

[0050] [Table 1]

[0051] As used herein, the term "L-amino acid" refers to the "L" isomeric form of an amino acid, and conversely, the term "D-amino acid" refers to the "D" isomeric form of an amino acid (e.g., (D)Asp or D-Asp, (D)Phe, or D-Phe). Any L-amino acid residue may be substituted with the D-isomer form of the amino acid residue, so long as the peptide retains the desired function. D-amino acids, when referred to using single-letter abbreviations, may by convention be designated by a lowercase letter. For example, D-arginine may be designated as "arg" or "r". Alternatively, a lowercase "d" may be used before an amino acid to indicate its D-isomer form, for example, D-lysine may be designated as dK.

[0052] Less common or non-naturally occurring amino acids are not referred to by their full names (e.g., sarcosine, ornithine, etc.), but rather by frequently used three-letter or four-letter codes for such residues, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid), or those defined below.

[0053] Some abbreviations useful in describing this invention are defined in Table 1 below.

[0054] [Table 2-1]

[0055] [Table 2-2]

[0056] [Table 2-3]

[0057] Those skilled in the art will understand that certain amino acids and other chemical moieties may be modified when attached to another molecule. For example, an amino acid side chain may be modified when forming an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogens may be removed or replaced upon attachment. Thus, as used herein, a reference to an amino acid or modified amino acid present in a peptide dimer of the invention (e.g., at position X4 or X9) is meant to include forms of such amino acid or modified amino acid present in the peptide both before and after forming an intramolecular bond.

[0058] As used herein, the term "NH" may refer to the free amino group present at the amino terminus of a polypeptide. As used herein, the term "OH" may refer to the free carboxy group present at the carboxy terminus of a peptide. Additionally, the terms "Ac" or "Ac-" as used herein refer to acetyl protection through acylation of the C- or N-terminus of a polypeptide. In certain peptides presented herein, the NH located at the C-terminus of the peptide indicates an amino group.

[0059] As used herein, the term "carboxy" refers to -CO2H.

[0060] As used herein, the term "cyclization" refers to the linking of one portion of a polypeptide molecule to another portion of a polypeptide molecule to form a closed ring, such as by forming a disulfide bridge or a thioether bond.

[0061] As used herein, the term "subunit" refers to one of a pair of polypeptide monomers that are joined to form a dimeric peptide composition.

[0062] As used herein, the term "pharmaceutically acceptable salts" refers to salts or zwitterionic forms of the peptides or compounds of the invention that are soluble or dispersible in water or oil, which are suitable for treating diseases without undue toxicity, irritation, and allergic response, and which are effective for their intended use, commensurate with a reasonable benefit-to-risk ratio. Salts can be prepared during the final isolation and purification of the compounds, or separately by reacting the amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate salts. Amino groups in the compounds of the present invention can also be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.Other examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and later editions thereof), "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66:2 (1977). Also, for a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0063] The term "alkyl" includes straight-chain or branched-chain, acyclic or cyclic saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Representative saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0064] "Halo" or "halogen" refers to a bromo (Br), chloro (Cl), fluoro (F), or iodo (I) substituent.

[0065] The term "haloalkyl" includes alkyl structures in which at least one hydrogen atom has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are all the same as each other. In other embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are not all the same as each other.

[0066] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0067] "Aminocarbonyl" or "carboxamide" refers to the -CONH2 radical.

[0068] "2-aminoethoxy" refers to the -OCH2CH2-NH2 radical.

[0069] "2-Acetylaminoethoxy" refers to the -OCH2CH2-N(H)C(O)Me radical.

[0070] The term "mammal" refers to any mammalian species, such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, farm animals, etc.

[0071] An "analog" of an amino acid, e.g., a "Phe analog" or a "Tyr analog," refers to an analog of the referenced amino acid. A variety of amino acid analogs, including Phe and Tyr analogs, are known and available in the art. In certain embodiments, an amino acid analog, e.g., a Phe analog or a Tyr analog, contains one, two, three, four, or five substitutions compared to Phe or Tyr, respectively. In certain embodiments, the substitutions are in the side chain of the amino acid. In certain embodiments, a Phe analog has the structure Phe(R 2 ) and R 2is Hy, OH, CH, COH, CONH, CONHOCHCHNH, t-Bu, OCHCHNH, phenoxy, OCH, Oallyl, Br, Cl, F, NH, N, or guanadino. 2 is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3, or CO2H. Examples of Phe analogs include hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy), Phe(4-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5 Examples of Tyr analogs include, but are not limited to, hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3), and βhTyr.

[0072] The substituents are those that result in the formation of a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not change substantially when subjected to conditions that allow for the production, detection, and preferably the recovery, purification, and use of the compound for one or more of the purposes disclosed herein. In some embodiments, a stable compound or a chemically feasible compound is one that does not change substantially when maintained at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0073] "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 intended to improve the oral delivery of therapeutic agents with poor bioavailability. PEs can increase the paracellular and / or transcellular passage of a drug. Pharmaceutical excipients that can increase permeation are called "absorption modifying excipients" (AMEs). AMEs can be used in oral compositions, for example, as humectants (sodium dodecyl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogolglycerides), and can be included in particular compositions as PEs to improve bioavailability. PEs can be classified according to how they alter barrier integrity via paracellular or transcellular pathways.

[0074] "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.

[0075] "Administering" refers to the administration of a composition of the present invention to a subject.

[0076] As used herein, "composition" or "pharmaceutical composition" 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 described herein, e.g., may include a pharmaceutically acceptable excipient, carrier, or diluent as described herein, in specific amounts defined herein.

[0077] A "granulated mixture" refers to a mixture of two or more drugs prepared 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 comprise a granulated mixture of the hydrochloride salt form of a peptide of SEQ ID NO: 1 or a solvate thereof and an absorption enhancer or permeation enhancer, such as sodium caprate, but is not limited to such a granulated mixture. Such a granulated mixture is formed into particles or a tablet containing the hydrochloride salt form of the compound of formula (I) or a solvate thereof and sodium caprate. In some embodiments, the composition may comprise a granulated mixture containing sodium caprate.

[0078] In one embodiment, provided herein is a pharmaceutical tablet comprising a crystalline form of a monocyclic peptide compound prepared by the methods described herein and a pharmaceutical excipient.

[0079] "Disintegrant" refers to a pharmaceutical additive incorporated into a composition to promote disintegration of the composition when it comes into contact with liquid. For example, a disintegrant is a pharmaceutically acceptable agent used in the preparation of tablets that causes the tablet to disintegrate and release the medicinal substance upon 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 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, etc. Exemplary disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates, and gums, as well as crosslinked starches, celluloses, and polymers, combinations thereof, etc.

[0080] "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 layer or coating, such that the layering of the phases and coatings does not leave substantial gaps between the layers.

[0081] "Enteric coating" refers to any of the commonly applied polymer coatings used for delayed release of active ingredients. As conventionally understood in the art, enteric coatings are generally polymer barriers applied to oral medications to prevent dissolution or disintegration of the oral medication in the stomach environment. This serves either by protecting the drug from stomach acidity, protecting the stomach from the 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 coatings are also an effective method for targeting drugs (such as gastroresistant drugs). Such delayed release is typically pH-dependent, allowing for further release of the active ingredient in the intestinal tract, where the pH differs 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 trimaleate, and film resins. 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 (CAP), poly(methacrylic acid-co-methyl methacrylate), poly(vinyl acetate phthalate) (PVAP), cellulose acetate trimellitate (CAT), and hydroxypropyl methylcellulose phthalate (HPMCP).Other suitable materials for use in the enteric coating may also include, but are not limited to, methacrylic acid copolymer, poly(ethyl methacrylate acrylate) 1:1, poly(methyl 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 HPMC-AS of type L, M, or H. In some embodiments, the enteric coating is disposed over the subcoating.

[0082] "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.

[0083] "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. 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 range from 50 to 1,000 nm. 2 / g or 50-600m 2 An example of silica has a surface area of ​​about 200 m / g. 2Aerosil 200, which has a specific surface area of ​​1000 nm / g, can be used. 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.

[0084] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds that function as lubricants can also have glidant properties. Examples of lubricants can include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0085] "Microcrystalline cellulose" or "MCC" refers to pharmaceutical-grade cellulose produced from refined wood pulp. MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can function as a bulking agent and can aid in tablet formation due to its favorable compressibility characteristics.

[0086] "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, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, horses, and other mammals. In some aspects, the patient is a human.

[0087] By "pharmaceutically acceptable" is meant that the carrier, diluent, or excipient must be compatible with the 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, pharmaceutically acceptable means approved or approvable as set forth in the United States Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, and more particularly, in humans.

[0088] A "hemi" hydrochloride salt refers to a salt having a substoichiometric amount of hydrochloride. For example, a hemi hydrochloride salt 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. For purposes of the present invention, the term "hemi" hydrochloride salt is indistinguishable from the term "partial" hydrochloride salt. In some embodiments, "hemi" refers to other pharmaceutically 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.

[0089] A "free base of the compound of formula (I)" refers to a compound having the following structure in its salt-free form:

[0090] [ka] It refers to the peptide of SEQ ID NO: 1 having the following structure:

[0091] "The free base of the compound of formula (II)" and "the free base of the compound of formula (III)" refer to the peptide of SEQ ID NO: 2 and the peptide of SEQ ID NO: 3, respectively, in salt-free form.

[0092] "Crystalline salt of the compound of formula (I)" refers to a crystalline form of a pharmaceutically 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). "Crystalline salt" also refers to a crystalline form of a pharmaceutically acceptable salt of the compound of formula (II) or formula (III), which may include, but is not limited to, the salts described herein.

[0093] The composition or pharmaceutical composition of the present invention may be in different pharmaceutically acceptable forms, including, but not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet may include, but is not limited to, different layers. The tablet composition may also include, but is not limited to, one or more coatings.

[0094] "Silicified 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. 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 comprise 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 be present in an amount of about 10 nm to about 40 μm. 2 / g~about 500m 2 / g, or approximately 50m 2 / g~about 500m 2 / g, or approximately 175m 2 / g ~ approx. 350m2 / g。 Silica gel can have a surface area of ​​10 ...

[0095] "Sodium caprate" or "NaC10" has the molecular formula C 10 H 19 NaO2 and structural formula:

[0096] [ka] It refers to the IUPAC compound sodium decanoate.

[0097] In some embodiments, sodium caprate functions as either an absorption enhancer or an additive 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.

[0098] As used herein, "solvate" refers to a 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 will be isolable. The term "solvate" is intended to encompass both solution-phase solvates and isolable solvates. Non-limiting examples of suitable solvates include hydrates.

[0099] "Sorbitol" refers to the sugar alcohol D-glucitol, which can function as a binder to promote adhesion of ingredients in a tablet composition.

[0100] As used herein, "sugar alcohol" refers to a compound derived from a 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.

[0101] "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, or 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 subcoating can be further covered by one or more additional coatings.

[0102] In some embodiments, subcoating refers to any number of film layers disposed over the core tablet. Examples of suitable materials for cosmetic subcoatings 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.

[0103] 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 includes 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 by 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.

[0104] 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 or functional coating. In some embodiments, the cosmetic coating can serve as a smooth 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 smooth surface to aid in swallowing the tablet.

[0105] "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 pharmaceutically acceptable salt thereof, or a solvate of the foregoing, and suitable additives. In some embodiments, the suitable additives are one or more of the following, but are not limited to: a filler, a disintegrant, a glidant, a lubricant, and an absorption enhancer. A subcoating, a cosmetic coating, an enteric coating, or any combination thereof, may be disposed on the core tablet.

[0106] A "therapeutically effective amount" refers to an amount of a compound (i.e., the peptide of SEQ ID NO: 1) or pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. A "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, for example, on factors such as the patient's general health, the patient's age, etc. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0107] "Treate," "treating," and "treatment" refer to any indication of success in treatment or amelioration of an injury, condition, or state, including any objective or subjective parameter, such as remission, remission, reducing symptoms or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, or 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, neuropsychiatric examination, and / or psychiatric evaluation.

[0108] 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 a composition 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 solvent mixture.

[0109] 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 total weight of the compositions disclosed herein. Thus, the amount is unitless and represents 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.

[0110] A systemic route of administration, as conventionally understood in the medical or pharmaceutical fields, 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 via the gastrointestinal tract), enteral (wherein drug absorption also occurs throughout the gastrointestinal tract), or parenteral (generally, such as by injection, infusion, or implantation).

[0111] "Systemically active" peptide drug therapy in the context of the present invention generally refers to treatment with a pharmaceutical composition comprising a peptide active ingredient, where the peptide resists rapid 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.

[0112] 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.

[0113] Bioavailability refers to the extent and rate at which an active moiety (drug or metabolite) enters the systemic circulation and thereby accesses its site of action. The bioavailability of a drug is affected by the properties of the dosage form, which in turn depend in part on the design and manufacture of the dosage form.

[0114] 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.

[0115] "Amorphous" refers to a solid material that has no long-range order at the location of its molecules. "Partially amorphous" refers to a solid material that has little or no long-range order at the location of its molecules. For example, amorphous and partially amorphous materials have a crystallinity of less than about 50%, less than about 60%, less than about 70%, less than about 80%, less than about 90%, or less than about 95%.

[0116] As used herein, the term "Dv50" (or "volume D50" or "volume-weighted D50") refers to the median particle size based on a volume-weighted particle size distribution. Thus, Dv50 typically describes the particle size (based on a volume-weighted distribution), preferably the diameter of the particles in micrometers (μm), such that 50% of the particles in the distribution have a size larger than Dv50 and 50% of the particles in the distribution have a size smaller than Dv50. In a volume-weighted distribution, the parameter "Dv50" typically relates to the diameter (e.g., in micrometers (μm)) of a hypothetical spherical particle having the volume of the corresponding actual particle (which may or may not be spherical) in the distribution.

[0117] As used herein, the term "Dv10" refers to the cutoff size (preferably in μm) of particles in a volume-weighted distribution, which represents 10% of the total volume of the sample and has a particle size less than or equal to the Dv10 value.

[0118] The term "Dv50" (or "volume D50" or "volume-weighted D50") refers to the median particle size based on a volume-weighted particle size distribution. Dv50 therefore typically describes the particle size (based on a volume-weighted distribution), preferably the diameter of the particles in micrometers (μm), such that 50% of the particles in the distribution have a size larger than Dv50 and 50% of the particles in the distribution have a size smaller than Dv50. In a volume-weighted distribution, the parameter "Dv50" typically relates to the diameter (e.g., in micrometers (μm)) of a hypothetical spherical particle having the volume of the corresponding actual particle (which may or may not be spherical) in the distribution.

[0119] As used herein, the term "Dv90" refers to the cutoff size (preferably in μm) of particles in a volume-weighted distribution, which represents 90% of the total volume of the sample and has a particle size less than or equal to the Dv90 value.

[0120] As used herein, "span," "particle size distribution span," or "span of particle size distribution" refers to a parameter used to describe the general width of the particle size distribution observed by laser diffraction. The span of a volumetric size distribution is defined as Span = (Dv90 - Dv10) / Dv50, which gives a measure of how far apart the 10th and 90th percentiles are, normalized to the midpoint.

[0121] The Dv10, Dv50, Dv90 and span of the particle size distribution described herein can be measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer in combination with an Aero S dry dispersion unit used to determine the particle size distribution.

[0122] III. Methods for Preparing Crystalline Forms Generally, the present invention relates to methods for the preparation of crystalline forms of monocyclic peptide compounds or pharmaceutically acceptable salts or solvates thereof. The peptide compounds are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystalline compounds and crystalline salts or solvates are useful in the preparation of pharmaceutical compositions as defined herein, and in methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0123] According to the present invention, it is possible to provide a monocyclic peptide compound having excellent rheological properties (fluidity) useful for producing pharmaceutical compositions. According to the present invention, it is possible to suppress aggregation that reduces the fluidity of pharmaceutical preparations. As a result, the crystalline form of the monocyclic peptide compound has excellent rheological properties (fluidity is realized), making the crystalline form suitable for producing pharmaceutical formulations.

[0124] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, having rheological properties suitable for the manufacture of a pharmaceutical composition, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing any residual solvent.

[0125] In another aspect, the present invention provides a method for improving the rheological properties of a monocyclic peptide compound, or a salt or solvate thereof, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing any residual solvent.

[0126] In another aspect, the present invention provides a method for the preparation of a crystalline form of a hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound has the structure:

[0127] [ka] is a compound having the formula Here's how: (a) dissolving a crude monocyclic peptide compound, including a hydrochloride salt of the monocyclic peptide compound, in a first solvent, optionally wherein the crude monocyclic peptide compound is obtained by liquid phase peptide synthesis; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing any residual solvent.

[0128] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, having rheological properties suitable for the manufacture of a pharmaceutical composition, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b') adding a second portion of solvent to the mixture obtained in step (a); (c) adding seeds of the crystalline monocyclic peptide compound to the mixture obtained in step (b') to obtain a slurry; (d') adding a third portion of the solvent to the mixture obtained in step (c); (e) isolating the crystalline monocyclic peptide compound from the mixture obtained in step (d') and removing any residual solvent.

[0129] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, having rheological properties suitable for the manufacture of a pharmaceutical composition, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (h) permeating the mixture obtained in step (a) through an ion exchange resin; (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (h) and removing any residual solvent.

[0130] Process (a) In step (a), the monocyclic peptide compound, or a salt or solvate thereof, is dissolved in a first solvent. In one embodiment, the monocyclic peptide compound, or a salt or solvate thereof dissolved in step (a) is an amorphous or partially amorphous form of the monocyclic peptide compound, or a salt or solvate thereof. In one embodiment, the monocyclic peptide compound, or a salt or solvate thereof dissolved in step (a) comprises a hydrochloride salt of the monocyclic peptide compound. In one embodiment, the monocyclic peptide compound, or a salt or solvate thereof dissolved in step (a) comprises an amorphous or partially amorphous form of the hydrochloride salt of the monocyclic peptide compound. In one embodiment, the hydrochloride salt of the monocyclic peptide compound comprises a crude product isolated from the synthesis of the monocyclic peptide compound.

[0131] In some embodiments, step (a) is carried out at about 25°C to about 60°C. In some embodiments, step (a) is carried out at about 25°C to about 55°C. In some embodiments, step (a) is carried out at about 35°C to about 50°C. In some embodiments, step (a) is carried out at about 40°C or about 45°C. In some embodiments, step (a) is carried out at about 40°C to about 55°C. In some embodiments, step (a) is carried out at about 45°C to about 50°C. In some embodiments, step (a) is carried out at about 50°C.

[0132] In some embodiments, step (a) is carried out at a pH of 5.0 to 6.5. In some embodiments, step (a) is carried out at a pH of 5.5 to 6.0.

[0133] In some embodiments, the first solvent in step (a) is a C1-C 12 In some embodiments, the first solvent in step (a) comprises one or more solvents selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the first solvent in step (a) comprises one or more solvents selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the first solvent in step (a) comprises methanol and water.

[0134] In some embodiments, the first solvent in step (a) comprises HO. In some embodiments, the first solvent in step (a) comprises C-C 12The first solvent in step (a) comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, and HO. In some embodiments, the first solvent in step (a) consists of methanol and HO.

[0135] In some embodiments, the first solvent in step (a) comprises methanol and HO in a volume ratio of 9:1 to 5:5. In some embodiments, the first solvent in step (a) comprises methanol and HO in a volume ratio of 8:2 to 13:7, or about 7:3. In some embodiments, the first solvent in step (a) comprises methanol and HO in a volume ratio.

[0136] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (a) is 5% w / v to 30% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (a) is 10% w / v to 25% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (a) is 15% w / v to 20% w / v.

[0137] In some embodiments, the mixture obtained in step (a) is stirred for about 7 hours or less. In some embodiments, the mixture obtained in step (a) is stirred for about 5 hours or less.

[0138] In some embodiments, the mixture obtained in step (a) is stirred at about 35° C. to about 55° C. In some embodiments, the mixture obtained in step (a) is stirred at about 45° C. In some embodiments, the mixture obtained in step (a) is stirred at about 50° C.

[0139] In some embodiments, the mixture obtained in step (a) is stirred until all of the hydrochloride salt of the monocyclic peptide compound is dissolved.

[0140] In some embodiments, the first solvent in step (a) comprises methanol and H2O in a volume ratio of 3:1 to 3:2.

[0141] In some embodiments, the mixture obtained in step (a) is filtered to provide a solution.

[0142] In some embodiments, step (a) comprises adjusting the pH of the solution to a range of about 4.5 to 6.5, about 5 to 6.5, about 5.5 to 6.1, or about 5.5 to 6. In some embodiments, step (a) comprises adjusting the pH of the solution to about 5.8. In some embodiments, step (a) comprises adjusting the pH of the solution to about 5.5 to 6.1. In some embodiments, adjusting the pH can occur before filtration in step (a). In some embodiments, adjusting the pH can occur after filtration in step (a).

[0143] In one embodiment, the amount of monocyclic peptide compound dissolved in step (a) is at least 10 kg. In another embodiment, the amount of monocyclic peptide compound dissolved in step (a) is at least 1 kg, at least 2 kg, at least 3 kg, at least 4 kg, at least 5 kg, at least 6 kg, at least 7 kg, at least 8 kg, at least 9 kg, at least 10 kg, at least 11 kg, at least 12 kg, at least 13 kg, at least 14 kg, or at least 15 kg.

[0144] Process (b) In step (b), a first portion of sodium chloride is added to the mixture obtained in step (a).

[0145] In some embodiments, in step (b), the sodium chloride is an aqueous sodium chloride solution. In some embodiments, in step (b), the sodium chloride is a 0.1 M to 2 M aqueous sodium chloride solution. In some embodiments, in step (b), the sodium chloride is a 0.5 M to 1.5 M aqueous sodium chloride solution. In some embodiments, in step (b), the sodium chloride is about 1 M aqueous sodium chloride solution. In some embodiments, in step (b), the sodium chloride is about 0.96 M aqueous sodium chloride solution.

[0146] In some embodiments, in step (b), sodium chloride is added over a period of at least 10 minutes. In some embodiments, in step (b), sodium chloride is added over a period of at least 30 minutes. In some embodiments, in step (b), sodium chloride is added over a period of at least 45 minutes. In some embodiments, in step (b), sodium chloride is added over a period of about 60 minutes. In some embodiments, in step (b), sodium chloride is added over a period of at least about 90 minutes. In some embodiments, in step (b), sodium chloride is added over a period of at least about 2 hours. In some embodiments, in step (b), sodium chloride is added over a period of at least about 3 hours. In some embodiments, in step (b), sodium chloride is added over a period of at least about 4 hours.

[0147] In some embodiments, in step (b), sodium chloride is added at a temperature of about 25° C. to about 55° C. In some embodiments, in step (b), sodium chloride is added at a temperature of about 35° C. to about 45° C. In some embodiments, in step (b), sodium chloride is added at a temperature of about 40° C.

[0148] In some embodiments, in step (b), 1.0 to 13.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 5.0 to 12.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 7.0 to 12.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 10.0 to 12.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 10.5 to 11.5 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 1.0 to 13.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 11.0 to 11.5 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), from about 11.05 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), 1.5 to 2.5 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a). In some embodiments, in step (b), about 2.3 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a).

[0149] Process (c) In step (c), seeds of the crystalline hydrochloride salt of the monocyclic peptide compound are added to the mixture obtained in step (b) to obtain a slurry.

[0150] In some embodiments, the seed of the crystalline monocyclic peptide compound comprises: (i) dissolving a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, in a first solvent; (ii) adding a second solvent to the mixture obtained in step (i); (iii) cooling the mixture obtained in step (ii); (iv) isolating the crystalline monocyclic peptide compound, or a salt or solvate thereof from the mixture obtained in step (iii) and removing the residual solvent.

[0151] In some embodiments, the amount of seed added is 0.005 to 0.1 molar equivalents based on the amount of monocyclic peptide compound in step (a). In some embodiments, the amount of seed added is 0.008 to 0.08 equivalents based on the amount of monocyclic peptide compound in step (a). In some embodiments, the amount of seed added is about 0.01 equivalents based on the amount of monocyclic peptide compound in step (a).

[0152] In some embodiments, the slurry obtained in step (c) is aged for at least 1 hour. In some embodiments, the slurry obtained in step (c) is aged for at least 3 hours. In some embodiments, the slurry obtained in step (c) is aged for at least 5 hours. In some embodiments, the slurry obtained in step (c) is aged for about 8 hours.

[0153] In some embodiments, prior to step (c), the slurry is aged at a temperature of about 25° C. to about 55° C. In some embodiments, prior to step (c), the slurry is aged at a temperature of about 35° C. to about 45° C. In some embodiments, prior to step (c), the slurry is aged at a temperature of about 40° C.

[0154] In some embodiments, the seeds of the crystalline monocyclic peptide compound are monocyclic peptide compound free base crystals.

[0155] In some embodiments, the slurry obtained in step (c) is stirred for at least 1 hour. In some embodiments, the slurry obtained in step (c) is stirred for at least 3 hours. In some embodiments, the slurry obtained in step (c) is stirred for at least 5 hours. In some embodiments, the slurry obtained in step (c) is stirred for about 8 hours. In some embodiments, the slurry obtained in step (c) is stirred for about 30 minutes to 4 hours. In some embodiments, the slurry obtained in step (c) is stirred for about 1 hour to 4 hours. In some embodiments, the slurry obtained in step (c) is stirred for about 1 hour to 3 hours. In some embodiments, the slurry obtained in step (c) is stirred for about 2 hours. In some embodiments, the slurry obtained in step (c) is stirred for less than 4 hours. In some embodiments, the slurry obtained in step (c) is stirred at a temperature of about 35°C to about 65°C. In some embodiments, the slurry obtained in step (c) is stirred at a temperature of about 45°C to about 65°C. In some embodiments, the slurry obtained in step (c) is stirred at a temperature of about 50°C.

[0156] Process (d) In step (d), a second portion of sodium chloride is added to the slurry obtained in step (c). Optionally, the slurry may be cooled before or after the addition of the second portion of sodium chloride.

[0157] In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature of about 0°C to about 10°C. In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature of about 3°C ​​to about 7°C. In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature of about 5°C.

[0158] In some embodiments, in step (d), the slurry is cooled to a temperature of about 0°C to about 10°C at a rate of less than 1°C / min. In some embodiments, in step (d), the slurry is cooled to a temperature of about 0°C to about 10°C at a rate of less than 0.5°C / min. In some embodiments, in step (d), the slurry is cooled to a temperature of about 0°C to about 10°C at a rate of about 0.1°C / min. In some embodiments, in step (d), the slurry is cooled to a temperature of about 3°C ​​to about 7°C at a rate of less than 0.5°C / min. In some embodiments, in step (d), the slurry is cooled to a temperature of about 3°C ​​to about 7°C at a rate of about 0.1°C / min.

[0159] In some embodiments, in step (d), the slurry is cooled at a rate of less than 0.5° C. / min to a temperature of about 5° C. In some embodiments, in step (d), the slurry is cooled at a rate of about 0.1° C. / min to a temperature of about 5° C.

[0160] In some embodiments, in step (d), the sodium chloride is an aqueous sodium chloride solution.

[0161] In some embodiments, in step (d), the sodium chloride is added at a temperature of about 25° C. to about 55° C. In some embodiments, in step (d), the sodium chloride is added at a temperature of about 35° C. to about 45° C.

[0162] In some embodiments, the sodium chloride in step (d) is a 0.1 M to 2 M aqueous sodium chloride solution. In some embodiments, the sodium chloride in step (d) is a 0.5 to 1.5 M aqueous sodium chloride solution. In some embodiments, the sodium chloride in step (d) is about 1 M aqueous sodium chloride solution.

[0163] In some embodiments, at least 4.0 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, at least 6.0 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, at least 8.0 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, at least 7.6 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, at least 2.0 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, at least 3.0 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, about 2-4 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, about 3 to 4 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, about 3 to 3.5 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a). In some embodiments, about 3.34 molar equivalents of NaCl are added in step (d) based on the amount of monocyclic peptide compound in step (a).

[0164] In some embodiments, in step (d), the sodium chloride is added over a period of at least 30 minutes. In some embodiments, in step (d), the sodium chloride is added over a period of at least 1 hour. In some embodiments, in step (d), the sodium chloride is added over a period of at least 2 hours. In some embodiments, in step (d), the sodium chloride is added over a period of about 4 hours.

[0165] In some embodiments, the slurry obtained in step (d) is aged for at least 1 hour. In some embodiments, the slurry obtained in step (d) is aged for at least 2 hours. In some embodiments, the slurry obtained in step (d) is aged for at least 3 hours. In some embodiments, the slurry obtained in step (d) is aged for about 5 hours.

[0166] Process (e) In step (e), the crystalline monocyclic peptide compound is isolated and the residual solvent is removed. Removal of the residual solvent is important for isolating the crystalline material. Residual solvent remaining on the isolated crystalline peptide compound may cause the crystalline peptide to become thixotropic. The thixotropy of the peptide compound can lead to the destruction of crystalline particles, making the particles unsuitable for subsequent processing steps, such as tableting. Therefore, removal of the residual solvent in step (d) is necessary to maintain the crystalline morphology and avoid thixotropy of the particles. In some embodiments, removing the residual solvent comprises one or more washing steps. In some embodiments, removing the residual solvent comprises two washing steps. In some embodiments, removing the residual solvent comprises washing the isolated crystalline peptide compound and then drying it under vacuum.

[0167] In some embodiments, residual solvent is removed by washing with a second solvent. In some embodiments, step (e) comprises first washing the isolated crystalline peptide with a mixture of water and an alkyl alcohol, followed by washing with a second solvent. In some embodiments, step (e) comprises first washing with a mixture of water and methanol (e.g., water / methanol: 65% / 35% v / v), followed by washing with isopropyl alcohol. In some embodiments, step (e) comprises washing with a mixture of water and methanol (e.g., water / methanol: 65% / 35% v / v), washing with isopropyl alcohol, and then drying under vacuum.

[0168] Some embodiments involve a first washing step in which the isolated crystalline peptide is washed with a mixture of water and an alkyl alcohol to remove residual NaCl. The amount of solvent used in the washing step needs to be sufficient to remove residual NaCl without causing a substantial loss in yield. In some embodiments, the amount of washing solvent ranges from 1 L to 3 L of water / alkyl alcohol per mole of crystalline peptide compound. In some embodiments, the amount of washing solvent ranges from 1.5 L to 2 L of water / alkyl alcohol per mole of crystalline peptide compound. In some embodiments, the amount of washing solvent is about 1.93 L of water / alkyl alcohol per mole of crystalline peptide compound. In some embodiments, the alkyl alcohol is methanol. In some embodiments, the solvent used for washing is water / methanol. In some embodiments, the solvent used for washing is water / methanol (65 / 35% v / v).

[0169] Some embodiments involve a second washing step in which the mixture of water and an alkyl alcohol (e.g., methanol) is removed by washing with isopropyl alcohol, such that the solvent used in the first washing step is replaced with isopropyl alcohol. The replacement of the washing with isopropyl alcohol is necessary to avoid thixotropy. The amount of solvent used in the second washing step needs to be sufficient to remove residual water without causing substantial loss of yield. In some embodiments, the amount of washing solvent ranges from 1 L to 3 L of second solvent per mole of crystalline peptide compound. In some embodiments, the amount of washing solvent ranges from 1.5 L to 2 L of second solvent per mole of crystalline peptide compound. In some embodiments, the amount of washing solvent is about 1.93 L of isopropanol per mole of crystalline peptide compound. In some embodiments, the second washing solvent is isopropanol.

[0170] In some embodiments, in step (e), the precipitate is isolated by filtration, then washed and dried.

[0171] In some embodiments, in step (e), the second solvent comprises an alkyl alcohol. In some embodiments, in step (e), the second solvent is an alkyl alcohol other than methanol. In some embodiments, in step (e), the second solvent comprises 2-propanol (isopropyl alcohol, IPA). In some embodiments, in step (e), the second solvent consists essentially of 2-propanol (isopropyl alcohol).

[0172] In some embodiments, in step (e), the precipitate is washed with the second solvent at a ratio of 1.5 to 2.5 L per mole of the monocyclic peptide compound of step (a). In some embodiments, in step (e), the precipitate is washed with the second solvent at a ratio of about 2 L per mole of the monocyclic peptide compound of step (a).

[0173] In some embodiments, in step (e), the crystalline monocyclic peptide compound is isolated by filtration, then washed, and dried. In some embodiments, in step (e), the crystalline monocyclic peptide compound is isolated by filtration, then washed, and dried under vacuum at a temperature below about 20°C. In some embodiments, the crystalline peptide compound is dried at a temperature ranging from about 10°C to 50°C. In some embodiments, the crystalline peptide compound is dried at a temperature ranging from about 20°C to 40°C. In some embodiments, the crystalline peptide compound is dried under vacuum.

[0174] This drying step can remove residual solvent from the crystallization process, such as isopropyl alcohol. The drying step can be performed, for example, at about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C. In another embodiment, the drying step is performed at about 20°C to 45°C. In yet another embodiment, the drying step is performed at about 20% relative humidity (RH), 30% RH, 40% RH, 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. In another embodiment, the drying step is performed at 50% to 70% RH, for example, about 65% RH.

[0175] In some embodiments, the amount of residual IPA in the crystalline peptide compound after the drying step is less than 9000 ppm, 8000 ppm, 7000 ppm, 6000 ppm, 5000 ppm, or 4000 ppm. In some embodiments, the amount of residual IPA is less than 5000 ppm after the drying step. In some embodiments, the amount of residual methanol in the crystalline peptide compound after the drying step is less than 8000 ppm, 7000 ppm, 6000 ppm, 5000 ppm, 4000 ppm, 3000 ppm, or 2000 ppm. In some embodiments, the amount of residual methanol is less than 3000 ppm after the drying step.

[0176] In some embodiments, the amount of water in the crystalline peptide compound after the drying step is in the range of about 3-10% by weight, 4-8% by weight, or 4-6% by weight. In some embodiments, the amount of water in the crystalline peptide compound after the drying step is in the range of about 4-6% by weight. In some embodiments, the drying step comprises drying the crystalline peptide compound under vacuum at a relative humidity in the range of 50-70%, while humidity is provided by a humidified nitrogen stream, and drying continues until the water content of the crystalline peptide compound is in the range of about 3-10% by weight.

[0177] In some embodiments, in step (e), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried at a relative humidity of about 45% to about 75%. In some embodiments, in step (e), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried at a relative humidity of about 50% to about 70%.

[0178] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of a hydrochloride salt.

[0179] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of an acetate salt.

[0180] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of a free base crystalline solid.

[0181] In some embodiments, the crystalline monocyclic peptide compound obtained in step (e) is dissolved in a solvent, which is removed by lyophilization.

[0182] Process (b') In step (b'), a second portion of the solvent is added to the mixture obtained in step (a).

[0183] In some embodiments, the second solvent in step (b') is a C1-C 12The second solvent in step (b') comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the second solvent in step (b') comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the second solvent in step (b') comprises methanol.

[0184] In some embodiments, the second solvent in step (b') comprises HO. In some embodiments, the second solvent in step (b') comprises C-C 12 The second solvent in step (b') comprises an alkyl alcohol, such as an alkyl alcohol, and HO. In some embodiments, the second solvent in step (b') comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, and HO. In some embodiments, the second solvent in step (b') comprises methanol and HO.

[0185] In some embodiments, the second solvent in step (b') comprises methanol and HO in a volume ratio of 9:1 to 5:5. In some embodiments, the second solvent in step (b') comprises methanol and HO in a volume ratio of 8:2 to 13:7, or about 7:3.

[0186] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (b') is 5% w / v to 30% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (b') is 10% w / v to 25% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (b') is 15% w / v to 20% w / v.

[0187] In some embodiments, the mixture obtained in step (b') is stirred for about 7 hours or less. In some embodiments, the mixture obtained in step (b') is stirred for about 5 hours or less.

[0188] In some embodiments, the mixture obtained in step (b') is stirred at about 35° C. to about 55° C. In some embodiments, the mixture obtained in step (b') is stirred at about 45° C.

[0189] In some embodiments, the second portion of the solvent is omitted.

[0190] In some embodiments, the mixture obtained in step (b') is cooled to about 10°C to about 25°C. In some embodiments, the process of cooling the mixture obtained in step (b') is completed in 15 to 60 minutes. In some embodiments, the process of cooling the mixture obtained in step (b') is completed in 45 minutes. In some embodiments, the process of cooling the mixture obtained in step (b') is completed in 20 minutes.

[0191] Process (d') In step (d'), a third portion of the solvent is added to the mixture obtained in step (c).

[0192] In some embodiments, the third solvent in step (d') is a C1-C 12In some embodiments, the third solvent in step (d') comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the third solvent in step (d') comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the third solvent in step (d') comprises methanol.

[0193] In some embodiments, the third solvent in step (d') comprises HO. In some embodiments, the third solvent in step (d') comprises C-C 12 and an alkyl alcohol such as HO. In some embodiments, the third solvent in step (d') comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, and HO. In some embodiments, the third solvent in step (d') comprises methanol and HO.

[0194] In some embodiments, the third solvent in step (d') comprises methanol and HO in a volume ratio of 9:1 to 5:5. In some embodiments, the third solvent in step (d') comprises methanol and HO in a volume ratio of 8:2 to 13:7, or about 7:3.

[0195] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (d') is 5% w / v to 30% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (d') is 10% w / v to 25% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (d') is 15% w / v to 20% w / v.

[0196] In some embodiments, the mixture obtained in step (d') is stirred for about 7 hours or less. In some embodiments, the mixture obtained in step (d') is stirred for about 5 hours or less.

[0197] In some embodiments, the mixture obtained in step (d') is stirred at about 35° C. to about 55° C. In some embodiments, the mixture obtained in step (d') is stirred at about 45° C.

[0198] In some embodiments, the third portion of solvent is omitted.

[0199] In some embodiments, the third portion of the solvent is added over a period of 1 to 5 hours. In some embodiments, the third portion of the solvent is added over a period of 3 hours. In some embodiments, the third portion of the solvent is added over a period of 1 to 5 hours.

[0200] In some embodiments, the mixture obtained in step (d') is cooled to -10 to 10°C.

[0201] In some embodiments, the mixture obtained in step (d') is cooled to -10 to 10°C, and the mixture is stirred for 6 to 18 hours.

[0202] In some embodiments, the mixture obtained in step (d') is cooled to -10 to 10°C and stirred for 6 to 18 hours, then warmed to 20 to 30°C and stirred for 2 to 6 hours.

[0203] In some embodiments, the mixture obtained in step (d') is cooled to -10 to 10°C and stirred for 6 to 18 hours, then warmed to 20 to 30°C and stirred for 2 to 6 hours, then cooled to -10 to 10°C and stirred for 6 to 18 hours.

[0204] Process (h) In step (h), the ion exchange resin is an anion exchange resin. In some embodiments, the ion exchange resin is an acetate anion exchange resin.

[0205] In some embodiments, the ion exchange resin is washed with a wash solvent. In some embodiments, the wash solvent in step (h) comprises HO. In some embodiments, the wash solvent in step (h) comprises an alkyl alcohol, e.g., a C-C 12 In some embodiments, the washing solvent in step (h) comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, and HO. In some embodiments, the washing solvent in step (h) comprises methanol and HO.

[0206] Starting materials In some embodiments, the method for preparing a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, further comprises preparing the monocyclic peptide compound by solid phase peptide synthesis or solution phase peptide synthesis. In some embodiments, the method for preparing a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, further comprises preparing the monocyclic peptide compound by solution phase peptide synthesis.

[0207] The method of the present invention provides a method for improving the rheological properties of monocyclic peptide compounds obtained by liquid phase peptide synthesis.

[0208] Thus, in another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent, wherein the monocyclic peptide compound is obtained by liquid phase peptide synthesis; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture and removing any residual solvent.

[0209] Method for Obtaining Crystalline Free Base In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, the method comprising: (a) dissolving the hydrochloride salt of a monocyclic peptide compound in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (e) and washing with a second solvent; (f) dissolving the hydrochloride salt obtained in step (e) in aqueous hydrochloric acid; (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; (h) isolating the crystalline monocyclic peptide compound in free base form from the mixture.

[0210] In some embodiments, the amount of hydrochloric acid added in step (f) is 1 to 2 molar equivalents. In some embodiments, the amount of hydrochloric acid added in step (f) is 1.3 to 1.7 molar equivalents. In some embodiments, the amount of hydrochloric acid added in step (f) is about 1.5 molar equivalents.

[0211] In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of 7.0 to 9.0. In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of 7.5 to 8.5. In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of about 8.

[0212] Method for preparing a salt substitute In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising: (a) dissolving a monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing residual solvent; (f) dissolving the hydrochloride salt obtained in step (e) in aqueous hydrochloric acid; (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; (h) isolating the crystalline monocyclic peptide compound in free base form from the mixture; (i) dissolving the crystalline free base of the monocyclic peptide compound in a second solvent; (j) adding a solution containing a counterion to the mixture obtained in step (a); (k) adding an anti-solvent; (l) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained from step (k).

[0213] In some embodiments, the second solvent in step (j) comprises methanol and / or water.

[0214] In some embodiments, the anti-solvent is an organic solvent. In some embodiments, the anti-solvent is a C1-C 12 The solvent is selected from alkyl alcohols such as alkyl alcohols, alkyl ethers such as diethyl ether, alkanes such as heptane and hexane, ethyl acetate, toluene, and acetonitrile. In some embodiments, the anti-solvent is selected from the group consisting of tert-butyl methyl ether (TBME), acetonitrile, and isopropanol (2-propanol).

[0215] In some embodiments, the solution comprising a counterion is a solution comprising a counterion selected from the group consisting of fumarate, glutarate, glycolate, mesylate, sulfate, and citrate.

[0216] Method for Obtaining Crystalline Seeds The present invention further provides a method for the preparation of a seed of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof.

[0217] Thus, in a further aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, the method comprising: (i) dissolving a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, in a first solvent; (ii) adding a second solvent to the mixture obtained in step (i); (iii) cooling the mixture obtained in step (ii); (iv) isolating the crystalline monocyclic peptide compound or a salt thereof from the mixture obtained in step (iii) and removing any residual solvent.

[0218] Process (i) In some embodiments, step (i) is carried out at a temperature of about 15°C to about 80°C. In some embodiments, step (i) is carried out at a temperature of about 25°C to about 55°C. In some embodiments, step (i) is carried out at a temperature of about 30°C to about 50°C, or about 35°C to about 45°C. In some embodiments, step (a) is carried out at a temperature of about 40°C.

[0219] In some embodiments, the first solvent is a C1-C 12 The first solvent comprises an alkyl alcohol, such as an alkyl alcohol. In some embodiments, the first solvent comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the first solvent comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the first solvent comprises methanol.

[0220] In some embodiments, the first solvent comprises HO. In some embodiments, the first solvent comprises C-C 12 The first solvent comprises an alkyl alcohol, such as an alkyl alcohol, and HO. In some embodiments, the first solvent comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and HO. In some embodiments, the first solvent comprises methanol and HO.

[0221] In some embodiments, the first solvent comprises methanol and HO in a volume ratio of 9:1 to 5:5, hi some embodiments, the first solvent comprises methanol and HO in a volume ratio of 8:2 to 13:7, or about 7:3.

[0222] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (i) is 5% w / v to 20% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (i) is 8% w / v to 12% w / v, or about 10% w / v. In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (i) is about 10% w / v.

[0223] Process (ii) In some embodiments, in step (ii), the second solvent is added over a period of at least 1 hour. In some embodiments, in step (ii), the second solvent is added over a period of at least 5 hours, or at least 6 hours, or at least 7 hours. In some embodiments, in step (ii), the second solvent is added over a period of about 10 hours.

[0224] In some embodiments, in step (ii), the volume ratio of the first solvent to the second solvent is 3:1 to 1:3. In some embodiments, in step (ii), the volume ratio of the first solvent to the second solvent is 6:4 to 4:6. In some embodiments, in step (ii), the volume ratio of the first solvent to the second solvent is about 1:1.

[0225] In some embodiments, the second solvent comprises HO. In some embodiments, the second solvent consists essentially of HO.

[0226] Process (iii) Optionally, the mixture obtained in step (ii) is cooled before step (iv).

[0227] In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 0°C to about 10°C. In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 3°C ​​to about 7°C. In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 5°C.

[0228] In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 0° C. to about 10° C. at a rate of less than 1° C. / min. In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 0° C. to about 10° C. at a rate of less than 0.5° C. / min. In some embodiments, in step (iii), the cooling rate is less than 0.1° C. / min, or about 0.05° C. / min.

[0229] In some embodiments, the temperature of the mixture before step (iii) and after the addition of the second solvent is maintained for at least 1 hour. In some embodiments, the temperature of the mixture before step (iii) and after the addition of the second solvent is maintained for at least 4 hours. In some embodiments, the temperature of the mixture before step (iii) and after the addition of the second solvent is maintained for at least 7 hours. In some embodiments, the temperature of the mixture before step (iii) and after the addition of the second solvent is maintained for about 9 hours.

[0230] In some embodiments, after step (iii), the temperature is maintained for at least 30 minutes. In some embodiments, after step (iii), the temperature is maintained for at least 60 minutes. In some embodiments, after step (iii), the temperature is maintained for at least 90 minutes. In some embodiments, after step (iii), the temperature is maintained for about 2 hours.

[0231] In some embodiments, after step (iii), the mixture is warmed to a temperature of about 25° C. to about 55° C. and then cooled to a temperature of about 0° C. to about 10° C. In some embodiments, after step (iii), the mixture is warmed to a temperature of about 35° C. to about 45° C. and then cooled to a temperature of about 3° C. to about 7° C.

[0232] In some embodiments, after step (iii), the mixture is warmed to a temperature of about 40°C and then cooled to a temperature of about 5°C.

[0233] Process (iv) In some embodiments, in step (iv), the third solvent comprises an alkyl alcohol. In some embodiments, in step (iv), the third solvent is an alkyl alcohol other than methanol. In some embodiments, in step (iv), the third solvent comprises 2-propanol (isopropyl alcohol). In some embodiments, in step (iv), the third solvent consists essentially of 2-propanol (isopropyl alcohol).

[0234] In some embodiments, in step (iv), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried. In some embodiments, in step (iv), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried under vacuum at a temperature of less than about 20°C.

[0235] In some embodiments, the monocyclic peptide compound isolated in step (iv) is in the form of a hydrochloride salt.

[0236] Grinding / Sieving In one embodiment, to obtain a crystalline form of a monocyclic peptide compound in particulate form having the particle size and / or particle size distribution described herein, one skilled in the art may use methods such as a grinding process or a sieving process. For example, after the isolation step, the monocyclic peptide compound may be subjected to a sieving step. The subsequent sieving step can remove the finest and largest particles, which may impair the achievement of suitable rheological properties for pharmaceutical processing. In one embodiment, the isolated crystalline monocyclic peptide is passed through a suitable sieve. In some embodiments, the sieve mesh size is about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 8 mm, or 10 mm. In some embodiments, the sieve mesh size is about 2 mm. In some embodiments, the sieve mesh size is about 4 mm.

[0237] Drying process In one embodiment, to obtain a crystalline form of the monocyclic peptide compound, one skilled in the art can dry the isolated crystalline monocyclic peptide. This drying step can, for example, remove residual solvent from the crystallization process, such as isopropyl alcohol. The drying step can be performed, for example, at about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C. In another embodiment, the drying step is performed at about 20°C to 45°C. In yet another embodiment, the drying step is performed at about 20% relative humidity (water RH), 30% RH, 40% RH, 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. In another embodiment, the drying step is performed at 50% to 70% RH, for example, about 65% RH. In some embodiments, humidity is provided using nitrogen as a carrier gas.

[0238] The drying step can include, for example, static drying or dynamic drying. Static drying is performed with little or no agitation of the crystalline form during the drying process. Dynamic drying involves agitating the crystalline monocyclic peptide compound during the drying step. Dynamic drying can further include heating, exposure to vacuum, or exposure to nitrogen gas.

[0239] Rheological properties (fluidity) Using the methods of the present invention, it is possible to improve the rheological properties of monocyclic peptide compounds, particularly those obtained using liquid phase peptide synthesis.

[0240] Thus, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, having rheological properties suitable for the manufacture of pharmaceutical compositions.

[0241] To be suitable for pharmaceutical processing factors such as the defined size and shape of the particles, uniformity of particle size, homogeneity of the blend, flowability (flow), moisture content, and ability to form compactly under pressure are important.

[0242] Rheological properties are used to characterize the flowability of a material. In particular, rheological properties suitable for the preparation of pharmaceutical compositions can be selected from the following: bulk density after conditioning, compressibility, basic flow energy, stability index, cohesive strength, flow function, internal friction angle, effective internal friction angle, and wall friction angle, and combinations thereof. Flow properties are measured according to standardized methods known in the art.

[0243] IV. Peptide inhibitors of the interleukin-23 receptor (IL-23R) The monocyclic peptide compounds of the present invention are peptide inhibitors of the interleukin-23 receptor. Peptide compounds of the present invention include peptides comprising or consisting of any of the amino acid sequences described herein, compounds having any of the structures described herein, including compounds comprising any of the peptide sequences described herein, and dimers of any of such peptides and compounds. Exemplary peptides of the present invention include the amino acid sequences or structures set forth in any of the accompanying tables.

[0244] In a first aspect, the monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof comprises an amino acid sequence of the following formula (I'): X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I') During the ceremony, X3 is absent or any amino acid; X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is a substituted or unsubstituted Trp; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is Tyr, or unsubstituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyl Ala, Lys, or Aib; X13 is any amino acid, X14 is any amino acid, X15 is Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, substituted or unsubstituted His, (D)His, Ile, Lue, (D)Lue, Lys, (D)Lys, Met, 2Pal, 3Pal, or 4Pal, Phe, Pro, 5-Pyal, 2Quin, 3Quin, Ser, Thr, Trp, Tyr, Val; X16 is absent or any amino acid; 2Pal is a 2-pyridyl substituted alanine, 3Pal is a 3-pyridyl substituted alanine, and 4Pal is a 4-pyridyl substituted alanine;

[0245] [ka] 5Pyal or (5-Pyal) is a 5-pyrimidine substituted alanine;

[0246] [ka] X4 and X9 form a disulfide bond or a thioether bond.

[0247] In certain embodiments, the peptide compound inhibits the binding of interleukin 23 (IL23) to the IL23 receptor.

[0248] In certain embodiments, X7 is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0249] In certain embodiments, X10 is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy.

[0250] In certain embodiments, X11 is 2-Nal, 2-Nal substituted with alkyl or hydroxy, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0251] In certain embodiments, X11 is 2-Nal or 1-Nal.

[0252] In certain embodiments, X11 is 2-Nal or 2-Nal substituted with alkyl or hydroxy.

[0253] In certain embodiments, X11 is 2-Nal.

[0254] In certain embodiments, X15 is 5-Pyal, His, (D)His, (1-Me)His, (3-Me)His, Lys, (D)Lys, Lue, (D)Leu, 2Pal, 3Pal, 4Pal, 2Quin, or 3Quin.

[0255] In certain embodiments, X15 is 5-Pyal, His, (D)His, (1-Me)His, (3-Me)His, (D)Lys, (D)Leu, 2Pal, 3Pal, 4Pal, and X16 is absent or Sarc.

[0256] In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal, and X16 is absent.

[0257] In certain embodiments, X16 is any D-amino acid.

[0258] In certain embodiments, the peptide compound comprises an amino acid sequence of formula (IIa), (IIb), (IIc), or (IId): X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16(IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IId) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal, Pal is 2Pal, 3Pal, or 4Pal, Unless otherwise indicated, X3 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0259] In certain embodiments, the peptide compound comprises an amino acid sequence of formula (IIa), (IIb), (IIc), or (IId): X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16(IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IId) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal, Pal is 2Pal, 3Pal, or 4Pal, X16 is Sarc, and unless otherwise indicated, X3 to X15 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0260] In certain embodiments, the peptide compound comprises an amino acid sequence of formula (IIIa), (IIIb), (IIIc), or (IIId): X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIIa), X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIIb), X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IIIc), X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16(IIId), X4-X5-X6-X7-X8-X9-[Phe]-X10-X11-X12-X13-X14-[Pal]-X16(IIIe), or X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16(IIIf) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal, Pal is 2Pal, 3Pal, or 4Pal, Unless otherwise indicated, X4 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0261] In certain embodiments, the peptide compound comprises an amino acid sequence of formula (IVa), (IVb), (IVc), (IVd), or (IVe): X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16(IVa), X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16(IVb), X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16(IVc), X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16(IVd), or X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16(IVe) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal, Pal is 2Pal, 3Pal, or 4Pal, Unless otherwise indicated, X4 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

[0262] In certain embodiments, a monocyclic peptide is one in which the peptide is cyclized via a Pen-Pen disulfide bond or via an Abu-Cys or Abu-Pen thioether bond.

[0263] In certain embodiments, X4 is (D)Pen, Pen, or Pen(sulfoxide).

[0264] In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp.

[0265] In certain embodiments, X4 or X9 is independently Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen, and the bond between X4 and X9 is a disulfide bond.

[0266] In certain embodiments, X5 is Asn, Ser, Gln, or Glu.

[0267] In certain embodiments, X5 is Asn.

[0268] In certain embodiments, X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val.

[0269] In certain embodiments, X6 is Thr.

[0270] In certain embodiments, X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp. In certain embodiments, X8 is Lys(Gly) or Lys(bAla).

[0271] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), Lys(Ac), or Glu.

[0272] In certain embodiments, X8 is Gln. In certain embodiments, X8 is Lys(Ac).

[0273] In certain embodiments, X9 is Pen, (D)Pen, Cys, (D)Cys, or alpha-MeCys. In certain embodiments, X9 is Pen or (D)Pen.

[0274] In certain embodiments, X4 is Pen, X9 is Pen, and the bond is a disulfide bond. In certain embodiments, X4 or X9 is Abu, and the bond between X4 and X9 is a thioether bond.

[0275] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH).

[0276] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X10 is Phe[4-(2-aminoethoxy)] or Phe[4-(2-acetylaminoethoxy)]. In certain embodiments, X10 is Phe[4-(2-aminoethoxy)].

[0277] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexyl Ala, Lys, or Aib.

[0278] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu.

[0279] In certain embodiments, X12 is alpha-MeLeu. In certain embodiments, X12 is THP.

[0280] In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), where Y2 is an amino acid. In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or b-homoGlu.

[0281] In certain embodiments, X13 is Glu, Gln, Lys(Ac), or Lys.

[0282] In certain embodiments, X13 is Lys(Ac) or Lys.

[0283] In certain embodiments, X13 is Lys(Ac). In certain embodiments, X13 is Glu.

[0284] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is unsubstituted Trp.

[0285] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamido, cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, and X11 is as described for Formula (I).

[0286] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamido, cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy, wherein the substitution is at the 4-, 5-, 6-, or 7-position.

[0287] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamido, cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxy, OMe, or OEt, and the substitution is at the 4-, 5-, 6-, or 7-position.

[0288] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamido), 5-F, 6-F, 7-F, 5-Cl, 6-Cl, 7-Cl, 5-Me, 6-Me, 7-Me, 5-OH, 6-OH, 7-OH, 5-OMe, 6-OMe, or 7-OMe.

[0289] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamido), 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4-OMe, 5-OMe, or 5-Br.

[0290] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamido), 7-Me, 6-Me, 4-OMe, or 6-Cl.

[0291] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamido), 7-Me.

[0292] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with phenyl, substituted phenyl, or thienyl.

[0293] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, substituted phenyl, or thienyl.

[0294] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is i) phenyl that is unsubstituted or substituted with cyano, halo, alkyl, haloalkyl, aryl, hydroxy, alkoxy, or haloalkoxy, or ii) Trp substituted with thienyl.

[0295] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with phenyl, unsubstituted, or substituted with Me, Et, n-Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl, or amido.

[0296] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Me.

[0297] In certain embodiments, particularly with respect to Formulae (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Ph.

[0298] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X16 is absent. In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X16 is Sarc.

[0299] In one particular embodiment, particularly with respect to formulae (IIa)-(IId), (IIIa)-(IIIf) and (IVa)-(IVe), X3 is absent.

[0300] In certain embodiments, the peptide compound is Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 1), The peptide compound is cyclized via a Pen-Pen disulfide bond or a pharmaceutically acceptable salt thereof.

[0301] In certain embodiments, the peptide compound is Ac-[Pen]-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH; (SEQ ID NO: 1)

[0302] [ka] or a pharmaceutically acceptable salt thereof.

[0303] In certain embodiments, the peptide compound is Ac-dArg-cyclo[Abu-Gln-Thr-Trp-Gln-Cys]-Phe(2-ae)-2-NaI-ThpGly-Glu-Asn-Asn-NH; (SEQ ID NO: 2):

[0304] [ka] or a pharmaceutically acceptable salt thereof.

[0305] In certain embodiments, the peptide compound is Ac-[Pen] * -Asn-Thr-Trp(7Me)-Lys(Ac)-[Pen] * -Tyr(2-ea)-2Nal-αMe-Lys-Lys(Ac)-Asn-D-Leu-NH2(where, [Pen] * -[Pen] * forms a disulfide bond), (SEQ ID NO: 3):

[0306] [ka] or a pharmaceutically acceptable salt thereof.

[0307] V. Crystal 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 unexpectedly obtained and isolated. Crystalline forms of pharmaceutically 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, as the corresponding amorphous forms are often not suitable for formulation, such as tableting.

[0308] In one aspect, the present invention provides a compound of formula (I):

[0309] [ka] or a compound of The present invention relates to pharmaceutical compositions of crystalline salts of pharmaceutically acceptable salts thereof, or solvates of the foregoing.

[0310] In another aspect, the present invention relates to a crystalline free base form of the compound of formula (I).

[0311] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO:1.

[0312] In one aspect, the present invention relates to pharmaceutical compositions of the hydrochloride salt of the compound of formula (I).

[0313] 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.

[0314] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of the peptide of SEQ ID NO: 1. The crystalline form of the pharmaceutically acceptable salt of the peptide of SEQ ID NO: 1 can be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bishydrochloride salt, and a crystalline citrate salt of the peptide of SEQ ID NO: 1.

[0315] 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).

[0316] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I). The crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline mesylate, crystalline sulfate, crystalline bishydrochloride, and crystalline citrate salt of the compound of formula (I).

[0317] In some embodiments, the crystalline hydrochloride salt form of the compound of Formula (I) has the structure:

[0318] [ka] It has solvates thereof.

[0319] 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.

[0320] 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 pharmaceutically acceptable excipients.

[0321] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline salt or solvate thereof described herein and one or more pharmaceutically acceptable excipients.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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 salt of the compound of Formula (I) or a solvate thereof is characterized by an XRPD pattern having 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.

[0328] 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.

[0329] 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.

[0330] 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 described herein, and one or more pharmaceutically acceptable excipients.

[0331] Salt ratio In some embodiments, the compound of Formula (I) is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is crystalline. In some embodiments, the crystalline pharmaceutically acceptable salt of the compound of Formula (I) comprises the cationic form of the compound of Formula (I) and a pharmaceutically acceptable anion. For example, a 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 include salts of the compound of Formula (I), wherein the salt is a pharmaceutically acceptable salt selected from acetate, fumarate, glycolate, glutarate, mesylate, sulfate, citrate, bishydrochloride, etc.

[0332] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is the hydrochloride salt, and the anion is chloride. In some embodiments, the salt of the compound of Formula (I) is the acetate salt, and the anion is acetic acid. In some embodiments, the salt of the compound of Formula (I) is the fumarate salt, and the anion is fumaric acid. In some embodiments, the salt of the compound of Formula (I) is the glutarate salt, and the anion is glutaric acid. In some embodiments, the salt of the compound of Formula (I) is the glycolate salt, and the anion is glycolic acid. In some embodiments, the salt of the compound of Formula (I) is the mesylate salt, and the anion is mesylic acid. In some embodiments, the salt of the compound of Formula (I) is the sulfate salt, and the anion is sulfuric acid. In some embodiments, the salt of the compound of Formula (I) is the citrate salt, and the anion is citric acid. In some embodiments, the salt of the compound of Formula (I) is the bishydrochloride salt, and the anion is chloride.

[0333] In some embodiments, the molar equivalents of the anion of the crystalline salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalents of the anion of the salt of the compound of Formula (I) per 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 and sub-amount therebetween.

[0334] In some embodiments, the molar equivalent of chloride anion of the crystalline hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of chloride anion of the crystalline hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of chloride anion of the crystalline hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5 to about 1.0. In certain embodiments, the molar equivalent of chloride anion of the crystalline hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.6 to about 0.7.

[0335] In some embodiments, the molar equivalent of acetate anion in the crystalline acetate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of acetate anion in the crystalline acetate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of acetate anion in the crystalline acetate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5 to about 1.0. In certain embodiments, the molar equivalent of acetic acid in the crystalline acetate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.6 to about 0.7. In certain embodiments, the molar equivalent of acetic acid in the crystalline acetate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.65.

[0336] In some embodiments, the molar equivalent of fumarate anion in the crystalline fumarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of fumarate anion in the crystalline fumarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of fumarate anion in the crystalline fumarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5 to about 1.0. In other embodiments, the molar equivalent of fumarate anion in the crystalline fumarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.0 to about 1.5. In other embodiments, the molar equivalent of fumarate anion in the crystalline fumarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 2.0.

[0337] In some embodiments, the molar equivalent of glutarate anion in the crystalline glutarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of glutarate anion in the crystalline glutarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 1.0. In other embodiments, the molar equivalent of glutarate anion in the crystalline glutarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.3 to about 0.6. In certain embodiments, the molar equivalent of glutarate anion in the crystalline glutarate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5.

[0338] In some embodiments, the molar equivalent of glycolate anion in the crystalline glycolic acid salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of glycolate anion in the crystalline glycolic acid salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 1.0. In other embodiments, the molar equivalent of glycolate anion in the crystalline glycolic acid salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.3 to about 0.6. In certain embodiments, the molar equivalent of glycolate anion in the crystalline glycolic acid salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5.

[0339] In some embodiments, the molar equivalents of mesylate anion in the crystalline mesylate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalents of mesylate anion in the crystalline mesylate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalents of mesylate anion in the crystalline mesylate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 2.0. In other embodiments, the molar equivalents of mesylate anion in the crystalline mesylate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.8 to about 1.9. In certain embodiments, the molar equivalents of mesylate anion in the crystalline mesylate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.8.

[0340] In some embodiments, the molar equivalent of sulfate anion in the crystalline sulfate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of sulfate anion in the crystalline sulfate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalent of sulfate anion in the crystalline sulfate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 2.0. In other embodiments, the molar equivalent of sulfate anion in the crystalline sulfate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 1.7. In certain embodiments, the molar equivalent of sulfate anion in the crystalline sulfate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.6.

[0341] In some embodiments, the molar equivalent of citrate anion in the crystalline citrate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of citrate anion in the crystalline citrate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of citrate anion in the crystalline citrate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.5 to about 1.0. In other embodiments, the molar equivalent of citrate anion in the crystalline citrate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.0 to about 1.5. In other embodiments, the molar equivalent of citrate anion in the crystalline citrate salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 2.0.

[0342] In some embodiments, the molar equivalent of chloride anion in the crystalline bis-hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of chloride anion in the crystalline bis-hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.0 to about 2.0. In other embodiments, the molar equivalent of chloride anion in the crystalline bis-hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.5 to about 2.0. In certain embodiments, the molar equivalent of chloride anion in the crystalline bis-hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 1.9 to about 2.0. In certain embodiments, the molar equivalent of chloride anion in the crystalline bis-hydrochloride salt of the compound of Formula (I) per mole of the compound of Formula (I) is about 2.0.

[0343] Salt Form Hydrochloride In some embodiments, the pharmaceutically 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.

[0344] In certain embodiments, the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate having a water content of about 1-20%, 2-15%, 3-10%, 4-8%, 4-6%, or about 5%.

[0345] In some embodiments, the pharmaceutically 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.

[0346] 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.

[0347] 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 a 2-theta angle 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 a 2-theta angle 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 a 2-theta angle 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 a 2-theta angle 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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 an XRPD pattern having 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.

[0352] 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.

[0353] 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.

[0354] 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% from 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 Figure 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 Figure 6.

[0355] 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 described herein and one or more pharmaceutically acceptable excipients.

[0356] Acetate In some embodiments, the pharmaceutically 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.

[0357] 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.

[0358] 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 a 2-theta angle 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 a 2-theta angle 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.

[0359] 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.

[0360] 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 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 with 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 with 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.

[0361] 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 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 with 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 with 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.

[0362] 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 with 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.

[0363] 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 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.±.0.2 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 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 with 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.

[0364] 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.

[0365] 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 an XRPD pattern having 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 Figure 7.

[0366] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof is characterized by having endothermic peaks 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.

[0367] 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% from about 26.5° C. to about 150.0° C. as determined by TGA. 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.

[0368] 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 pharmaceutically acceptable excipient.

[0369] Fumarate In some embodiments, the pharmaceutically 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.

[0370] 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.

[0371] 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 a 2-theta angle 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 a 2-theta angle 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.

[0372] 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.

[0373] 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.

[0374] 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.

[0375] 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 Figure 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% from 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 Figure 16.

[0376] 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 pharmaceutically acceptable excipient.

[0377] Glutarate In some embodiments, the pharmaceutically 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 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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 + / - 0.2 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, 4.3, 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.

[0382] 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 an XRPD pattern having 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.

[0383] 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 Figure 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 Figure 20.

[0384] 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 pharmaceutically acceptable excipient.

[0385] Glycolate salt of peptide of SEQ ID NO: 1 In some embodiments, the pharmaceutically 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.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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 an XRPD pattern having 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.

[0391] 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.

[0392] 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 Figure 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 Figure 23.

[0393] 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 pharmaceutically acceptable excipients.

[0394] Sulfate of peptide of SEQ ID NO: 1 In some embodiments, the pharmaceutically 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.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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.

[0401] 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 pharmaceutically acceptable excipient.

[0402] Mesylate of peptide of SEQ ID NO: 1 In some embodiments, the pharmaceutically 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.

[0403] 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.

[0404] 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.

[0405] 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 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 with 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 with 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.

[0406] 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.

[0407] 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 Figure 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% from 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 Figure 25.

[0408] 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 pharmaceutically acceptable excipient.

[0409] Citrate salt of peptide of SEQ ID NO: 1 In some embodiments, the pharmaceutically 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.

[0410] 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.

[0411] 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.

[0412] 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 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 with 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 with 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.

[0413] 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.

[0414] 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 pharmaceutically acceptable excipient.

[0415] Bishydrochloride salt of peptide of SEQ ID NO: 1 In some embodiments, the pharmaceutically 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.

[0416] 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 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 bishydrochloride 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 bishydrochloride 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.

[0417] 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 a 2-theta angle 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 a 2-theta angle 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 bishydrochloride 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.

[0418] 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.

[0419] 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 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 bishydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with 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 bishydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern with 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.

[0420] 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 3.4, 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 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 3.4, 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.

[0421] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having endothermic peaks 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.

[0422] 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.

[0423] 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.

[0424] 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 pharmaceutically acceptable excipient.

[0425] 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% to 100%. In some embodiments, the crystalline 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 fraction therebetween. In other embodiments, the crystalline salt of the compound of Formula (I) or a solvate thereof has a purity level of about 95.0% to 99.9%. In some embodiments, the crystalline salt of the compound of Formula (I) or a solvate thereof has a purity level of at least 95%. In some embodiments, the crystalline salt of the compound of Formula (I) or a solvate thereof 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%.

[0426] 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 fraction 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%.

[0427] In some embodiments, the crystalline acetate 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 fraction therebetween. In certain embodiments, the crystalline acetate salt of the compound of Formula (I) or a solvate thereof has a purity level of at least 99.0%. In other embodiments, the crystalline salt of the compound of Formula (I) or a solvate thereof has a purity level of about 99.0% to 99.5%.

[0428] In some embodiments, the crystalline fumarate 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%, about 98%, or about 99%, including any amount and fraction therebetween. In other embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof has a purity level of about 86% to 90%. In other embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof has a purity level of about 86% to 87%. In certain embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof has a purity level of at least 86%.

[0429] 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 fraction 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% to 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% to 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% to 99%. In some embodiments, the crystalline glutarate 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 glutarate salt of the compound of Formula (I) or a solvate thereof has a purity level of at least 99.0%.

[0430] 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%, about 98%, or about 99%, including any amount and fraction 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% to 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% to 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% to 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%.

[0431] 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 fraction 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% to 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% to 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% to 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%.

[0432] 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 fraction 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%.

[0433] In some embodiments, the crystalline free base 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 fraction therebetween. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof has a purity level of at least 97.0%. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof has a purity level of at least 98.0%. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof 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 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 about 99.0%.

[0434] Crystalline form of formula (II) In one aspect, the present invention provides a compound of formula (II):

[0435] [ka] or a compound of The present invention relates to pharmaceutical compositions of crystalline salts of pharmaceutically acceptable salts thereof, or solvates of the foregoing.

[0436] In another aspect, the present invention relates to a crystalline free base form of the compound of formula (II).

[0437] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO:2.

[0438] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (II).

[0439] 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:2.

[0440] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 2. The crystalline form of the pharmaceutically acceptable salt of a peptide of SEQ ID NO: 2 can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline mesylate, crystalline sulfate, crystalline bishydrochloride, and crystalline citrate salt of the peptide of SEQ ID NO: 2.

[0441] In another aspect, the present invention relates to a pharmaceutical composition of the crystalline form of the hydrochloride salt of the compound of formula (II).

[0442] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of the compound of formula (II). The crystalline form of the pharmaceutically acceptable salt of the compound of formula (II) can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline mesylate, crystalline sulfate, crystalline bishydrochloride, and crystalline citrate salt of the compound of formula (II).

[0443] In some embodiments, the crystalline hydrochloride salt form of the compound of Formula (II) has the structure:

[0444] [ka] It has solvates thereof.

[0445] Crystalline form of formula (III) In one aspect, the present invention provides a compound of formula (III):

[0446] [ka] or a compound of The present invention relates to pharmaceutical compositions of crystalline salts of pharmaceutically acceptable salts thereof, or solvates of the foregoing.

[0447] In another aspect, the present invention relates to a crystalline free base form of the compound of formula (III).

[0448] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO:3.

[0449] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (III).

[0450] 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:3.

[0451] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of the peptide of SEQ ID NO: 3. The crystalline form of the pharmaceutically acceptable salt of the peptide of SEQ ID NO: 3 can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline mesylate, crystalline sulfate, crystalline bishydrochloride, and crystalline citrate salt of the peptide of SEQ ID NO: 3.

[0452] In another aspect, the present invention relates to a pharmaceutical composition of the crystalline form of the hydrochloride salt of the compound of formula (III).

[0453] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of the compound of formula (III). The crystalline form of the pharmaceutically acceptable salt of the compound of formula (III) can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline mesylate, crystalline sulfate, crystalline bishydrochloride, and crystalline citrate salt of the compound of formula (III).

[0454] In some embodiments, the crystalline hydrochloride salt form of the compound of Formula (III) has the structure:

[0455] [ka] It has solvates thereof.

[0456] VI. Particle size of crystalline morphology In one embodiment, the method provided herein for crystallizing a compound of Formula (I) provides a crystalline material characterized by laser diffraction (LD) as having a mean particle size distribution (PSD) range of about 1-100 μm. In another embodiment, the characterized crystalline material has a mean particle size distribution range of about 1-90 μm. In yet another embodiment, the crystalline material has a particle size distribution range of about 2-80 μm. In yet another embodiment, the crystalline material has a particle size distribution range of about 3-70 μm.

[0457] In one embodiment, the PSD of the crystalline compound of Formula (I) is characterized by a Dv10 in the range of about 1 μm to 30 μm. In another embodiment, the PSD is characterized by a Dv10 in the range of about 2 μm to 20 μm. In yet another embodiment, the PSD is characterized by a Dv10 in the range of about 3 μm to 10 μm.

[0458] In one embodiment, the PSD of the crystalline compound of Formula (I) is characterized by having a Dv50 in the range of 3 μm to 80 μm. In another embodiment, the PSD is characterized by having a Dv50 in the range of 5 μm to 60 μm. In yet another embodiment, the PSD is characterized by having a Dv50 in the range of 10 μm to 40 μm. In some embodiments, the crystalline compound has a Dv50 in the range of about 8 to 50 μm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 to 30 μm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 to about 25 μm. In one embodiment, the PSD of the crystalline compound is characterized by having a Dv50 in the range of 5 μm to 60 μm, 10 μm to 55 μm, 15 μm to 25 μm, 15 μm to 16 μm, and 20 μm to 24 μm.

[0459] In one embodiment, the PSD of the crystalline compound of Formula (I) is characterized by a Dv90 in the range of 10 μm to 110 μm. In another embodiment, the PSD is characterized by a Dv90 in the range of 20 μm to 100 μm. In yet another embodiment, the PSD is characterized by a Dv90 in the range of 30 μm to 90 μm.

[0460] In certain embodiments, the PSD values ​​of the crystalline compound of Formula (I) are as follows: 4 μm to 6 μm (Dv10), 14 μm to 19 μm (Dv50), and 34 μm to 60 μm (Dv90).

[0461] In certain embodiments, the PSD values ​​of the crystalline compound of Formula (I) are as follows: 4.5 μm to 5.4 μm (Dv10), 14 μm to 19 μm (Dv50), and 34 μm to 60 μm (Dv90).

[0462] In another embodiment, the PSD comprises a Dv10 in the range of about 3.0 μm to 11 μm, a Dv50 in the range of 11 μm to 33 μm, and a Dv90 in the range of 34 μm to 90 μm. In another embodiment, the PSD values ​​of the crystalline compound of Formula (I) are as follows: about 9 μm (Dv10), about 26 μm (Dv50), and about 61 μm (Dv90). In yet another embodiment, the PSD values ​​of the crystalline compound of Formula (I) are as follows: about 3 μm (Dv10), about 11 μm (Dv50), and about 34 μm (Dv90).

[0463] In one embodiment, the methods provided herein for crystallizing a compound of Formula (I) provide a crystalline material characterized by laser diffraction (LD) as having a particle size distribution (PSD) span of 1 to 3. In certain embodiments, the span is 1.5 to 3.5. In certain embodiments, the PSD span of the crystalline hydrochloride salt of the compound of Formula (I) is about 2.2. In some embodiments, the particle size distribution span is less than 5, 4, or 3. In some embodiments, the particle size distribution span is less than 3. In some embodiments, the particle size distribution span is less than 4. In some embodiments, the particle size distribution span is less than 5.

[0464] In one embodiment, the methods provided herein for crystallizing a compound of Formula (I) provide crystalline material characterized by laser diffraction (LD) as having a particle size distribution (PSD) span of 1.99 to 2.90. In certain embodiments, the span is 1.99 to 2.47. In certain embodiments, the PSD span of the crystalline hydrochloride salt of the compound of Formula (I) is about 2.21.

[0465] In one embodiment, the PSD values ​​and ranges above are measured for the crystalline hydrochloride salt of the compound of formula (I).

[0466] VII.Synthesis method The compounds of formula (I') or pharmaceutically acceptable salts or solvates thereof can be prepared using solid phase peptide synthesis or by convergent solution phase synthesis. For example, cyclic peptide molecules can be made in solution phase by coupling a cyclic moiety with a linear moiety in a liquid phase reaction medium.

[0467] However, further processing is required to provide solid forms of the peptide inhibitors for use as pharmaceutical ingredients with characteristics that provide improved handling, such as improved rheological (flow) properties, particle size, and hygroscopicity.

[0468] VIII. Pharmaceutical Compositions Generally, the present invention relates to pharmaceutical hydrochloride salt forms and compositions of peptide inhibitors of 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.

[0469] Furthermore, the present invention relates to pharmaceutical crystalline salt forms and compositions of peptide inhibitors of 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.

[0470] 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 the chemical structure shown below:

[0471] [ka] or a compound having It relates to pharmaceutical compositions of the hydrochloride salt of the corresponding solvate.

[0472] 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 pharmaceutically 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.

[0473] 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% by weight, 0.5% to about 15% by weight, about 1% to about 10% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight, about 1% to about 3% by weight, about 0.1% to about 5% by weight, about 0.1% to about 4% by weight, 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.

[0474] 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 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 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 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 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.

[0475] In another embodiment, the hydrochloride salt of the compound of formula (I) or its corresponding solvate may exist in any form, such as a hydrate or other solvate. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof may be provided in a crystalline, amorphous, or semi-crystalline form. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof is in a crystalline form. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof is in amorphous form. In some embodiments, the hydrochloride salt of the compound of formula (I) or a solvate thereof is in semi-crystalline form.

[0476] 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, e.g., about 0.2 to about 0.8, or about 0.3 to about 0.7 molar equivalents of hydrogen chloride relative 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 relative to the compound of Formula (I). In some embodiments, the hemihydrochloride salt has about 0.5 molar equivalents of hydrogen chloride relative to the compound of Formula (I).

[0477] In some embodiments, the hydrochloride salt form of the compound of Formula (I) or a solvate thereof can be a hydrate. In some embodiments, the hydrate of the hydrochloride salt 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 other embodiments, the hydrate can be present in a range of about 2% w / w to about 10% w / w of water relative to the hydrochloride salt of the compound of Formula (I). The present invention relates to hydrochloride salt compositions of the present invention, which can be in liquid or solid compositions.

[0478] In some embodiments, the hydrochloride salt 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 salt 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.

[0479] The hydrochloride salt compositions of the present invention can 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 oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. In some embodiments, the administration of the hydrochloride salt compositions of the present invention is adapted for oral administration.

[0480] In another aspect, 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 one or more pharmaceutically acceptable excipients.

[0481] In another aspect, the present invention provides a composition comprising the hydrochloride salt of the compound of formula (I) or a solvate thereof and about 50 mM aqueous phosphate buffer at pH 7.4.

[0482] In another aspect, the present invention relates to 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, an absorption enhancer in an amount of about 10% to about 60% (w / w), and one or more pharmaceutically acceptable excipients.

[0483] 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.

[0484] In another aspect, 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; sodium caprate in an amount of about 20% to about 45% (w / w) of the composition; and microcrystalline cellulose.

[0485] In another embodiment, the hydrochloride salt of the compound of Formula (I) or a solvate thereof may be present in any amount from about 0.1% to about 15% (w / w) of the composition. For example, the hydrochloride salt of the compound of Formula (I) or a solvate thereof 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 salt of the compound of Formula (I) or a solvate thereof may be present in an amount of about 1% to about 5% (w / w).

[0486] In another embodiment, the hydrochloride salt of the compound of Formula (I) or a solvate thereof may be present in an amount of about 1 to about 5% (w / w). For example, the hydrochloride salt of the compound of Formula (I) or a solvate thereof 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 subdivision therebetween. In another embodiment, the hydrochloride salt of the compound of Formula (I) or a solvate thereof may be present in an amount of about 1.8% (w / w).

[0487] In another embodiment, the hydrochloride salt 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 salt 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 salt 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 salt 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 salt of the compound of formula (I) or a solvate thereof may be about 25 mg to about 100 mg. In another embodiment, the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present in an amount of about 1 mg to about 100 mg. In another embodiment, the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present in an amount of about 20 mg to about 40 mg. In another embodiment, the hydrochloride salt of the compound of formula (I) or a solvate thereof may be present in an amount of about 20 mg to about 30 mg.

[0488] In yet another embodiment, the hydrochloride salt of the compound of Formula (I) or a solvate thereof 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 and sub-amounts therebetween. In another embodiment, the amount of the hydrochloride salt of the compound of Formula (I) or a solvate thereof may be present at about 5 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 10 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 25 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 50 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 75 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 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.

[0489] In another embodiment, the amount of the crystalline form of a pharmaceutically 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 subportions thereof.

[0490] Generally, the pharmaceutical compositions of the present invention can be formed into different dosage forms prepared using conventional materials and techniques known in the fields of pharmacy and formulation, including, but not limited to, techniques such as mixing, blending, and the like, and techniques described throughout this disclosure. Furthermore, the pharmaceutical compositions used to form dosage forms can also include, but are not limited to, suitable adjuvants, carriers, additives, stabilizers, etc., and can be in solid or liquid form, such as, but not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions. According to the present invention, the solid unit dosage form can be of other conventional types known in the art.

[0491] 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.

[0492] 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.

[0493] The compositions of the present invention may contain a variety of other pharmaceutically acceptable components or additives, including, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or additives, such as those described herein.

[0494] According to the present invention, the compositions described herein may contain at least one filler. In some embodiments, the compositions of the present invention may contain 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, calcium carbonate, and the like. In some embodiments, the compositions of the present invention may contain mannitol. In other embodiments, the compositions of the present invention may contain sorbitol.

[0495] 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 conventionally known in the art, typically used in the formulation of pharmaceutical compounds. Examples of such fillers or diluents for use in 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 embodiments, such fillers or diluents suitable for use in the present invention may include, but are not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0496] Furthermore, in another embodiment, a bulking agent for use in the present invention, as defined herein, 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. Furthermore, 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 the amount may include any subdivision therebetween, as defined herein.

[0497] 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 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).

[0498] 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 is not limited to, MICROCEL® or AVICEL® types PH101, PH102, PH103, PH105, PH112, PH113, PH200, and PH301, as well as other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one embodiment, the composition 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).

[0499] In another embodiment, microcrystalline cellulose, as defined herein, 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. In some embodiments, microcrystalline cellulose may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, and the amount may include any fraction therebetween, as defined. In some embodiments, microcrystalline cellulose may also be present in an amount of about 3% to about 5% (w / w) of the composition.

[0500] 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 believed 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.

[0501] 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 fraction therebetween. In some embodiments, SMCC is present in an amount of about 80% to about 85% (w / w), including, but not limited to, any fraction 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 fraction therebetween. In some embodiments, SMCC is present in an amount of about 50%, including, but not limited to, any fraction therebetween. In some embodiments, SMCC is present in an amount of about 60%, including, but not limited to, any fraction therebetween. In some embodiments, SMCC is present in an amount of about 70%, including, but not limited to, any fraction therebetween. In some embodiments, SMCC is present in an amount of about 80%, including, but not limited to, any fraction therebetween. In some embodiments, SMCC is present in an amount of about 90%, including, but not limited to, any amount subdivision therebetween.

[0502] In some embodiments, the SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0503] 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.

[0504] In some embodiments, the compositions of the present invention may contain 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%, 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) of the composition. 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.

[0505] In some embodiments, the compositions of the present invention may contain 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%, 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) of the composition. 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 fraction 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.

[0506] In one embodiment, the sugar alcohol is present in an amount ranging from about 1% to about 50% (w / w) of the composition, or from about 5% to about 50%, or from about 5% to about 30%, or from about 10% to about 30% (w / w) of the composition. In some aspects, the sugar alcohol is 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 sugar alcohol is present in an amount greater than about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some embodiments, the amount of 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.

[0507] In some embodiments, the pharmaceutical compositions described herein do not contain sugar alcohols. In some embodiments, the pharmaceutical compositions described herein do not contain sorbitol. In some embodiments, the pharmaceutical compositions described herein do not contain mannitol.

[0508] 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 to this.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 polymers, combinations thereof, etc.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, etc.

[0509] In some embodiments, the disintegrant is crosslinked carboxymethyl cellulose (croscarmellose), starch glycolate, polyvinylpyrrolidone, sago starch, psyllium husk, silicate, or soy polysaccharide. In some embodiments, the disintegrant is sodium croscarmellose or crospovidone. In some embodiments, the disintegrant for use in the present invention may include, but is not limited to, sodium croscarmellose. In some embodiments, the disintegrant for use in the present invention can include crospovidone. In some embodiments, the disintegrant is 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). The disintegrant 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, and the amount includes any fractional amount between these, but is not limited thereto. In some embodiments, the amount of the 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 the 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 the disintegrant may be present in an amount of about 3% to about 8% (w / w) of the composition of the present invention.

[0510] In another embodiment, the composition of the present invention may also include, but is not limited to, any amount of silica for the purposes of the present invention. In particular, silica is exemplified by Aerosil 200 having a specific surface area of about 200 m 2 / g. Alternatives to silica can 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.

[0511] In some embodiments, the compositions of the present invention may further comprise silica. In one embodiment, silica may be present in the compositions 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 embodiments, 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.

[0512] Compositions can also contain binder.The binder for use in the compositions of the present invention includes binders commonly used in pharmaceutical preparations.Examples of binders for use in the present invention include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, 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.

[0513] In some embodiments, the binder is hydroxypropyl methylcellulose (HPMC). In some embodiments, binders 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.

[0514] 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.

[0515] In some embodiments, the lubricant may include, but is not limited to, magnesium stearate. In one embodiment, the amount of lubricant may be present in 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 lubricant may be present in 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 lubricant may be present in about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, the amount of lubricant is about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the amount of lubricant is about 0.5% (w / w) of the composition. The lubricant can also be present in an amount of about 0.10% (w / w) of the composition, or about 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or about 0.30% (w / w) of the composition. The lubricant can also be present in an amount of about 0.5% (w / w) of the composition, or about 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, or about 2.5% (w / w) of the composition. In some embodiments, the lubricant may be present in an amount of about 0.25% (w / w).

[0516] 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.

[0517] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically 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.

[0518] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically 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.

[0519] 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 pharmaceutically 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 (iii) silicified microcrystalline cellulose in an amount of about 10% to about 50% (w / w) of the composition.

[0520] 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 pharmaceutically 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, (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.

[0521] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically 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 pharmaceutically 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; (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; (vii) 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.

[0522] 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 pharmaceutically 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.

[0523] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically 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 pharmaceutically 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) a disintegrant in an amount of about 0.5% to about 1.0% (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.

[0524] 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.

[0525] 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.

[0526] 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 comprise one or more coatings.

[0527] The compositions described herein may contain a variety of other pharmaceutically acceptable components or additives, including, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or additives.

[0528] The compositions described herein may contain 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 another embodiment, the disintegrant may include crospovidone. 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, including any fraction therebetween as defined herein. In another embodiment of the present invention, the disintegrant may be present in an amount of about 1 to 10% (w / w) of the composition, but is not limited thereto, or in another embodiment, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0529] In some embodiments, the microcrystalline cellulose can be present in an amount of about 1% to about 10% (w / w) of the composition. In some embodiments, the microcrystalline cellulose can be present in an amount of about 3.9% (w / w) of the composition.

[0530] 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.

[0531] 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.

[0532] 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.

[0533] 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).

[0534] 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).

[0535] 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).

[0536] The microcrystalline cellulose can include any microcrystalline cellulose known in the art, hi some embodiments, the microcrystalline cellulose can include silicified microcrystalline cellulose (SMCC).

[0537] In some embodiments, the microcrystalline cellulose for use in the present invention 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.

[0538] The composition may include any suitable amount of at least one disintegrant according to the present invention. Representative disintegrants for use in the present invention 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. 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.

[0539] 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 / g. Alternatives to silica include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof. Silica (e.g., Aerosil 200) can 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 subdivision therebetween.

[0540] 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 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.

[0541] The compositions described herein can include various other pharmaceutical additives or components, including, but not limited to, lubricants, disintegrants, binders, desiccants, fillers, and other ingredients. For use in the present invention, the disintegrant can 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 can further comprise a disintegrant. In some embodiments, the composition can further comprise 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 can further comprise a disintegrant in an amount of about 0.25% (w / w) of the composition.

[0542] 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.

[0543] 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.

[0544] 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), 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).

[0545] 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).

[0546] 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).

[0547] 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.

[0548] Some embodiments described herein, e.g., with respect to pharmaceutical compositions, tablets, methods, processes, etc., exclude absorption enhancers. Some embodiments described herein, e.g., with respect to compositions, tablets, methods, processes, etc., include absorption enhancers.

[0549] In other aspects, preferred compositions of the present invention may exhibit improved bioavailability when administered with an absorption enhancer.

[0550] In some embodiments, the compositions of the present invention may include an absorption enhancer. When present, the absorption enhancer may be zwitterionic, cationic, anionic, or nonionic. In one embodiment, the absorption enhancer is an intestinal permeation enhancer. In some embodiments, 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.

[0551] 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 coconut, sucrose mono- dodecanoate, sucrose mono-tridecanoate, sucrose monotetradecanoate, coco-glucoside, cyclodextrin, alkanoylcarnitines such as lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine, lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride, sodium lauroylalaninate, N-dodecanoyl-L-alanine, sodium lauroylasparaginate, N-dodecanoyl-L-asparagine, sodium lauroylaspartate , N-Dodecanoyl-L-Aspartic Acid, Sodium Lauroyl Cysteinate, N-Dodecanoyl-L-Cysteine, Sodium Lauroyl Glutamate, N-Dodecanoyl-L-Glutamic Acid, Sodium Lauroyl Glutaminate, 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 Si Stenate, N-Decanoyl-L-Cysteine, Sodium Caprylic Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Caprylic Glutaminate, N-Decanoyl-L-Glutamine, Sodium Caprylic Glycinate, N-Decanoyl-L-Glycine, Sodium Caprylic Histidinate, N-Decanoyl-L-Histidine, Sodium Caprylic 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., 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 pharmaceutically acceptable salts of any of the foregoing compounds; or alkanoyl sarcosinates (e.g., lauroyl sarcosinates, such as sodium lauroyl sarcosinate), or C to 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 monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, 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 polyoxylglyceride (e.g., caprylocaproyl polyoxyl-8 glyceride, 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), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (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.

[0552] 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 acid (e.g., LABRASOL®, available from Gattefosse, USA), sucrose laurate, or lauroyl-L-carnitine (LC, e.g., PEPTELLIGENCE®, available from Enteris BioPharma, NJ, USA). 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).

[0553] The absorption enhancer 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, the absorption enhancer is present in an amount of about 5% to about 50% (w / w). In some embodiments, the absorption e...

Claims

1. 1. A process for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, having rheological properties suitable for the manufacture of a pharmaceutical composition, said process comprising: (a) dissolving the monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing residual solvent. A method comprising:

2. 1. A method for improving the rheological properties of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, said method comprising: (a) dissolving the monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing residual solvent. A method comprising:

3. 3. The method of claim 1 or 2, wherein step (a) is carried out at about 25 to about 55°C.

4. The method of any one of claims 1 to 3, wherein the first solvent comprises an alkyl alcohol.

5. The method of any one of claims 1 to 4, wherein the first solvent comprises methanol.

6. The first solvent is methanol and H ２ The method of any one of claims 1 to 5, comprising O.

7. The first solvent is a mixture of alkyl alcohol and H ２ 7. The method according to claim 1, wherein the amount of the hydroxybenzoate is 9:1 to 5:5 by volume.

8. The method according to any one of claims 1 to 7, wherein the concentration of the monocyclic peptide compound in the mixture obtained in step (a) is 10% to 25% w / v.

9. The first solvent is methanol and H ２ 9. The method according to claim 1, wherein the amount of the hydroxybenzoate is 3:1 to 3:2 by volume.

10. 10. The method of any one of claims 1 to 9, wherein step (a) is carried out at a pH of 5.0 to 6.

5.

11. The method according to any one of claims 1 to 10, wherein in step (a), the monocyclic peptide compound, or the salt or solvate thereof is in an amorphous or partially amorphous form of the monocyclic peptide compound, or the salt or solvate thereof.

12. The method according to any one of claims 1 to 11, wherein in step (b), the sodium chloride is a 0.1 to 2 M aqueous sodium chloride solution.

13. 13. The method according to any one of claims 1 to 12, wherein in step (b), 9 to 12 moles, 10 to 11.5 moles, or 1.0 to 3.0 mole equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a).

14. 14. The method of any one of claims 1 to 13, wherein in step (b), the sodium chloride is added over a period of at least 10 minutes.

15. The method according to any one of claims 1 to 14, wherein the amount of inoculant added is 0.005 to 0.1 molar equivalents based on the amount of monocyclic peptide compound in step (a).

16. 16. The method of any one of claims 1 to 15, wherein prior to step (c), the slurry is aged at a temperature of from about 25°C to about 55°C for at least 30 minutes.

17. 17. The method according to any one of claims 1 to 16, wherein in step (d), the sodium chloride is an aqueous sodium chloride solution.

18. 18. The method according to any one of claims 1 to 17, wherein in step (d), the sodium chloride is a 0.1 M to 2 M aqueous sodium chloride solution.

19. 19. The method of any one of claims 1 to 18, wherein in step (d), at least 2.0 molar equivalents, at least about 3.0 molar equivalents, or at least 4.0 molar equivalents of NaCl are added based on the amount of monocyclic peptide compound in step (a).

20. 20. The method of any one of claims 1 to 19, wherein in step (d), the sodium chloride is added over a period of at least 30 minutes.

21. The method of any one of claims 1 to 20, wherein the slurry obtained in step (d) is aged for at least 1 hour.

22. 22. The method of any one of claims 1 to 21, wherein the slurry obtained in step (d) is aged at a temperature of about 25°C to about 55°C for a period of at least 1 hour.

23. 23. The method of any one of claims 1 to 22, wherein in step (d), the slurry is cooled to a temperature of from about 0°C to about 10°C.

24. 24. The method of any one of claims 1 to 23, wherein in step (d), the slurry is cooled to a temperature of about 0°C to about 10°C at a rate of less than 1°C / min.

25. 25. The method of any one of claims 1 to 24, wherein in step (e), the removal of the residual solvent is by washing with a second solvent.

26. 26. The method of any one of claims 1 to 25, wherein in step (e), the removal of the residual solvent is by washing with a second solvent, and the second solvent comprises an alkyl alcohol.

27. 27. The method of any one of claims 1 to 26, wherein in step (e), the removal of the residual solvent is by washing with a second solvent, and the second solvent comprises 2-propanol.

28. The method according to any one of claims 1 to 27, wherein in step (e), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried.

29. The method according to any one of claims 1 to 28, wherein the crystalline monocyclic peptide compound obtained in step (f) is in the form of the hydrochloride salt.

30. 30. The method of any one of claims 1 to 29, further comprising preparing the monocyclic peptide compound by solid phase peptide synthesis.

31. 30. The method of any one of claims 1 to 29, further comprising preparing the monocyclic peptide compound by solution phase peptide synthesis.

32. The method according to any one of claims 1 to 31, wherein the amount of the monocyclic peptide compound dissolved in step (a) is at least 10 kg.

33. 1. A process for the preparation of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, comprising: (i) dissolving the monocyclic peptide compound, or a salt or solvate thereof, in a first solvent; (ii) adding a second solvent to the mixture obtained in step (i); (iii) optionally cooling the mixture obtained in step (ii); (iv) isolating the crystalline monocyclic peptide compound or a salt thereof from the mixture obtained in step (iii) and removing any residual solvent; A method comprising:

34. 34. The method of claim 33, wherein step (i) is carried out at a temperature of from about 25°C to about 55°C.

35. 35. The method of claim 33 or 34, wherein the first solvent comprises an alkyl alcohol.

36. 36. The method of any one of claims 33 to 35, wherein the first solvent comprises methanol.

37. The first solvent is methanol and H ２ The method of any one of claims 33 to 36, comprising O.

38. The method according to any one of claims 33 to 37, wherein the concentration of the monocyclic peptide compound in the mixture obtained in step (i) is 5% w / v to 20% w / v.

39. The first solvent is methanol and H ２ 39. The method of any one of claims 33 to 38, comprising: O in a volume ratio of 9:1 to 5:

5.

40. 40. The method of any one of claims 33 to 39, wherein in step (ii), the second solvent is added over a period of at least 1 hour.

41. 41. The method of any one of claims 33 to 40, wherein in step (ii), the volume ratio of the first solvent to the second solvent is from 3:1 to 1:

3.

42. The second solvent is H ２ The method of any one of claims 33 to 41, comprising O.

43. 43. The method of any one of claims 33 to 42, wherein in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 0°C to about 10°C.

44. 44. The method of any one of claims 33 to 43, wherein in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 0°C to about 10°C at a rate of less than 1°C / min.

45. 45. The method of any one of claims 33 to 44, wherein the temperature of the mixture is maintained for at least 1 hour before step (iii) and after the addition of the second solvent.

46. 46. ​​The method of any one of claims 33 to 45, wherein after step (iii), the temperature is maintained for a period of at least 30 minutes.

47. 47. The method of any one of claims 33 to 46, wherein after step (iii), the mixture is warmed to a temperature of about 25 to about 55°C and then cooled to a temperature of about 0°C to about 10°C.

48. 48. The method of any one of claims 33 to 47, wherein in step (iv), the removal of the residual solvent is by washing with a third solvent, and the third solvent comprises an alkyl alcohol.

49. 49. The method of any one of claims 33 to 48, wherein in step (iv), the removal of the residual solvent is by washing with a third solvent, and the third solvent comprises 2-propanol.

50. 50. The method of any one of claims 33 to 49, wherein in step (iv), the crystalline monocyclic peptide compound is isolated by filtration.

51. The method according to any one of claims 33 to 50, wherein in step (iv), the crystalline monocyclic peptide compound is washed with a solvent.

52. 52. The method of claim 51, wherein the solvent is an alkyl alcohol or water.

53. 53. The method of any one of claims 50 to 52, wherein the crystalline monocyclic peptide compound is isolated and dried.

54. 54. The method of claim 53, wherein the crystalline monocyclic peptide compound is dried in a dynamic drying step, the dynamic drying step comprising agitating the crystalline monocyclic peptide compound.

55. 55. The method of claim 54, wherein the dynamic drying step further comprises heating, exposure to vacuum, or exposure to nitrogen gas.

56. 50. The method according to any one of claims 33 to 49, wherein in step (iv), the crystalline monocyclic peptide compound is isolated by filtration, then washed and dried under vacuum at a temperature below 20°C.

57. 57. The method of any one of claims 33 to 56, wherein the monocyclic peptide compound is in the form of a hydrochloride salt.

58. The method according to any one of claims 1 to 32, wherein said seed of crystalline monocyclic peptide compound is obtained by a method according to any one of claims 33 to 51.

59. below: (f) dissolving the hydrochloride salt obtained in step (e) in aqueous hydrochloric acid; (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; (h) isolating the crystalline monocyclic peptide compound in the form of a free base from the mixture obtained in step (g); 33. The method of any one of claims 1 to 32, further comprising:

60. 60. The method of claim 59, wherein in step (f), the amount of hydrochloric acid added is 1 to 2 molar equivalents.

61. 61. The method of claim 59 or 60, wherein the buffer solution is a phosphate buffer having a pH between pH 7 and pH 9.

62. (i) dissolving the crystalline free base of the monocyclic peptide compound in a second solvent; (j) adding a solution containing a counterion to the mixture obtained in step (i); (k) adding an anti-solvent; (l) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained from step (k).

62. The method of any one of claims 59 to 61, further comprising:

63. 63. The method of claim 62, wherein the second solvent comprises methanol and / or water.

64. 64. The method of claim 62 or 63, wherein the anti-solvent is selected from the group consisting of tert-butyl methyl ether (TBME), acetonitrile, and isopropanol (IPA).

65. 65. The method of any one of claims 62 to 64, wherein the solution comprising a counterion is a solution comprising a counterion selected from the group consisting of fumarate, glutarate, glycolate, mesylate, sulfate, and citrate.

66. 66. The method of any one of claims 1 to 65, wherein the monocyclic peptide compound is an inhibitor of interleukin-23 receptor (IL-23R).

67. 67. The method of any one of claims 1 to 66, further comprising passing the isolated crystalline monocyclic peptide through a suitable sieve.

68. The method of any one of claims 1 to 53 and 56 to 67, wherein the crystalline monocyclic peptide compound is isolated and then dried in a dynamic drying step, the dynamic drying step comprising agitating the crystalline monocyclic peptide compound.

69. 69. The method of claim 68, wherein the dynamic drying step further comprises heating, exposure to vacuum, or exposure to nitrogen gas.

70. 70. The method of any one of claims 1 to 69, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv10 in the range of about 1 μm to 30 μm, about 2 μm to 20 μm, or about 3 μm to 10 μm.

71. 71. The method of any one of claims 1 to 70, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv50 in the range of about 3 μm to 80 μm, about 5 μm to 60 μm, or about 10 μm to 40 μm.

72. 72. The method of any one of claims 1 to 71, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv90 in the range of about 10 μm to 110 μm, about 20 μm to 100 μm, or about 30 μm to 90 μm.

73. 73. The method of any one of claims 1 to 72, wherein the crystalline monocyclic peptide compound is a crystalline solid having a particle size distribution span calculated to be about 1 to 3.

74. A pharmaceutical tablet comprising a crystalline form of a monocyclic peptide compound prepared by the method of any one of claims 1 to 73 and a pharmaceutical excipient.

75. The monocyclic peptide compound comprises an amino acid sequence of formula (I'): X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I') During the ceremony, X3 is absent or any amino acid; X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, substituted Gly, Leu, lie, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is substituted or unsubstituted Trp; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl, Ac), Lys(propyl, Ac), or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is Tyr, or unsubstituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; X11 is substituted or unsubstituted 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is any amino acid; X14 is any amino acid; X15 is Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, substituted or unsubstituted His, (D)His, Ile, Lue, (D)Lue, Lys, (D)Lys, Met, 2Pal, 3Pal, or 4Pal, Phe, Pro, 5-Pyal, 2Quin, 3Quin, Ser, Thr, Trp, Tyr, Val; 74. The method of any one of claims 1 to 73, wherein X16 is absent or any amino acid, and X4 and X9 form a disulfide bond or a thioether bond.

76. the peptide compound comprises an amino acid sequence of formula (IIa), (IIb), (IIc), or (IId); X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16 (IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16 (IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16 (IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16 (IId) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal; Pal is 2 Pal, 3 Pal, or 4 Pal; 76. The method of any one of claims 1 to 75, wherein, unless otherwise indicated, X3 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

77. the peptide compound comprises an amino acid sequence of formula (IIa), (IIb), (IIc), or (IId); X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16 (IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16 (IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16 (IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16 (IId) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal; Pal is 2 Pal, 3 Pal, or 4 Pal; 77. The method of any one of claims 1 to 76, wherein X16 is Sarc and, unless otherwise indicated, X3 to X15 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

78. the peptide compound comprises an amino acid sequence of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf); X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16 (IIIa), X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16 (IIIb), X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16 (IIIc), X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16 (IIId), X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16 (IIIe), or X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16 (IIIf) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal; Pal is 2 Pal, 3 Pal, or 4 Pal; 78. The method of any one of claims 1 to 77, wherein, unless otherwise indicated, X4 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

79. the peptide compound comprises an amino acid sequence of formula (IVa), (IVb), (IVc), or (IVd); X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16 (IVa), X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16 (IVb), X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVc), or X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVd) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal; Pal is 2 Pal, 3 Pal, or 4 Pal; 79. The method of any one of claims 1 to 78, wherein, unless otherwise indicated, X4 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

80. The peptide compound comprises an amino acid sequence of formula (IVe): X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVe) wherein Trp is unsubstituted Trp or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; 2-Nal is unsubstituted 2-Nal; Pal is 2 Pal, 3 Pal, or 4 Pal; 80. The method of any one of claims 1 to 79, wherein, unless otherwise indicated, X4 to X16 are as described for formula (I'), and the peptide compound is cyclized via a Pen-Pen disulfide bond, or the peptide compound is cyclized via an Abu-Cys or Abu-Pen thioether bond.

81. 81. The method of any one of claims 1 to 80, wherein X4 is Pen, X9 is Pen, and the bond is a disulfide bond.

82. 82. The method of any one of claims 1 to 81, wherein X5 is Asn.

83. 83. The method of any one of claims 1 to 82, wherein X6 is Thr.

84. 84. The method of any one of claims 1 to 83, wherein X8 is Lys(Ac).

85. 85. The method of any one of claims 1 to 84, wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP).

86. 86. The method of any one of claims 1 to 85, wherein X13 is GIu.

87. 87. The method of any one of claims 1 to 86, wherein X14 is Asn.

88. 88. The method of claims 1 to 87, wherein X16 is Sarc.

89. The monocyclic peptide compound has the structure: 【Chemistry 1】 or a compound having 89. The method of any one of claims 1 to 88, a pharmaceutically acceptable salt thereof.

90. 1. A method for the preparation of a crystalline form of a hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound has the structure: 【Chemistry 2】 is a compound having the formula The method comprises: (a) dissolving the monocyclic peptide compound, including the hydrochloride salt of the monocyclic peptide compound, in a first solvent; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding a seed of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry; (d) adding a second portion of sodium chloride to the slurry obtained in step (c); (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture and removing residual solvent. A method comprising:

91. 91. The method of claim 90, further comprising preparing a crude monocyclic peptide compound by solution phase peptide synthesis.

92. 1. A method for the preparation of a crystalline form of a hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound has the structure: 【Transformation 3】 is a compound having the formula The method comprises: (a) mixing the monocyclic peptide compound in a first solvent; (b) heating the mixture to 30-40°C; (c) adding a second solvent to the solution obtained in step (b); (d) cooling the mixture to 20-30°C; (e) adding seeds of the crystalline monocyclic peptide compound to the mixture obtained in step (d); (f) stirring the mixture at 20-30°C for 1-3 hours; (g) cooling the mixture to 5°C and stirring for 2 to 4 hours; (h) heating the mixture to 22°C and stirring for 2 to 4 hours; (i) cooling the mixture to 5°C and stirring for 8 to 10 hours; (j) isolating the crystalline monocyclic peptide compound from the mixture and removing residual solvent. A method comprising:

93. 93. The method of claim 92, wherein the monocyclic peptide compound is obtained by liquid phase peptide synthesis.

94. 1. A method for the preparation of a crystalline form of a hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound has the structure: 【Chemistry 4】 is a compound having the formula The method comprises: (a) mixing a crude monocyclic peptide compound in a first solvent; (b) heating the mixture to 30-50°C; (c) filtering the suspension obtained in step (b) to obtain a solution; (d) cooling the solution obtained in step (c) to 10-20°C; (e) adding a seed of the crystalline monocyclic peptide compound to the mixture obtained in step (d) to obtain a mixture; (f) stirring the mixture for 1 to 2 hours; (g) adding a second solvent to the mixture obtained in step (f); (h) cooling the mixture to 0° C. over a period of 3 to 5 hours; (i) stirring the mixture at 0-5°C for 12-18 hours; (j) isolating the crystalline monocyclic peptide compound from the mixture and removing residual solvent. A method comprising:

95. 95. The method of claim 94, further comprising preparing the crude monocyclic peptide compound by solution phase peptide synthesis.

96. 1. A method for the preparation of a crystalline form of an acetate salt of a monocyclic peptide compound, wherein the monocyclic peptide compound has the structure: 【Transformation 5】 is a compound having the formula The method comprises: (a) dissolving the monocyclic peptide compound, including the hydrochloride salt of the monocyclic peptide compound, in a first solvent; (b) permeating the mixture obtained in step (a) through an anion exchange resin in acetate form; (c) washing the resin with a second solvent; (d) filtering the resulting mixture; (e) freezing the solution obtained in step (d); (f) freeze-drying the solid obtained in step (e) to isolate the dry solid. A method comprising:

97. 97. The method of claim 96, further comprising preparing a crude monocyclic peptide compound by solution phase peptide synthesis.

98. A crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, prepared by the method of any one of claims 75 to 97.

99. 99. The method of any one of claims 75 to 98, further comprising passing the isolated crystalline monocyclic peptide through a suitable sieve.

100. The method of any one of claims 75 to 98, wherein the crystalline monocyclic peptide compound is isolated and then dried in a dynamic drying step, the dynamic drying step comprising agitating the crystalline monocyclic peptide compound.

101. 101. The method of claim 100, wherein the dynamic drying step further comprises heating, exposure to vacuum, or exposure to nitrogen gas.

102. 102. The method of any one of claims 75 to 101, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv10 in the range of about 1 μm to 30 μm, about 2 μm to 20 μm, or about 3 μm to 10 μm.

103. 103. The method of any one of claims 75 to 102, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv50 in the range of about 3 μm to 80 μm, about 5 μm to 60 μm, or about 10 μm to 40 μm.

104. 104. The method of any one of claims 75 to 103, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv90 in the range of about 10 μm to 110 μm, about 20 μm to 100 μm, or about 30 μm to 90 μm.

105. The method of any one of claims 75 to 104, wherein the crystalline monocyclic peptide compound is a crystalline solid having a particle size distribution span calculated to be about 1 to 3.

106. A pharmaceutical tablet comprising a crystalline form of a monocyclic peptide compound prepared by the method of any one of claims 75 to 105 and a pharmaceutical excipient.

107. 91. The method of any one of claims 29, 57, and 90, wherein the crystalline monocyclic peptide compound is in the form of a hydrochloride hydrate having a water content of about 5%.

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