Process for preparing crystalline peptide inhibitors of interleukin-23 receptor

Abstract

The present invention relates to a process for preparing a crystalline form of a monocyclic peptide compound, which is a peptide inhibitor of the interleukin-23 receptor (IL-23R), or a salt or solvate thereof. The crystalline forms are pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related conditions.

Description

[0001] Sequence Listing

[0002] The contents of the electronic sequence listing (747883-NTT-4258PC_SL.xml; size: 13,484 bytes; creation date: January 30, 2024) are incorporated herein by reference in their entirety.

[0003] Related applications

[0004] 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 each of these applications are incorporated herein by reference in their entirety. Technical Field

[0005] The present invention relates to methods for preparing crystalline monocyclic peptide compounds and their salts or solvates, which are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystalline monocyclic peptide compounds and their salts or solvates have favorable rheological (flow) properties, making them suitable for pharmaceutical processing. The peptide inhibitors are useful in treating autoimmune inflammatory diseases and related conditions. Background Art

[0006] Interleukin-23 (IL-23) cytokines have been considered to play a key role in the pathogenesis of autoimmune inflammation and related diseases and conditions such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis and inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the major role of IL-23R and downstream effector cytokines in the pathogenesis of the disease. IL-23R is expressed on various adaptive and innate immune cells, including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages and innate lymphoid cells found in large quantities in the intestine. At the intestinal mucosal surface, it was found that the gene expression and protein levels of IL-23R were elevated in IBD patients. It is believed that IL-23 promotes the production of pathogenic CD4 T cells that produce IL-6, IL-17 and tumor necrosis factor (TNF). + This effect is mediated by the development of T cell populations.

[0007] IL-23 production is abundant in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T cell-dependent and T cell-independent pathways of intestinal inflammation through its effects on T helper 1 (Th1) and Th17-related cytokines, and in limiting regulatory T cell responses in the intestine, thereby favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the key role of the IL-23 pathway in intestinal homeostasis.

[0008] 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 considered to be a key player in the pathogenesis of psoriasis, purportedly maintaining chronic autoimmune inflammation by inducing interleukin-17, regulating T memory cells, and activating macrophages. The expression of IL-23 and IL-23R has been shown to be increased in tissues of psoriasis patients, and antibodies that neutralize IL-23 have been shown to inhibit IL-23-dependent psoriasis progression in animal models of psoriasis.

[0009] IL-23 is a heterodimer composed of a unique p19 subunit and a p40 subunit shared with IL-12, a T helper 1 (T helper 1) molecule involved in the production of interferon-γ (IFN-γ). H 1) Cytokines for cell development. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic properties. For example, animals lacking IL-12 are susceptible to inflammatory autoimmune diseases, while animals lacking IL-23 are resistant, which may be due to the production of IL-6, IL-17, and TNF in the CNS of animals lacking IL-23. + The number of T cells decreases. IL-23 binds to IL-23R, a heterodimeric receptor composed of IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Sta t 5, but Stat4 activation is significantly weaker and forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. IL-23R constitutively associates with Jak2 and associates with Stat3 in a ligand-dependent manner. Unlike IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0010] Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway for the treatment of IL-23-related diseases and conditions. A variety of 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 and 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. 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. US2013 / 0029907). Clinical trials in Crohn's disease or psoriasis with briakinumab (which also targets the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) highlight the potential of IL-23 signaling blockade in treating human inflammatory diseases. While these findings are promising, challenges remain in successfully delivering such therapeutic agents to their targets. Effective delivery could improve the treatment of intestinal inflammation, such as intestinal diseases including Crohn's disease, ulcerative colitis, and related conditions.

[0011] Inhibitors of IL-23R are described as peptide #104 in PCT publications WO 2021 / 146441 and US 2021 / 0261622, the disclosures of which are incorporated herein by reference in their entireties.

[0012] Peptide compounds (such as those described in PCT Publications WO 2021 / 146441 and US2021 / 0261622) can be prepared using solid phase peptide synthesis (SPPS). In solid phase peptide synthesis, amino acids or peptides are typically bound to a solid support via the C-terminus. New amino acids are added to the bound amino acids or peptides via a coupling reaction. Although solid phase peptide synthesis technology has been widely used, its process is laborious and the reaction products usually need to be purified by chromatography, which is costly, slow, and difficult.

[0013] Therefore, there is a need for alternative methods for synthesizing the peptides described herein, particularly those that would improve the operability of the peptide inhibitors for use as pharmaceutical agents, such as improving their rheological (flow) properties, particle size, and hygroscopicity.

[0014] There remains a need in the art to develop methods for preparing peptide inhibitors of the interleukin-23 receptor (IL-23R) in a form suitable for large-scale commercial development, and to provide solid forms of the peptide inhibitors with characteristics that improve their operability 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

[0015] Provided herein are methods for preparing crystalline forms of peptide inhibitors of interleukin-23 receptor (IL-23R). Compared to similar amorphous forms, crystalline forms have advantageous properties such as ease of separation, processability, manipulability, improved purity, and greater physical and chemical stability. These attributes may be particularly important for pharmaceutical preparations where large-scale production, reproducibility, and compound purity are required. Crystalline forms of peptides may have unique advantages because the corresponding amorphous forms are generally not suitable for formulation, such as tableting.

[0016] In general, the present invention relates to methods for preparing monocyclic peptide compounds or their hydrochlorides, solvates or forms 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, as well as methods for preparing monocyclic peptide compounds having rheological properties suitable for manufacturing pharmaceutical compositions.

[0017] In particular, the present invention relates to a process for preparing a crystalline form of the peptide of SEQ ID NO: 1:

[0018] 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); or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has the structure of formula (I):

[0019]

[0020] In particular, the present invention provides a process for preparing a crystalline hydrochloride salt form of a compound of formula (I) having the following structure:

[0021]

[0022] or a solvate thereof.

[0023] The present invention also relates to a process for preparing a crystalline form of the peptide of SEQ ID NO: 2:

[0024] Ac-dArg-cyclo[Abu-Gln-Thr-Trp-Gln-Cys]-Phe(2-ae)-2-NaI-ThpGly-Glu-Asn-Asn-NH2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has the structure of a compound of formula (II):

[0025]

[0026] In another embodiment, the present invention provides a process for preparing a crystalline acetate salt form of a compound of formula (II) having the following structure:

[0027]

[0028] or a solvate thereof.

[0029] In another embodiment, the present invention relates to a process for preparing a crystalline form of the peptide of SEQ ID NO: 3:

[0030] Ac-[Pen]*-Asn-Thr-Trp(7Me)-Lys(Ac)-[Pen]*-Tyr(2-ea)-2Nal-αMe-Lys-Lys(Ac)-Asn-D-Leu-NH2 (wherein [Pen]*-[Pen]* forms a disulfide bond); or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has the structure of a compound of formula (III):

[0031]

[0032] The present invention also provides a process for preparing a crystalline hydrochloride salt form of a compound of formula (III) having the following structure:

[0033]

[0034] or a solvate thereof.

[0035] The present invention also provides a method for preparing a crystalline form of a peptide compound of any one of Formulas (I'), (IIa) to (IId), (IIIa) to (IIIf), (IVa) to (IVd) as described herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Pharmaceutically acceptable salts of the compounds of any one of Formulas (I'), (IIa) to (IId), (IIIa) to (IIIf), (IVa) to (IVd) provided herein include hydrochloride, dihydrochloride, acetate, fumarate, glutarate, glycolate, methanesulfonate, sulfate, and citrate.

[0036] The present invention also provides a method for preparing a crystalline form of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof. Pharmaceutically acceptable salts of the compound of formula (I) provided herein include hydrochloride, dihydrochloride, acetate, fumarate, glutarate, glycolate, methanesulfonate, sulfate and citrate.

[0037] Also provided herein is a crystalline form of the free base of a peptide of a compound of formula (I) prepared according to the process of the present invention, or a crystalline form of the free base of a peptide of any one of formulae (I'), (IIa) to (IId), (IIIa) to (IIIf), (IVa) to (IVd), or a solvate thereof of any of the foregoing.

[0038] Also provided herein is a crystalline form of the free base of a compound of formula (I) prepared according to the process of the present invention, or a crystalline form of the free base of any one of formulae (I'), (IIa) to (IId), (IIIa) to (IIIf), (IVa) to (IVd), or a solvate thereof of any one of the foregoing.

[0039] The present invention also provides a method for preparing a crystalline form of a peptide compound of any one of formula (II) or formula (III) as described herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Pharmaceutically acceptable salts of the compounds of any one of formula (II) or formula (III) provided herein may include hydrochloride, dihydrochloride, acetate, fumarate, glutarate, glycolate, methanesulfonate, sulfate, and citrate.

[0040] Also provided herein is a crystalline form of the free base of a compound of formula (I), or a crystalline form of the free base of any of formula (II) or formula (III), or a solvate thereof of any of the foregoing, prepared according to the process of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Shown is the X-ray powder diffraction (XRP D) pattern of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0042] Figure 2 Shown is the XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0043] Figure 3 Shown is the XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0044] Figure 4 Shown is a thermogravimetric analysis (TGA) chart of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0045] Figure 5Shown is a differential scanning calorimetry (DSC) chart of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0046] Figure 6 Shown is the dynamic vapor sorption (DVS) curve of the crystalline form of the hydrochloride salt of the compound of formula (I).

[0047] Figure 7 Shown is the XRPD pattern of the crystalline form of the acetate salt of the compound of formula (I).

[0048] Figure 8 Shown is a TGA chart of the crystalline form of the acetate salt of the compound of formula (I).

[0049] Figure 9 Shown is a DSC chart of the crystalline form of the acetate salt of the compound of formula (I).

[0050] Figure 10 Shown is the DVS curve of the crystalline form of the acetate salt of the compound of formula (I).

[0051] Figure 11 Shown is the XRPD pattern of the crystalline form of the free base of the compound of formula (I).

[0052] Figure 12 Shown is a TGA chart of the crystalline form of the free base of the compound of formula (I).

[0053] Figure 13 Shown is a DSC chart of the crystalline form of the free base of the compound of formula (I).

[0054] Figure 14 Shown is the DVS curve of the crystalline form of the free base of the compound of formula (I).

[0055] Figure 15 Shown is the XRPD pattern of the crystalline form of the fumarate salt of the compound of formula (I).

[0056] Figure 16 Shown is a TGA chart of the crystalline form of the fumarate salt of the compound of formula (I).

[0057] Figure 17 Shown is a DSC chart of the crystalline form of the fumarate salt of the compound of formula (I).

[0058] Figure 18 Shown is the XRPD pattern of the crystalline form of the glutarate salt of the compound of formula (I).

[0059] Figure 19 Shown is a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the glutarate salt of the compound of formula (I).

[0060] Figure 20 Shown is the DVS curve of the crystalline form of the glutarate salt of the compound of formula (I).

[0061] Figure 21 Shown is the XRPD pattern of the crystalline form of the glycolate salt of the compound of formula (I).

[0062] Figure 22 Shown is a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the glycolate salt of the compound of formula (I).

[0063] Figure 23 Shown is the DVS curve of the crystalline form of the glycolate salt of the compound of formula (I).

[0064] Figure 24 Shown is the XRPD pattern of the crystalline form of the mesylate salt of the compound of formula (I).

[0065] Figure 25 Shown is a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the mesylate salt of the compound of formula (I).

[0066] Figure 26 Shown is the XRPD pattern of the crystalline form of the sulfate salt of the compound of formula (I).

[0067] Figure 27 Shown is a simultaneous thermal analysis (SDT) thermogram of the crystalline form of the sulfate salt of the compound of formula (I).

[0068] Figure 28 Shown is the XRPD pattern of the crystalline form of the citrate salt of the compound of formula (I).

[0069] Figure 29 Shown is the XRPD pattern of the crystalline form of the dihydrochloride salt of the compound of formula (I).

[0070] Figure 30 Shown is a TGA chart of the crystalline form of the bis-hydrochloride salt of the compound of formula (I).

[0071] Figure 31 Shown is a DSC chart of the crystalline form of the dihydrochloride salt of the compound of formula (I).

[0072] Figure 32 Shown is the DVS curve of the crystalline form of the dihydrochloride salt of the compound of formula (I).

[0073] Figure 33 is a process flow diagram for preparing a crystalline form of the compound of formula (I).

[0074] Figure 34 Shown is a PLM diagram of the crystalline form of the hydrochloride salt of the compound of formula (II).

[0075] Figure 35 Shown is a PLM diagram of the crystalline form of the sulfate salt of the compound of formula (II).

[0076] Figure 36 Shown is a PLM diagram of the crystalline form of the acetate salt of the compound of formula (II).

[0077] Figure 37 Shown is a graph of PSD data comparing material isolated from SPPS, LPPS and material recovered following tableting of the crystalline form of the compound of formula (I).

[0078] Figure 38 Shown is a graph of PSD data comparing static dried material and dynamic dried material of the crystalline form of the compound of Formula (I).

[0079] Figure 39 Shown is a graph of PSD data comparing sieved material and unsieved material of the crystalline form of the compound of Formula (I).

[0080] Figure 40 Shown is a graph of PSD data comparing milled and sieved material of the crystalline form of the compound of Formula (I) with a control. DETAILED DESCRIPTION

[0081] I. Overview

[0082] The present invention relates to a method for preparing a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, which is a peptide inhibitor of the interleukin-23 receptor (IL-23R). The crystalline form of the monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, has rheological (flow) properties suitable for manufacturing a pharmaceutical composition. The present invention also relates to a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, prepared by the method of the present invention, which is a peptide inhibitor of IL-23R.

[0083] The present invention provides a method for preparing a crystalline form of a monocyclic peptide compound from a monocyclic peptide compound, such as those obtained via liquid phase peptide synthesis (LPPS). The method of the present invention provides a crystalline form of a peptide compound with improved manipulability, rheological properties and purity, suitable for large-scale commercial manufacturing without the need for chromatography. The monocyclic peptide compound can be a thixotropic material. The method of the present invention is capable of separating a crystalline form of a thixotropic monocyclic peptide compound.

[0084] Specifically, the present invention provides a method for preparing a crystalline form of the hydrochloride salt of a monocyclic peptide compound having the structure of formula (I) (SEQ ID NO: 1):

[0085]

[0086] The present invention also provides a method for preparing a crystalline form of a peptide compound having the structure of formula (II) (SEQ ID NO: 2):

[0087]

[0088] The present invention also provides a method for preparing a crystalline form of the hydrochloride salt of a peptide compound having the structure of formula (III) (SEQ ID NO: 3):

[0089]

[0090] The present invention also provides a method for preparing a crystalline form of the acetate salt of the peptide compound having the structure of formula (III).

[0091] II. Definitions

[0092] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art.

[0093] As used herein, the following terms have the meanings ascribed to them unless otherwise indicated.

[0094] "A" and "an" are indefinite articles and when used herein to refer to a group of substituents or a "substituent group" mean at least one.

[0095] When referring to a value, "about" includes the value of the value + / - 10%. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 molar equivalents to 22 molar equivalents. Therefore, when referring to a range, "about" refers to the value of each of the two ends of the range + / - 10%. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3. In some embodiments, a reference to about a value or parameter includes a description of the value or parameter itself. For example, a reference to about 20 molar equivalents includes and describes 20 molar equivalents itself.

[0096] As used in the specification and claims, as used herein, "comprising," "including," "having," "may," "containing" and variations thereof are intended to be open transitional phrases, terms or words that require the presence of the named 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 to X16, the peptide may also include, but is not limited to, additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, an N-terminal or C-terminal blocking group, a chemical or biological moiety (including but not limited to, for example, a lipophilic substituent, an antibody, an imaging agent, etc.) conjugated to the peptide at any position, etc. The terms "comprising," "including," "having," "may," or "containing" may include embodiments encompassed by the terms "consisting essentially of" or "consisting of."

[0097] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein and generally 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.).

[0098] Unless otherwise indicated, naturally occurring L- and D-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid names of Table A 1. In some embodiments, naturally occurring L-amino acids are represented by the conventional three-letter or uppercase single-letter amino acid names of Table 1. In some embodiments, D-amino acids are represented by lowercase single-letter amino acid names corresponding to the single-letter names of Table A 1 (i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t).

[0099] Table A1: Naturally occurring amino acids

[0100]

[0101] 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). An amino acid residue in the D isomeric form can replace any L-amino acid residue as long as the peptide retains the desired function. When referred to using single-letter abbreviations, D-amino acids can be indicated in lower case by convention. For example, D-arginine can be represented as "arg" or "r". Alternatively, a lower case "d" in front of an amino acid can be used to indicate that it is in the D isomeric form, for example, D-lysine can be represented by dK.

[0102] Less common or non-naturally occurring amino acids are represented by their full names (e.g., sarcosine, ornithine, etc.), or by the commonly employed 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-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid), or as defined below.

[0103] Some abbreviations that may be used to describe the present invention are defined below in Table 1 below.

[0104] Table 1. Abbreviations of unnatural amino acids and chemical moieties

[0105]

[0106]

[0107]

[0108] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when forming an intramolecular bridge with another amino acid side chain, for example, one or more hydrogens may be removed or replaced by a bond. Thus, as used herein, reference to an amino acid or modified amino acid present in a peptide dimer of the invention (e.g., at position X4 or position X9) is intended to include forms of such amino acids or modified amino acids present in the peptide both before and after formation of the intramolecular bond.

[0109] As used herein, the term "NH2" 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 carboxyl group present at the carboxyl terminus of a peptide. Additionally, as used herein, the term "Ac" or "Ac-" refers to acetyl protection by acylation of the C-terminus or N-terminus of a polypeptide. In certain peptides shown herein, the NH2 at the C-terminus of the peptide indicates an amino group.

[0110] As used herein, the term "carboxyl" refers to -CO2H.

[0111] As used herein, the term "cyclization" refers to the joining of one part of a polypeptide molecule to another part of a polypeptide molecule to form a closed ring, such as by forming a disulfide bond or a thioether bond to form a closed ring.

[0112] As used herein, the term "subunit" refers to one of a pair of polypeptide monomers that join to form a dimeric peptide composition.

[0113] As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a peptide or compound of the present invention that is water-soluble or oil-soluble or dispersible, suitable for treating a disease without excessive toxicity, irritation, and allergic response; commensurate with a reasonable benefit / risk ratio, and effective for its intended use. Salts can be prepared during the final isolation and purification of the compound or separately by reacting an 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, p-toluenesulfonate, and undecanoate. Likewise, amino groups in the compounds of the present invention may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and dipentyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that 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 in "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and latest editions thereof), in "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (ed.), Informa Health care USA (Inc.), NY, USA, 2007 and in J. Pharm. Sci. Vol. 66: p. 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).

[0114] The term "alkyl" includes straight or branched, acyclic or cyclic saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like, while saturated branched-chain alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

[0115] "Halo" or "halogen" refers to a bromo (Br), chloro (Cl), fluoro (F), or iodo (I) substituent.

[0116] The term "haloalkyl" includes alkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are all identical to one another. In other embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not all identical to one another.

[0117] An "alkoxy" group refers to an (alkyl)O- group where alkyl is as defined herein.

[0118] "Aminocarbonyl" or "carboxamido" refers to a -CONH2 group.

[0119] "2-Aminoethoxy" refers to the -OCH2CH2-NH2 group.

[0120] "2-Acetylaminoethoxy" refers to the group -OCH2CH2-N(H)C(O)Me.

[0121] The term "mammal" refers to any mammalian species, such as humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, livestock, and the like.

[0122] An "analog" of an amino acid, such as a "Phe analog" or a "Tyr analog" refers to an analog of the reference amino acid. A variety of amino acid analogs are known and available in the art, including Phe and Tyr analogs. In certain embodiments, an amino acid analog, such as a Phe analog or a Tyr analog, comprises 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 ), where R 2 is Hy, OH, CH3, CO2H, CONH2, CONH2OCH2CH2NH2, t-Bu, OCH2CH2NH2, phenoxy, OCH3, Oallyl, Br, Cl, F, NH2, N3 or guanidino. In certain embodiments, R2 is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3 or CO2H. Examples of Phe analogs include, but are not limited to, hPhe, Phe(4-OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH2), Phe(4-phenoxy), Phe(4-guanidino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5 ... F), Phe(CH2CO2H), Phe(5-F), Phe(3,4-Cl2), Phe(3,4-F2), Phe(4-CF3), ββ-diPheAla, Phe(4-N3), Phe[4-(2-aminoethoxy)], 4-phenylbenzylalanine, Phe(4-CONH2), Phe(3,4-dimethoxy), Phe(4-CF3), Phe(2,3-Cl2), and Phe(2,3-F2). Examples of Tyr analogs include, but are not limited to, hTr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3), and βhTyr.

[0123] Substituents are those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not undergo substantial alteration when subjected to conditions that allow the compound to be produced, detected, and preferably recovered, purified, and used 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 substantially change when kept at 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0124] "Absorption enhancer" refers to a component that improves or promotes mucosal absorption of a drug in the gastrointestinal tract, such as 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 drugs with poor bioavailability. PE can increase the intercellular and / or transcellular passage of a drug.

[0125] Pharmaceutical excipients that increase permeation have been termed "absorption-modifying excipients" (AMEs). AMEs can be used in oral compositions, for example, as wetting agents (sodium lauryl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., macrogol glycerides), and can be included in compositions, particularly as PEs, to improve bioavailability. PEs can be classified based on how they alter barrier integrity via paracellular or transcellular pathways.

[0126] "Intestinal permeation enhancer (IPE)" refers to a component that improves the bioavailability of a component. Suitable representative IPEs for use in the present invention include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroidal detergents, acylcarnitines and alkanoylcholines, N-acetylated α-amino acids and N-acetylated non-α-amino acids, as well as chitosan, other mucoadhesive polymers, and the like. For example, a suitable IPE for use in the present invention may be sodium caprate.

[0127] "Administering" refers to administering a composition of the present invention to a subject.

[0128] As used herein, "composition" or "pharmaceutical composition" is intended to encompass an invention or product comprising a specified active ingredient (API), which may comprise a pharmaceutically acceptable excipient, carrier or diluent as described herein, such as in a specific amount as defined herein, which invention or product results from the combination of specified components, such as specified ingredients in specified amounts as described herein.

[0129] "Granulated mixture" refers to a mixture of two or more agents prepared by mixing two or more agents and granulating them together into a granular form. This mixture provides a granular material composed of two or more agents. For example, in the present invention, these compositions may include, but are not limited to, a granulated mixture of a hydrochloride form of a peptide of SEQ ID NO: 1 or a solvate thereof and an absorption or penetration enhancer (such as sodium decanoate). Such granulated mixtures are made into microparticles or tablets containing a hydrochloride form of a compound of formula (I) or a solvate thereof and sodium decanoate. In some embodiments, the composition may comprise a granulated mixture containing sodium decanoate.

[0130] In one embodiment, provided herein is a pharmaceutical tablet comprising a pharmaceutical excipient and a crystalline form of a monocyclic peptide compound prepared by the method described herein.

[0131] "Disintegrant" refers to a pharmaceutical excipient that is incorporated into a composition to promote its disintegration when it comes into contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent used to prepare a tablet that causes the tablet to disintegrate and release the drug substance when in contact with moisture. Examples of disintegrants include, but are not limited to, cross-linked polymers, including cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked sodium carboxymethyl cellulose (croscarmellose sodium), and 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, cross-linked sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starches, clays, other algins, other celluloses, gums (such as gellan gum), low-substituted hydroxypropyl cellulose, or mixtures thereof. In some aspects, disintegrants for use in the present invention may include, but are not limited to, cross-linked sodium carboxymethyl cellulose. Additional representative disintegrants for use in the present invention may include, but are not limited to, microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum, combinations thereof, etc. Representative disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates and gums as well as cross-linked starches, celluloses and polymers, combinations thereof, etc.

[0132] "Disposed on" means placing one phase or coating on top of another phase or coating. Such placement can conform to the shape of the underlying phase or coating so that the layering of the phases and coatings does not leave a significant gap between them.

[0133] "Enteric coating" refers to any conventional polymer coating for delayed release of active ingredient. As conventionally understood in the art, enteric coating is typically a polymer barrier applied to oral medications that prevents them from dissolving or disintegrating in the gastric environment. This helps protect the drug from the acidity of the stomach, protects the stomach from the harmful effects of the drug, or releases the drug after the stomach (usually in the upper section of the intestine). Some drugs are unstable and need to be protected to avoid degradation at the pH of gastric acid. Enteric coating is also an effective method for obtaining drug targeting (such as gastric tolerance drugs). This delayed release is typically pH dependent, and allows active ingredient to be further released in the intestinal tract that is different from the stomach at pH. Generally speaking, suitable materials for enteric coating can include but are not limited to fatty acids, waxes, shellac, plastics and plant fibers, wherein such enteric materials can include but are not limited to cellulose acetate phthalate, polyvinyl alcohol phthalate, shellac, zein, hydroxypropyl methylcellulose phthalate, cellulose acetate trimaleate, film resins etc. Additional examples of enteric coatings for use in the present invention may include, but are not limited to, enteric coatings based on esters of eleugelic acid, cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), poly(vinyl acetate phthalate) (PVAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), and the like. Other suitable materials for enteric coatings may also include, but are not limited to, methacrylic acid copolymers, poly(ethyl methacrylate) 1:1, poly(methyl methacrylate) 1:2, poly(ethyl methacrylate) (L100D-55); methyl acrylate, methyl methacrylate, hydroxypropyl methylcellulose (HPMC), methacrylic acid (FS30D), A combination of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and HPMC-AS forms L, M, or H. In some embodiments, an enteric coating is provided over the subcoat.

[0134] "Glidant" refers to a substance added to a powder to improve its flowability and / or lubricity. Examples of glidants may include, but are not limited to, magnesium stearate, fumed silica, starch, talc, and the like.

[0135] "Silicon dioxide" refers to a pharmaceutical excipient that can be used as a leveling agent (anti-caking), adsorbent, and desiccant in solid product forms. It can also be used to improve the mechanical stability and disintegration rate of the composition. The silicon dioxide can be pyrolytic, that is, it refers to the production of fine particles of silicon dioxide by a pyrolysis process. The size of the particles of pyrolytic silicon dioxide can vary, such as 5 nm to 100 nm or 5 nm to 50 nm. These particles can be non-porous and have a diameter of 50 nm. 2 / g to 1,000m 2 / g or 50m 2 / g to 600m 2 / g surface area. Examples of silicon dioxide include those having a surface area of ​​about 200 m 2 / g specific surface area of ​​Aerosil 200. 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 silica, and the like.

[0136] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds used as lubricants may also have the properties of glidants. Examples of lubricants may include, but are not limited to, talc, silicon dioxide, and fats such as vegetable stearin, magnesium stearate, or stearic acid.

[0137] "Microcrystalline cellulose" or "MCC" refers to a pharmaceutical grade cellulose made from refined wood pulp. MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can act as a bulking agent and aid in tablet formation due to its favorable compressibility properties.

[0138] "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 administering a pharmaceutical composition as provided herein. Additional non-limiting examples can include but are not limited to humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other mammals. In some aspects, the patient is a human.

[0139] By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other components or ingredients of the composition of the present invention, i.e., it is useful, safe, and non-toxic for pharmaceutical use. According to the present invention, pharmaceutically acceptable means approved or approvable for use in animals, and more particularly in humans, as listed in the United States Pharmacopoeia or other generally recognized pharmacopeia.

[0140] A "half" hydrochloride salt refers to a salt having a substoichiometric amount of hydrochloride. For example, a half hydrochloride salt may have from about 0.1 molar equivalents to about 0.9 molar equivalents of hydrogen chloride associated with the peptide of SEQ ID NO: 1. Representative, non-limiting, half hydrochloride salts include, but are not limited to, 0.2 equivalents, 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, and 0.7 equivalents of HCl associated with the peptide of SEQ ID NO: 1. With respect to the present invention, the term "half" 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 acetate of the peptide of SEQ ID NO: 1, fumarate of the peptide of SEQ ID NO: 1, glutarate of the peptide of SEQ ID NO: 1, glycolate of the peptide of SEQ ID NO: 1, methanesulfonate of the peptide of SEQ ID NO: 1, dihydrochloride of the peptide of SEQ ID NO: 1, citrate of the peptide of SEQ ID NO: 1, or sulfate of the peptide of SEQ ID NO: 1.

[0141] "The free base of the compound of formula (I)" refers to the peptide of SEQ ID NO: 1 having the following structure:

[0142] In salt-free form.

[0143] "Free base of the compound of formula (II)" and "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 their free salt forms.

[0144] "Crystalline salt of a compound of formula (I)" refers to a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I), which may include, but is not limited to, a crystalline acetate salt of a compound of formula (I), a crystalline hydrochloride salt of a compound of formula (I), a crystalline fumarate salt of a compound of formula (I), a crystalline glutarate salt of a compound of formula (I), a crystalline glycolate salt of a compound of formula (I), a crystalline methanesulfonate salt of a compound of formula (I), a crystalline citrate salt of a compound of formula (I), a crystalline dihydrochloride salt of a compound of formula (I), or a crystalline sulfate salt of a compound of formula (I). "Crystalline salt" also refers to a crystalline form of a pharmaceutically acceptable salt of a compound of formula (II) or formula (III), which includes, but is not limited to, the salts described herein.

[0145] The compositions or pharmaceutical compositions of the present invention may be in different pharmaceutically acceptable forms, including but not limited to liquid compositions, tablets or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet may include but not limited to different layers. The tablet composition may also include but not limited to one or more coatings.

[0146] "Silicified microcrystalline cellulose" or "SMCC" refers to a particle agglomerate of co-processed microcrystalline cellulose and silicon dioxide. SMCC suitable for use in the present invention may include, but is not limited to, from about 0.1% to about 20% silicon dioxide by weight of the microcrystalline cellulose, wherein the silicon dioxide may have a particle size of from about 1 nanometer (nm) to about 100 micrometers (μm) based on the average primary particle size. For example, the silicon dioxide may contain from about 0.5% to about 10% silicified microcrystalline cellulose, or from about 1.25% to about 5% by weight relative to the microcrystalline cellulose. In addition, the silicon dioxide may have a particle size of from about 5 nm to about 40 μm or from about 5 nm to about 50 μm. The silicon dioxide may have a particle size of from about 10 nm to about 100 μm. 2 / g to about 500m 2 / g, or about 50m 2 / g to about 500m 2 / g or about 175m 2 / g to about 350m 2 Silicified microcrystalline cellulose is available from many suppliers known to those skilled in the art, including Penwest Pharmaceuticals, Inc., under the trademark PR Available in a variety of grades, including e.g. SMCC 50, SMCC 90 and HD. Other products include but are not limited to SMCC 50LD, SMCC HD90 and SMCC 90LM.

[0147] "Sodium decanoate" or "NaC10" refers to a substance with the molecular formula C 10 H 19 NaO2 and the IUPAC compound sodium decanoate of the following structural formula:

[0148]

[0149] In some embodiments, sodium caprate functions as an absorption enhancer or excipient in tablet formulations.Sodium caprate is approved by the European Union and the U.S. Food and Drug Administration (FDA) as a direct food additive for human consumption.

[0150] As used herein, "solvate" means a physical association of a 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 some cases, the solvate will be capable of being isolated. The term "solvate" is intended to encompass both solution-phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include hydrates.

[0151] "Sorbitol" refers to the sugar alcohol D-glucitol, and it can be used as a binder to promote adhesion of ingredients in tablet compositions.

[0152] As used herein, "sugar alcohol" refers to a compound derived from a sugar and containing one or more hydroxyl groups. Sugar alcohols can contain multiple -OH groups and are classified as polyols. Examples of sugar alcohols include, but are not limited to, sorbitol, mannitol, and xylitol.

[0153] "Subcoating" refers to any number of film layers disposed on a core tablet that provide one or more benefits, such as providing a smooth tablet surface for easier swallowing of the composition, providing pigmentation to aid tablet identification, providing a moisture barrier, and providing a high tensile strength outer layer for the tablet. Such subcoatings may include, but are not limited to, graft copolymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG). Commercial products that provide subcoatings include those marketed under the trade names of The bottom coating may be further covered by one or more additional coatings.

[0154] In some embodiments, a subcoat refers to any number of film layers disposed on a core tablet. Examples of suitable materials for decorative subcoats include polyvinyl alcohol polyethylene glycol (PVA-PEG) graft copolymers (e.g., Other coatings include, but are not limited to, HPMC, HPC, PVA, Eudragit E-based coatings, and the like.

[0155] In some embodiments, the subcoat may be further covered with one or more additional coatings, such as an enteric coating or a functional coating. In certain embodiments, the subcoat comprises one or more of a plasticizer, an anti-adherent, a colorant, HPMC, HPC, PVA, and a Eudragit E-based coating. In some embodiments, the subcoat is covered with one or more additional coatings. In certain embodiments, the one or more additional coatings on the subcoat are enteric coatings. In other embodiments, the one or more additional coatings on the subcoat are functional coatings.

[0156] In some aspects, the base coating is not covered by one or more additional coatings and is referred to as a decorative base coating. For example, in certain embodiments, the core tablet is covered with a decorative coating and the decorative coating is not further covered by an enteric coating or a functional coating. In some embodiments, the decorative coating can be used as a smooth surface to help swallow the tablet. In some embodiments, the decorative coating can provide a vehicle for pigmentation that is used for tablet identification. It can be used as a smooth surface to help swallow the tablet.

[0157] "Core tablet" refers to a mixture of components of a core tablet. In some embodiments, the components are one or more of a crystalline form of a peptide of SEQ ID NO: 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a suitable excipient. In some embodiments, suitable excipients 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 base coating, a decorative coating, an enteric coating, or any combination thereof may be provided on the core tablet.

[0158] "Therapeutically effective amount" refers to the amount of a compound (i.e., a peptide of SEQ ID NO: 1) or a pharmaceutical composition that can be used to treat or improve an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. "Therapeutically effective amount" further includes within its meaning a non-toxic but sufficient amount of the specific drug to which it refers to provide the desired therapeutic effect. The precise amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc. The precise amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, for example, 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, edited by Gennaro, Lippincott, Williams & Wilkins Publishers).

[0159] "Treatment" refers to any indicator of successful treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, such as elimination; remission; alleviation of symptoms or rendering the patient more tolerant to the injury, pathology, or condition; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improvement in the patient's physical or mental health. 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.

[0160] The abbreviation "(V / V)" refers to the phrase "volume to volume," i.e., the ratio of a particular substance within a mixture, as measured by the volume or volume amount of a component of a composition disclosed herein relative to the total volume of the composition. Thus, the quantity is smaller in units and represents the volume percent amount of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture may indicate that 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0161] The abbreviation "(w / w)" refers to the phrase "weight to weight," i.e., the ratio of a particular substance within a mixture, as measured by the weight or mass or weight amount of a component of a composition disclosed herein relative to the total weight of the composition. Thus, the amount is smaller in units and represents the weight percent 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.

[0162] Systemic administration routes, as conventionally understood in the medical or pharmaceutical arts, refer to or are defined as routes by which a drug, pharmaceutical composition or formulation, or other substance is administered into the circulatory system such that various body tissues and organs are exposed to the drug, formulation, or other substance. As conventionally understood in the art, administration can be performed orally (wherein the drug or oral formulation is taken orally and absorbed via the gastrointestinal tract), enterally (drug absorption also occurs via the gastrointestinal tract), or parenterally (usually by injection, infusion, or implant, etc.).

[0163] When referring to the present invention, "systemically active" peptide drug therapy generally refers to treatment by means of a pharmaceutical composition comprising a peptide active ingredient, wherein the peptide resists immediate metabolism and / or excretion, resulting in its exposure to various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous or immune systems.

[0164] Systemic drug activity in the present invention also refers to treatment with substances that travel through the bloodstream, 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.

[0165] "Bioavailability" refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation and thereby reaches the site of action. The bioavailability of a drug is affected by the properties of the dosage form, which depends in part on its design and manufacture.

[0166] As used herein, "digestive tract tissue" refers to all tissues that constitute the digestive tract. For example only, but not limited to, "digestive tract tissue" includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, and anus.

[0167] "Amorphous" refers to a solid material that has no long-range order in its molecular positions. "Partially amorphous" refers to a solid material that has little or no long-range order in its molecular positions. 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%.

[0168] 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 generally describes the particle size (based on a volume-weighted distribution), preferably the particle diameter in micrometers (μm), at which 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" generally relates to the diameter (e.g., in micrometers (μm)) of a hypothetical spherical particle, with the volume of the corresponding actual particle in the distribution (which may or may not be spherical).

[0169] As used herein, the term "Dv10" refers to the cutoff size (preferably in μm) of particles in the volume-weighted distribution, which account for 10% of the total volume of the sample and have a particle size equal to or less than the Dv10 value.

[0170] 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 generally describes the particle size (based on a volume-weighted distribution), preferably the particle diameter in micrometers (μm), at which 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" generally relates to the diameter (e.g., in micrometers (μm)) of a hypothetical spherical particle, with the volume of the corresponding actual particle in the distribution (which may or may not be spherical).

[0171] As used herein, the term "Dv90" refers to the cutoff size (preferably in μm) of particles in a volume-weighted distribution, accounting for 90% of the total volume of the sample and having a particle size equal to or less than the Dv90 value.

[0172] As used herein, "span," "particle size distribution span," or "span of a particle size distribution" refers to a parameter used to describe the general width of a particle size distribution as observed by laser diffraction. The span of a volume-based size distribution is defined as span = (Dv90 - Dv10) / Dv50, indicating the distance between the 10% and 90% points, normalized to the midpoint.

[0173] The Dv10, Dv50, Dv90 and particle size distribution span described herein can be measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer in combination with an Aero S dry dispersion unit for determining the particle size distribution.

[0174] III. Methods of Preparing Crystalline Forms

[0175] In general, the present invention relates to methods for preparing 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 suitable for preparing pharmaceutical compositions as defined herein, and are suitable for methods and / or uses for treating autoimmune inflammatory diseases and related conditions as defined herein.

[0176] According to the present invention, a monocyclic peptide compound having excellent rheological properties (flowability) useful for the manufacture of pharmaceutical compositions can be provided. According to the present invention, agglomeration that reduces the flowability of pharmaceutical formulations can be suppressed. Therefore, the crystalline form of the monocyclic peptide compound has excellent rheological properties (achieves flowability), making the crystalline form suitable for preparing pharmaceutical formulations.

[0177] In another aspect, the present invention provides a method for preparing 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, wherein the method comprises the following steps:

[0178] (a) dissolving the monocyclic peptide compound or a salt or solvate thereof in a first solvent;

[0179] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0180] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0181] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0182] (e) isolating the crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing the residual solvent.

[0183] 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, wherein the method comprises the following steps:

[0184] (a) dissolving the monocyclic peptide compound or a salt or solvate thereof in a first solvent;

[0185] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0186] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0187] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0188] (e) isolating the crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing the residual solvent.

[0189] In another aspect, the present invention provides a method for preparing a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the following structure:

[0190]

[0191] The method comprises the following steps:

[0192] (a) dissolving a monocyclic peptide compound comprising a hydrochloride salt of the monocyclic peptide compound in a first solvent, optionally wherein the crude monocyclic peptide compound has been obtained by liquid phase peptide synthesis;

[0193] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0194] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0195] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0196] (e) isolating the crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing the residual solvent.

[0197] In another aspect, the present invention provides a method for preparing 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, wherein the method comprises the following steps:

[0198] (a) dissolving the monocyclic peptide compound or a salt or solvate thereof in a first solvent;

[0199] (b') adding a second portion of the solvent to the mixture obtained in step (a);

[0200] (c) adding seed crystals of the crystalline monocyclic peptide compound to the mixture obtained in step (b') to obtain a slurry;

[0201] (d') adding a third portion of solvent to the mixture obtained in step (c);

[0202] (e) isolating the crystalline monocyclic peptide compound from the mixture obtained in step (d') and removing the residual solvent.

[0203] In another aspect, the present invention provides a method for preparing 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, wherein the method comprises the following steps:

[0204] (a) dissolving the monocyclic peptide compound or a salt or solvate thereof in a first solvent;

[0205] (h) diafiltration of the mixture obtained in step (a) through an ion exchange resin;

[0206] (e) isolating the crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (h) and removing the residual solvent.

[0207] Step (a)

[0208] In step (a), the monocyclic peptide compound or its salt or solvate is dissolved in a first solvent. In one embodiment, the monocyclic peptide compound or its salt or solvate dissolved in step (a) is an amorphous or partially amorphous form of the monocyclic peptide compound or its salt or solvate. In one embodiment, the monocyclic peptide compound or its salt or solvate dissolved in step (a) comprises the hydrochloride of the monocyclic peptide compound. In one embodiment, the monocyclic peptide compound or its salt or solvate dissolved in step (a) comprises an amorphous or partially amorphous form of the hydrochloride of the monocyclic peptide compound. In one embodiment, the hydrochloride of the monocyclic peptide compound comprises a crude product separated from the synthesis of the monocyclic peptide compound.

[0209] 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.

[0210] In some embodiments, step (a) is performed at a pH between 5.0 and 6.5. In some embodiments, step (a) is performed at a pH between 5.5 and 6.0.

[0211] In some embodiments, the first solvent in step (a) comprises an alkyl alcohol, such as a C1-C 12Alkyl alcohol.In some embodiments, the first solvent in step (a) comprises one or more solvents selected from methanol, ethanol, 1-propyl alcohol, 2-propyl alcohol, 1-butanol, 2-butanol, 2-methyl-1-propyl alcohol, 2-methyl-2-propyl alcohol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol and 1-heptanol and their combination.In some embodiments, the first solvent in step (a) comprises one or more solvents selected from methanol, ethanol, 2-propyl alcohol, 1-butanol, 2-butanol, 2-methyl-1-propyl alcohol, 2-methyl-2-propyl alcohol and their combination.In some embodiments, the first solvent in step (a) comprises methanol and water.

[0212] In some embodiments, the first solvent in step (a) comprises H2O. In some embodiments, the first solvent in step (a) comprises an alkyl alcohol, such as C1-C 12 In some embodiments, the 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.

[0213] 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 of 1:4 to 1:5.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] In some embodiments, the mixture obtained in step (a) is stirred until all of the hydrochloride salt of the monocyclic peptide compound is dissolved.

[0218] In some embodiments, the first solvent in step (a) comprises methanol and H2O in a volume ratio of 3:1 to 3:2.

[0219] In some embodiments, the mixture obtained in step (a) is filtered to provide a solution.

[0220] In some embodiments, step (a) includes 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) includes adjusting the pH of the solution to about 5.8. In some embodiments, step (a) includes adjusting the pH of the solution to about 5.5 to 6.1. In some embodiments, adjusting the pH can be performed before the filtration in step (a). In some embodiments, adjusting the pH can be performed after the filtration in step (a).

[0221] In one embodiment, the amount of the monocyclic peptide compound dissolved in step (a) is at least 10 Kg. In another embodiment, the amount of the 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, at least 15 Kg.

[0222] Step (b)

[0223] In step (b), a first portion of sodium chloride is added to the mixture obtained in step (a).

[0224] In some embodiments, in step (b), sodium chloride is a sodium chloride aqueous solution. In some embodiments, in step (b), sodium chloride is a 0.1M to 2M sodium chloride aqueous solution. In some embodiments, in step (b), sodium chloride is a 0.5M to 1.5M sodium chloride aqueous solution. In some embodiments, in step (b), sodium chloride is about 1M sodium chloride aqueous solution. In some embodiments, in step (b), sodium chloride is about 0.96M sodium chloride aqueous solution.

[0225] 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.

[0226] In some embodiments, in step (b), sodium chloride is added at a temperature between about 25° C. and about 55° C. In some embodiments, in step (b), sodium chloride is added at a temperature between about 35° C. and about 45° C. In some embodiments, in step (b), sodium chloride is added at a temperature of about 40° C.

[0227] In some embodiments, in step (b), based on the amount of the monocyclic peptide compound in step (a), 1.0 molar equivalents to 13.0 molar equivalents of NaCl are added. In some embodiments, in step (b), based on the amount of the monocyclic peptide compound in step (a), 5.0 molar equivalents to 12.0 molar equivalents of NaCl are added. In some embodiments, in step (b), based on the amount of the monocyclic peptide compound in step (a), 7.0 molar equivalents to 12.0 molar equivalents of NaCl are added. In some embodiments, in step (b), based on the amount of the monocyclic peptide compound in step (a), 10.0 molar equivalents to 12.0 molar equivalents of NaCl are added. In some embodiments, in step (b), based on the amount of the monocyclic peptide compound in step (a), 10.5 molar equivalents to 11.5 molar equivalents of NaCl are added. In some embodiments, in step (b), 1.0 to 13.0 molar equivalents of NaCl are added based on the amount of the 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 the monocyclic peptide compound in step (a). In some embodiments, in step (b), about 11.05 molar equivalents of NaCl are added based on the amount of the 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 the 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 the monocyclic peptide compound in step (a).

[0228] Step (c)

[0229] In step (c), seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound are added to the mixture obtained in step (b) to obtain a slurry.

[0230] In some embodiments, seed crystals of a crystalline monocyclic peptide compound are obtained by a method comprising the steps of:

[0231] (i) dissolving the monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof in a first solvent;

[0232] (ii) adding a second solvent to the mixture obtained in step (i);

[0233] (iii) cooling the mixture obtained in step (ii); and

[0234] (iv) isolating the crystalline monocyclic peptide compound or its salt or solvate from the mixture obtained in step (iii) and removing the residual solvent.

[0235] In some embodiments, the amount of seed crystals added is 0.005 molar equivalents to 0.1 molar equivalents based on the amount of the monocyclic peptide compound in step (a). In some embodiments, the amount of seed crystals added is 0.008 equivalents to 0.08 equivalents based on the amount of the monocyclic peptide compound in step (a). In some embodiments, the amount of seed crystals added is about 0.01 equivalents based on the amount of the monocyclic peptide compound in step (a).

[0236] In some embodiments, the slurry obtained in step (c) is aged for a period of at least 1 hour. In some embodiments, the slurry obtained in step (c) is aged for a period of at least 3 hours. In some embodiments, the slurry obtained in step (c) is aged for a period of at least 5 hours. In some embodiments, the slurry obtained in step (c) is aged for a period of about 8 hours.

[0237] 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.

[0238] In some embodiments, the seed crystals of the crystalline monocyclic peptide compound are free base crystals of the monocyclic peptide compound.

[0239] In some embodiments, the slurry obtained in step (c) is stirred for a period of at least 1 hour. In some embodiments, the slurry obtained in step (c) is stirred for a period of at least 3 hours. In some embodiments, the slurry obtained in step (c) is stirred for a period of at least 5 hours. In some embodiments, the slurry obtained in step (c) is stirred for a period of 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.

[0240] Step (d)

[0241] 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.

[0242] In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature between about 0° C. and about 10° C. In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature between about 3° C. and about 7° C. In some embodiments, in step (d), the slurry obtained in step (c) is cooled to a temperature of about 5° C.

[0243] In some embodiments, in step (d), the slurry is cooled to a temperature between about 0°C and 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 between about 0°C and 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 between about 0°C and 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 between about 3°C ​​and 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 between about 3°C ​​and about 7°C at a rate of about 0.1°C / min.

[0244] 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.

[0245] In some embodiments, in step (d), the sodium chloride is an aqueous sodium chloride solution.

[0246] In some embodiments, in step (d), sodium chloride is added at a temperature between about 25° C. and about 55° C. In some embodiments, in step (d), sodium chloride is added at a temperature between about 35° C. and about 45° C.

[0247] In some embodiments, in step (d), the sodium chloride is a 0.1M to 2M sodium chloride aqueous solution. In some embodiments, in step (d), the sodium chloride is a 0.5M to 1.5M sodium chloride aqueous solution. In some embodiments, in step (d), the sodium chloride is about a 1M sodium chloride aqueous solution.

[0248] In some embodiments, in step (d), at least 4.0 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), at least 6.0 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), at least 8.0 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), at least 7.6 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), at least 2.0 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), at least 3.0 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), about 2 to 4 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), about 3 to 4 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), about 3 to 3.5 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a). In some embodiments, in step (d), about 3.34 molar equivalents of NaCl are added based on the amount of the monocyclic peptide compound in step (a).

[0249] In some embodiments, in step (d), sodium chloride is added over a period of at least 30 minutes. In some embodiments, in step (d), sodium chloride is added over a period of at least 1 hour. In some embodiments, in step (d), sodium chloride is added over a period of at least 2 hours. In some embodiments, in step (d), sodium chloride is added over a period of about 4 hours.

[0250] In some embodiments, the slurry obtained in step (d) is aged for a period of at least 1 hour. In some embodiments, the slurry obtained in step (d) is aged for a period of at least 2 hours. In some embodiments, the slurry obtained in step (d) is aged for a period of at least 3 hours. In some embodiments, the slurry obtained in step (d) is aged for a period of about 5 hours.

[0251] Step (e)

[0252] In step (e), the crystalline monocyclic peptide compound is separated and the residual solvent is removed. In order to separate the crystalline material, it is important to remove the residual solvent. The residual solvent left on the separated crystalline peptide compound can cause the crystalline peptide to become thixotropic. The thixotropy of the peptide compound causes the crystalline particles to break, making the particles unsuitable for subsequent processing steps, such as tableting. Therefore, it is necessary to remove the residual solvent in step (d) to maintain the crystalline form of the particles and avoid the thixotropy of the particles. In some embodiments, removing the residual solvent includes one or more washing steps. In some embodiments, removing the residual solvent includes two washing steps. In some embodiments, removing the residual solvent includes washing the separated crystalline peptide compound and then vacuum drying.

[0253] In some embodiments, residual solvent is removed by washing with a second solvent. In some embodiments, step (e) comprises first washing the isolated crystallized peptide with a mixture of water and an alkyl alcohol, and then 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), and then washing with isopropanol. In some embodiments, step (e) comprises washing with a mixture of water and methanol (e.g., water / methanol: 65% / 35% v / v), washing with isopropanol, and then vacuum drying.

[0254] Some embodiments relate to a first washing step of washing the separated crystalline peptide with a mixture of water and an alkyl alcohol, which helps to remove residual NaCl. The amount of solvent used in the washing step needs to be sufficient to remove residual NaCl without causing a significant loss in yield. In some embodiments, the amount of the washing solvent is in the range of 1 L to 3 L water / alkyl alcohol per 1 mole of crystalline peptide compound. In some embodiments, the amount of the washing solvent is in the range of 1.5 L to 2 L water / alkyl alcohol per 1 mole of crystalline peptide compound. In some embodiments, the amount of the washing solvent is approximately 1.93 L water / alkyl alcohol per 1 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).

[0255] Some embodiments relate to a second washing step of removing a mixture of water and an alkyl alcohol (e.g., methanol) by washing with isopropyl alcohol so that the solvent used in the first washing step is replaced by isopropyl alcohol. It is necessary to use isopropyl alcohol for displacement washing to avoid thixotropy. The amount of the solvent used in the second washing step needs to be sufficient to remove residual water without causing a significant loss in yield. In some embodiments, the amount of the washing solvent is in the range of 1L to 3L of the second solvent per 1 mole of crystalline peptide compound. In some embodiments, the amount of the washing solvent is in the range of 1.5L to 2L of the second solvent per 1 mole of crystalline peptide compound. In some embodiments, the amount of the washing solvent is about 1.93L of isopropyl alcohol per 1 mole of crystalline peptide compound. In some embodiments, the second washing solvent is isopropyl alcohol.

[0256] In some embodiments, in step (e), the precipitate is isolated by filtration and then washed and dried.

[0257] 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-propyl alcohol (isopropyl alcohol, IPA). In some embodiments, in step (e), the second solvent consists essentially of 2-propyl alcohol (isopropyl alcohol).

[0258] In some embodiments, in step (e), the precipitate is washed with a second solvent at a ratio of 1.5 L / mole to 2.5 L / mole of the monocyclic peptide compound of step (a). In some embodiments, in step (e), the precipitate is washed with a second solvent at a ratio of about 2 L / mole of the monocyclic peptide compound of step (a).

[0259] In some embodiments, in step (e), the crystallized monocyclic peptide compound is isolated by filtration, then washed and dried. In some embodiments, in step (e), the crystallized monocyclic peptide compound is isolated by filtration, then washed and dried under vacuum at a temperature below about 20°C. In some embodiments, the crystallized peptide compound is dried at a temperature in the range of about 10°C to 50°C. In some embodiments, the crystallized peptide compound is dried at a temperature in the range of about 20°C to 40°C. In some embodiments, the crystallized peptide compound is dried under vacuum.

[0260] In another embodiment, the drying step is carried out 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 carried out at 50% RH to 70% RH (for example, about 65% RH).

[0261] In some embodiments, after the drying step, the amount of residual IPA in the crystallized peptide compound is less than 9000 ppm, 8000 ppm, 7000 ppm, 6000 ppm, 5000 ppm, or 4000 ppm. In some embodiments, after the drying step, the amount of residual IPA is less than 5000 ppm. In some embodiments, after the drying step, the amount of residual methanol in the crystallized peptide compound is less than 8000 ppm, 7000 ppm, 6000 ppm, 5000 ppm, 4000 ppm, 3000 ppm, or 2000 ppm. In some embodiments, after the drying step, the amount of residual methanol is less than 3000 ppm.

[0262] In some embodiments, after the drying step, the amount of water in the crystallized peptide compound is in the range of about 3% to 10%, 4% to 8%, or 4% to 6% by weight. In some embodiments, after the drying step, the amount of water in the crystallized peptide compound is in the range of about 4% to 6%. In some embodiments, the drying step comprises drying the crystallized peptide compound under vacuum at a relative humidity in the range of 50% to 70%, wherein the humidity is provided by a humidified nitrogen flow, and the drying is continued until the water content of the crystallized peptide compound is in the range of about 3% to 10% by weight.

[0263] In some embodiments, in step (e), the crystallized monocyclic peptide compound is isolated by filtration, then washed and dried at a relative humidity between about 45% and about 75%. In some embodiments, in step (e), the crystallized monocyclic peptide compound is isolated by filtration, then washed and dried at a relative humidity between about 50% and about 70%.

[0264] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) as a hydrochloride salt.

[0265] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) as an acetate salt.

[0266] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of a free base crystalline solid.

[0267] In some embodiments, the crystalline monocyclic peptide compound obtained in step (e) is dissolved in a solvent, which is removed by freeze-drying.

[0268] Step (b')

[0269] In step (b'), a second portion of solvent is added to the mixture obtained in step (a).

[0270] In some embodiments, the second solvent in step (b') comprises an alkyl alcohol, such as a C1-C 12 In some embodiments, the second solvent in step (b') comprises a solvent selected from 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 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.

[0271] In some embodiments, the second solvent in step (b') comprises H2O. In some embodiments, the second solvent in step (b') comprises an alkyl alcohol, such as C1-C 12 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 H2O. In some embodiments, the second solvent in step (b') comprises methanol and H2O.

[0272] In some embodiments, the second solvent in step (b') comprises methanol and H2O in a volume ratio of 9:1 to 5:5. In some embodiments, the second solvent in step (b') comprises methanol and H2O in a volume ratio of 8:2 to 13:7 or about 7:3.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] In some embodiments, the second portion of solvent is omitted.

[0277] 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 within 15 minutes to 60 minutes. In some embodiments, the process of cooling the mixture obtained in step (b') is completed within 45 minutes. In some embodiments, the process of cooling the mixture obtained in step (b') is completed within 20 minutes.

[0278] Step (d')

[0279] In step (d'), a third portion of solvent is added to the mixture obtained in step (c).

[0280] In some embodiments, the third solvent in step (d') comprises an alkyl alcohol, such as a C1-C 12 In some embodiments, the third solvent in step (d') comprises a solvent selected from 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 a combination thereof. In some embodiments, the third solvent in step (d') comprises a solvent selected from methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol and a combination thereof. In some embodiments, the third solvent in step (d') comprises methanol.

[0281] In some embodiments, the third solvent in step (d') comprises H2O. In some embodiments, the third solvent in step (d') comprises an alkyl alcohol, such as C1-C 12 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 H2O. In some embodiments, the third solvent in step (d') comprises methanol and H2O.

[0282] In some embodiments, the third solvent in step (d') comprises methanol and H2O in a volume ratio of 9:1 to 5:5. In some embodiments, the third solvent in step (d') comprises methanol and H2O in a volume ratio of 8:2 to 13:7 or about 7:3.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] In some embodiments, the third portion of solvent is omitted.

[0287] In some embodiments, the third portion of solvent is added over the course of 1 hour to 5 hours. In some embodiments, the third portion of solvent is added over the course of 3 hours. In some embodiments, the third portion of solvent is added over the course of 1 hour to 5 hours.

[0288] In some embodiments, the mixture obtained in step (d') is cooled to -10°C to 10°C.

[0289] In some embodiments, the mixture obtained in step (d') is cooled to -10°C to 10°C, and the mixture is stirred for 6 hours to 18 hours.

[0290] 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.

[0291] 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.

[0292] Step (h)

[0293] 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.

[0294] In some embodiments, the ion exchange resin is washed with a wash solvent. In some embodiments, the wash solvent in step (h) comprises H2O. In some embodiments, the wash solvent in step (h) comprises an alkyl alcohol, such as C1-C 12 In some embodiments, the wash 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 wash solvent in step (h) comprises methanol and HO.

[0295] Starting materials

[0296] 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 liquid 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 liquid phase peptide synthesis.

[0297] The method of the present invention provides a method for improving the rheological properties of single-cyclic peptide compounds obtained by liquid phase peptide synthesis.

[0298] Therefore, in another aspect, the present invention provides a method for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of:

[0299] (a) dissolving the 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;

[0300] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0301] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0302] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0303] (e) isolating the crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture and removing the residual solvent.

[0304] Method for obtaining crystalline free base

[0305] In another aspect, the present invention provides a method for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0306] (a) dissolving the hydrochloride salt of the monocyclic peptide compound in a first solvent;

[0307] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0308] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0309] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0310] (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (e) and washing it with a second solvent;

[0311] (f) dissolving the hydrochloride obtained in step (e) in aqueous hydrochloric acid;

[0312] (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; and

[0313] (h) isolating the crystalline monocyclic peptide compound in free base form from the mixture.

[0314] In some embodiments, in step (f), the amount of hydrochloric acid added is 1 to 2 molar equivalents. In some embodiments, in step (f), the amount of hydrochloric acid added is 1.3 to 1.7 molar equivalents. In some embodiments, in step (f), the amount of hydrochloric acid added is about 1.5 molar equivalents.

[0315] In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH between pH 7.0 and pH 9.0. In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH between pH 7.5 and pH 8.5. In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of about 8.

[0316] Method for preparing alternative salts

[0317] In another aspect, the present invention provides a method for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of:

[0318] (a) dissolving the monocyclic peptide compound or a salt or solvate thereof in a first solvent;

[0319] (b) adding a first portion of sodium chloride to the mixture obtained in step (a);

[0320] (c) adding seed crystals of the crystalline hydrochloride salt of the monocyclic peptide compound to the mixture obtained in step (b) to obtain a slurry;

[0321] (d) adding a second portion of sodium chloride to the slurry obtained in step (c);

[0322] (e) isolating the crystalline monocyclic peptide compound in the form of a hydrochloride salt from the mixture obtained in step (d) and removing the residual solvent;

[0323] (f) dissolving the hydrochloride obtained in step (e) in aqueous hydrochloric acid;

[0324] (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; and

[0325] (h) isolating the crystalline monocyclic peptide compound in free base form from the mixture;

[0326] (i) dissolving the crystalline free base of the monocyclic peptide compound in a second solvent;

[0327] (j) adding a solution comprising a counterion to the mixture obtained in step (a);

[0328] (k) adding an antisolvent;

[0329] (1) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained in step (k).

[0330] In some embodiments, the second solvent in step (j) comprises methanol and / or water.

[0331] In some embodiments, the anti-solvent is an organic solvent. In some embodiments, the anti-solvent is selected from alkyl alcohols such as C1-C 12 Solvents of alkyl alcohols, alkyl ethers such as diethyl ether, alkanes such as heptane and hexane, ethyl acetate, toluene, and acetonitrile. In some embodiments, the antisolvent is selected from tert-butyl methyl ether (TBME), acetonitrile, and isopropyl alcohol (2-propanol).

[0332] In some embodiments, the solution comprising a counterion is a solution comprising a counterion selected from the group consisting of fumarate, glutarate, glycolate, methanesulfonate, sulfate, and citrate.

[0333] Method for obtaining seed crystals

[0334] The present invention also provides a method for preparing seed crystals of a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt thereof.

[0335] Therefore, in another aspect, the present invention provides a method for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0336] (i) dissolving the monocyclic peptide compound or a pharmaceutically acceptable salt thereof in a first solvent;

[0337] (ii) adding a second solvent to the mixture obtained in step (i);

[0338] (iii) cooling the mixture obtained in step (ii); and

[0339] (iv) isolating the crystalline monocyclic peptide compound or its salt from the mixture obtained in step (iii) and removing the residual solvent.

[0340] Step (i)

[0341] In some embodiments, step (i) is performed at a temperature of about 15° C. to about 80° C. In some embodiments, step (i) is performed at a temperature of about 25° C. to about 55° C. In some embodiments, step (i) is performed at a temperature of about 30° C. to about 50° C., or about 35° C. to about 45° C. In some embodiments, step (i) is performed at a temperature of about 40° C.

[0342] In some embodiments, the first solvent comprises an alkyl alcohol, such as a C1-C 12 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.

[0343] In some embodiments, the first solvent comprises H2O. In some embodiments, the first solvent comprises an alkyl alcohol, such as a C1-C 12 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 H2O. In some embodiments, the first solvent comprises methanol and H2O.

[0344] In some embodiments, the first solvent comprises methanol and H 2 O in a volume ratio of 9: 1 to 5: 5. In some embodiments, the first solvent comprises methanol and H 2 O in a volume ratio of 8:2 to 13:7 or about 7:3.

[0345] 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.

[0346] Step (ii)

[0347] 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.

[0348] 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.

[0349] In some embodiments, the second solvent comprises H 2 O. In some embodiments, the second solvent consists essentially of H 2 O.

[0350] Step (iii)

[0351] Optionally, the mixture obtained in step (ii) is cooled prior to step (iv).

[0352] In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature between about 0° C. and about 10° C. In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature between about 3° C. and about 7° C. In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature of about 5° C.

[0353] In some embodiments, in step (iii), the mixture obtained in step (ii) is cooled to a temperature between about 0° C. and 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 between about 0° C. and 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.

[0354] In some embodiments, before step (iii) and after adding the second solvent, the temperature of the mixture is maintained for a period of at least 1 hour. In some embodiments, before step (iii) and after adding the second solvent, the temperature of the mixture is maintained for a period of at least 4 hours. In some embodiments, before step (iii) and after adding the second solvent, the temperature of the mixture is maintained for a period of at least 7 hours. In some embodiments, before step (iii) and after adding the second solvent, the temperature of the mixture is maintained for a period of about 9 hours.

[0355] In some embodiments, after step (iii), the temperature is maintained for a period of at least 30 minutes. In some embodiments, after step (iii), the temperature is maintained for a period of at least 60 minutes. In some embodiments, after step (iii), the temperature is maintained for a period of at least 90 minutes. In some embodiments, after step (iii), the temperature is maintained for a period of about 2 hours.

[0356] 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 between about 0° C. and 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 between about 3° C. and about 7° C.

[0357] 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.

[0358] Step (iv)

[0359] 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 (isopropanol). In some embodiments, in step (iv), the third solvent consists essentially of 2-propanol (isopropanol).

[0360] 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 below about 20°C.

[0361] In some embodiments, the monocyclic peptide compound isolated in step (iv) is in the form of a hydrochloride salt.

[0362] Grinding / Sieving

[0363] In one embodiment, in order to obtain a crystalline form of a monocyclic peptide compound in the form of particles with a particle size and / or particle size distribution as described herein, those skilled in the art can use methods such as grinding or screening. For example, after the separation step, the monocyclic peptide compound can be processed with a screening step. The subsequent screening step can remove the finest and largest particles, which may impair the appropriate rheological properties for pharmaceutical processing. In one embodiment, the separated crystalline monocyclic peptide is passed through a suitable sieve. In some embodiments, the size of the sieve is about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 8 mm, or 10 mm. In some embodiments, the size of the sieve is about 2 mm. In some embodiments, the size of the sieve is about 4 mm.

[0364] Drying step

[0365] In one embodiment, in order to obtain the crystalline form of the monocyclic peptide compound, those skilled in the art can dry the separated crystalline monocyclic peptide.For example, the drying step can remove residual solvent from the crystallization process, such as removing isopropyl alcohol.The drying step can be carried out at, for example, about 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.In another embodiment, the drying step is carried out at about 20 ℃ to 45 ℃.In another embodiment, the drying step is carried out 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 carried out at 50% RH to 70% RH (for example, about 65% RH).In some embodiments, nitrogen is used as a carrier gas to provide humidity.

[0366] The drying step can, for example, comprise static drying or dynamic drying. The static drying step is performed with little or no stirring during the drying process. The dynamic drying step comprises stirring the crystallized monocyclic peptide compound during the drying step. The dynamic drying step can also comprise heating, exposure to vacuum, or exposure to nitrogen.

[0367] Rheological properties (fluidity)

[0368] Using the method of the present invention, the rheological properties of single-cyclic peptide compounds can be improved, particularly those obtained using liquid phase peptide synthesis.

[0369] Thus, the present invention provides a process for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt thereof having rheological properties suitable for the manufacture of a pharmaceutical composition.

[0370] For suitability for pharmaceutical processing, factors such as: absolute size and shape of the particles; uniformity of particle size; uniformity of mixing; flowability (flow); moisture content; and ability to compact under pressure are important.

[0371] Rheological properties are those used to characterize the flowability of a material. In particular, rheological properties suitable for preparing pharmaceutical compositions can be selected from adjusted bulk density, compressibility, basic flow energy, stability index, cohesion, 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.

[0372] IV. Peptide Inhibitors of Interleukin-23 Receptor (IL-23R)

[0373] The monocyclic peptide compounds of the present invention are peptide inhibitors of the interleukin-23 receptor. The 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 these peptides and compounds. Exemplary peptides of the present invention include the amino acid sequences or structures described in any of the accompanying tables.

[0374] In the first aspect, a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof comprises an amino acid sequence of formula (I'):

[0375] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16(I')

[0376] in

[0377] X3 does not exist or is any amino acid;

[0378] X4 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

[0379] X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln or Asp;

[0380] X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val;

[0381] X7 is substituted or unsubstituted Trp;

[0382] X8 is Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), D ab(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;

[0383] X9 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

[0384] X10 is Tyr or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 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;

[0385] X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys or Aib;

[0386] X13 is any amino acid;

[0387] X14 is any amino acid;

[0388] as well as

[0389] 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;

[0390] X16 does not exist or is any amino acid;

[0391] 2Pal is a 2-pyridyl-substituted alanine, 3Pal is a 3-pyridyl-substituted alanine, and 4Pal is a 4-pyridyl-substituted alanine.

[0392] and 5Pyal or (5-Pyal) is a 5-pyrimidine-substituted alanine:

[0393] and

[0394] wherein X4 and X9 form a disulfide bond or a thioether bond.

[0395] In certain embodiments, the peptide compound inhibits the binding of interleukin 23 (IL 23) and the IL 23 receptor.

[0396] 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.

[0397] In certain embodiments, X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy.

[0398] 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.

[0399] In certain embodiments, X11 is 2-Nal or 1-Nal.

[0400] In certain embodiments, X11 is 2-Nal or 2-Nal substituted with alkyl or hydroxy.

[0401] In certain embodiments, X11 is 2-Nal.

[0402] 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.

[0403] 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 is Sarc.

[0404] In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is absent.

[0405] In certain embodiments, X16 is any D-amino acid.

[0406] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IIa), (IIb), (IIc), or (IId):

[0407] X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16(IIa),

[0408] X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIb) or

[0409] X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIc) or

[0410] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IId)

[0411] wherein Trp is unsubstituted Trp, or Trp substituted by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0412] wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;

[0413] wherein 2-Nal is unsubstituted 2-Nal;

[0414] Wherein Pal is 2Pal, 3Pal or 4Pal;

[0415] 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.

[0416] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IIa), (IIb), (IIc), or (IId):

[0417] X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16(IIa),

[0418] X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIb) or

[0419] X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIc) or

[0420] X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IId)

[0421] wherein Trp is unsubstituted Trp, or Trp substituted by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0422] wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;

[0423] wherein 2-Nal is unsubstituted 2-Nal;

[0424] Wherein Pal is 2Pal, 3Pal or 4Pal;

[0425] 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.

[0426] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf):

[0427] X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16(IIIa),

[0428] X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16(IIIb),

[0429] X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16(IIIc),

[0430] X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16(IIId),

[0431] X4-X5-X6-X7-X8-X9-[Phe]-X10-X11-X12-X13-X14-[Pal]-X16(IIIe) or

[0432] X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16(IIIf);

[0433] wherein Trp is unsubstituted Trp, or Trp substituted by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0434] wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;

[0435] wherein 2-Nal is unsubstituted 2-Nal;

[0436] Wherein Pal is 2Pal, 3Pal or 4Pal;

[0437] 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.

[0438] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IVa), (IVb), (IVc), (IVd), or (IVe):

[0439] X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16(IVa)、

[0440] X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16(IVb),

[0441] X4-X5-X6-X7-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16(IVc)、

[0442] X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16(IVd); or

[0443] 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;

[0444] wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy;

[0445] wherein 2-Nal is unsubstituted 2-Nal;

[0446] Wherein Pal is 2Pal, 3Pal or 4Pal;

[0447] 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.

[0448] 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.

[0449] In certain embodiments, X4 is (D)Pen, Pen, or Pen(sulfoxide).

[0450] In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-Me Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp.

[0451] In certain embodiments, X4 or X9 are independently Cys, (D)Cys, α-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond.

[0452] In certain embodiments, X5 is Asn, Ser, Gln, or Glu.

[0453] In certain embodiments, X5 is Asn.

[0454] In certain embodiments, X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer, or Val.

[0455] In certain embodiments, X6 is Thr.

[0456] In certain embodiments, X8 is Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, α-MeGln, α-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).

[0457] In certain embodiments, X8 is Gln, α-Me-Lys, α-MeLys(Ac), Lys(Ac), Lys(Ac), or Glu.

[0458] In certain embodiments, X8 is Gln. In certain embodiments, X8 is Lys(Ac).

[0459] In certain embodiments, X9 is Pen, (D)Pen, Cys, (D)Cys, or α-MeCys. In certain embodiments, X9 is Pen or (D)Pen.

[0460] In certain embodiments, X4 is Pen and 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.

[0461] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetamidoethoxy)] or Phe(4-CONH2).

[0462] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf), and (IVa) to (IVe), X10 is Phe[4-(2-aminoethoxy)] or Phe[4-(2-acetamidoethoxy)]. In certain embodiments, X10 is Phe[4-(2-aminoethoxy)].

[0463] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeLys, α-MeLeu, Ala, cyclohexylAla, Lys, or Aib.

[0464] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), α-MeL ys, or α-MeLeu.

[0465] In certain embodiments, X12 is α-MeLeu. In certain embodiments, X12 is TH P.

[0466] In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLeu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, PEGylated Lys, b-homoGlu, or Lys(Y2-Ac); wherein Y2 is an amino acid. In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), α-MeArg, α-MeGlu, α-MeLys, α-Me-Asn, α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or b-homoGlu.

[0467] In certain embodiments, X13 is Glu, Gln, Lys(Ac) or Lys.

[0468] In certain embodiments, X13 is Lys(Ac) or Lys.

[0469] In certain embodiments, X13 is Lys(Ac).In certain embodiments, X13 is Glu.

[0470] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is unsubstituted Trp.

[0471] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf), and (IVa) to (IVe), X7 is Trp substituted with N-phenylacetamide, cyano, halo, alkyl, haloalkyl, hydroxyl, or alkoxy; and X11 is as described for Formula (I).

[0472] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X7 is Trp substituted with N-phenylacetamide, cyano, halo, alkyl, haloalkyl, hydroxy or alkoxy; and the substitution is at the 4-, 5-, 6- or 7-position.

[0473] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X7 is Trp substituted with N-phenylacetamide, cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxyl, OMe or OEt; and the substitution is at the 4-, 5-, 6- or 7-position.

[0474] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X7 is Trp substituted with 7-(N-phenylacetamide), 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.

[0475] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf), and (IVa) to (IVe), X7 is Trp substituted with 7-(N-phenylacetamide), 7-Me, 5-F, 7-F, 6-Cl, 6-Me, 4-OMe, 5-OMe, or 5-Br.

[0476] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamide), 7-Me, 6-Me, 4-OMe, or 6-Cl.

[0477] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-(N-phenylacetamide), 7-Me.

[0478] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with phenyl, substituted phenyl, or thienyl.

[0479] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, substituted phenyl, or thienyl.

[0480] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X is Trp substituted with: i) phenyl, which is unsubstituted or substituted with cyano, halo, alkyl, haloalkyl, aromatic hydroxy, alkoxy or haloalkoxy; or ii) thienyl.

[0481] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X7 is Trp substituted with a phenyl group, which phenyl group is unsubstituted or substituted with Me, Et, n-Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl, or amido.

[0482] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Me.

[0483] In certain embodiments, particularly with respect to Formulas (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Ph.

[0484] In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X16 is absent. In certain embodiments, particularly with respect to Formulas (IIa) to (IId), (IIIa) to (IIIf) and (IVa) to (IVe), X16 is Sarc.

[0485] In a specific embodiment, in particular with respect to formulae (IIa) to (IId), (IIIa) to (IIIf) and (IV a) to (IVe), X3 is absent.

[0486] 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),

[0487] wherein the peptide compound is cyclized via a Pen-Pen disulfide bond; or a pharmaceutically acceptable salt thereof.

[0488] 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)

[0489]

[0490] or a pharmaceutically acceptable salt thereof.

[0491] 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-NH2; (SEQ ID NO: 2):

[0492]

[0493] or a pharmaceutically acceptable salt thereof.

[0494] 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 (wherein [Pen]*-[Pen]* forms a disulfide bond); (SEQ ID NO: 3):

[0495]

[0496] or a pharmaceutically acceptable salt thereof.

[0497] V. Crystalline Form

[0498] Provided herein are crystalline forms of peptide inhibitors of the interleukin-23 receptor (IL-23R). Unexpectedly, a crystalline form of a compound of formula (I) was obtained and isolated. A crystalline form of a pharmaceutically acceptable salt of the compound of formula (I) was prepared, isolated, and found to be suitable for pharmaceutical formulations. Thus, crystalline forms of peptides may have unique advantages because the corresponding amorphous forms are generally not suitable for formulation, such as tableting.

[0499] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of formula (I):

[0500] or

[0501] Its pharmaceutically acceptable salt, or the aforementioned solvate.

[0502] In another aspect, the present invention relates to the crystalline free base form of the compound of formula (I).

[0503] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO: 1.

[0504] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (I).

[0505] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the peptide of SEQ ID NO: 1.

[0506] 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, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline methanesulfonate, crystalline sulfate, crystalline dihydrochloride, and crystalline citrate of the peptide of SEQ ID NO: 1.

[0507] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the compound of formula (I).

[0508] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a compound of formula (I). The crystalline form of a pharmaceutically acceptable salt of a compound of formula (I) can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline methanesulfonate, crystalline sulfate, crystalline dihydrochloride, and crystalline citrate of the compound of formula (I).

[0509] In some aspects, the crystalline hydrochloride salt form of the compound of Formula (I) has the following structure:

[0510] or

[0511] its solvates.

[0512] In other aspects, the crystalline hydrochloride salt form of the compound of formula (I) is characterized by being substantially as Figure 1 In some aspects, the crystalline hydrochloride salt form or a solvate thereof is a hemi-hydrochloride salt. In some embodiments, the crystalline hydrochloride salt form of the compound of Formula (I) is characterized by being substantially as Figure 1 or Figure 2 The XRPD pattern described in .

[0513] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline hydrochloride salt or a solvate thereof as described herein and one or more pharmaceutically acceptable excipients.

[0514] In other aspects, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline salt described herein or a solvate thereof and one or more pharmaceutically acceptable excipients.

[0515] Free base form

[0516] In some embodiments, the compound of formula (I) is the 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 is in the form of a solvate.

[0517] In some embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.2 degrees 2θ. In some embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.3 degrees 2θ. In some embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.4 degrees 2θ.

[0518] In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0519] In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ.

[0520] In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0521] In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In certain embodiments, the crystalline free base of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In certain embodiments, the crystalline free base salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline free base salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. Figure 11 The XRPD pattern described in .

[0522] In some embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof is characterized by having endothermic peaks 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 substantially Figure 13 The DSC curve is shown.

[0523] 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 substantially Figure 12 In some embodiments, the crystalline dihydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having substantially Figure 14DVS diagram shown.

[0524] In some aspects, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline free base of a compound of Formula (I) as described herein, or a solvate thereof, and one or more pharmaceutically acceptable excipients.

[0525] Salt ratio

[0526] 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 a cationic form of the compound of formula (I) and a pharmaceutically acceptable anion. For example, the crystalline hydrochloride of the compound of formula (I) comprises a compound of formula (I) in its cationic form and a chloride anion. The salt compositions described herein comprise salts of the compound of formula (I), wherein the salt is a pharmaceutically acceptable salt selected from acetate, fumarate, glycolate, glutarate, methanesulfonate, sulfate, citrate, dihydrochloride, etc.

[0527] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride and the anion is a chloride ion. In some embodiments, the salt of the compound of formula (I) is an acetate and the anion is acetate. In some embodiments, the salt of the compound of formula (I) is a fumarate and the anion is fumarate. In some embodiments, the salt of the compound of formula (I) is a glutarate and the anion is glutarate. In some embodiments, the salt of the compound of formula (I) is a glycolate and the anion is glycolate. In some embodiments, the salt of the compound of formula (I) is a methanesulfonate and the anion is methanesulfonate. In some embodiments, the salt of the compound of formula (I) is a sulfate and the anion is sulfate. In some embodiments, the salt of the compound of formula (I) is a citrate and the anion is citrate. In some embodiments, the salt of the compound of formula (I) is a dihydrochloride and the anion is a chloride ion.

[0528] In some embodiments, the molar equivalents of the anion of the crystalline salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from 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) relative to one mole of the compound of formula (I) are 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 amounts therebetween and fractions thereof.

[0529] In some embodiments, the molar equivalents of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.4 to about 1.5. In other embodiments, the molar equivalents of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.6 to about 0.7.

[0530] In some embodiments, the molar equivalents of the acetate anion of the crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the acetate anion of the crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.4 to about 1.5. In other embodiments, the molar equivalents of the acetate anion of the crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of the acetate anion of the crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.6 to about 0.7. In certain embodiments, the molar equivalents of the acetate anion of the crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are about 0.65.

[0531] In some embodiments, the molar equivalents of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.4 to about 1.5. In other embodiments, the molar equivalents of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.5 to about 1.0. In other embodiments, the molar equivalents of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.0 to about 1.5. In other embodiments, the molar equivalents of the fumarate anion of the crystalline fumarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 2.0.

[0532] In some embodiments, the molar equivalents of the glutarate anion of the crystalline glutarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the glutarate anion of the crystalline glutarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 1.0. In other embodiments, the molar equivalents of the glutarate anion of the crystalline glutarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of the glutarate anion of the crystalline glutarate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are about 0.5.

[0533] In some embodiments, the molar equivalents of the glycolate anion of the crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the glycolate anion of the crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.2 to about 1.0. In other embodiments, the molar equivalents of the glycolate anion of the crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of the glycolate anion of the crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) are about 0.5.

[0534] In some embodiments, the molar equivalents of the mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.0 to about 2.0. In other embodiments, the molar equivalents of the mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 2.0. In other embodiments, the molar equivalents of the mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.8 to about 1.9. In certain embodiments, the molar equivalents of the mesylate anion of the crystalline mesylate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are about 1.8.

[0535] In some embodiments, the molar equivalents of the sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.0 to about 2.0. In other embodiments, the molar equivalents of the sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 2.0. In other embodiments, the molar equivalents of the sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 1.7. In certain embodiments, the molar equivalents of the sulfate anion of the crystalline sulfate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are about 1.6.

[0536] In some embodiments, the molar equivalents of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.4 to about 1.5. In other embodiments, the molar equivalents of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.5 to about 1.0. In other embodiments, the molar equivalents of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.0 to about 1.5. In other embodiments, the molar equivalents of the citrate anion of the crystalline citrate salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 2.0.

[0537] In some embodiments, the molar equivalents of the chloride anion of the crystalline dihydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 0.2 to about 2.0. In some embodiments, the molar equivalents of the chloride anion of the crystalline dihydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.0 to about 2.0. In other embodiments, the molar equivalents of the chloride anion of the crystalline dihydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.5 to about 2.0. In certain embodiments, the molar equivalents of the chloride anion of the crystalline hydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are from about 1.9 to about 2.0. In certain embodiments, the molar equivalents of the chloride anion of the crystalline dihydrochloride salt of the compound of formula (I) relative to one mole of the compound of formula (I) are about 2.0.

[0538] Salt form

[0539] hydrochloride

[0540] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride. In some embodiments, the hydrochloride of the compound of formula (I) is crystalline. In some embodiments, the hydrochloride of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride of the compound of formula (I) is a hydrate. In some other embodiments, the hydrochloride of the compound of formula (I) is crystalline and is in the form of a solvate.

[0541] 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% to 20%, 2% to 15%, 3% to 10%, 4% to 8%, 4% to 6%, or about 5%.

[0542] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride. In some embodiments, the hydrochloride of the compound of formula (I) is crystalline. In some embodiments, the hydrochloride of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride of the compound of formula (I) is a hydrate. In some other embodiments, the hydrochloride of the compound of formula (I) is crystalline and is in the form of a solvate.

[0543] 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0544] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7 or 17.1 + / - 0.2 degrees 2θ. 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 having two or more diffraction peaks at 2θ angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8 or 17.1 + / - 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ.

[0545] In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0546] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at 2θ 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 2θ. ... Figure 1 In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by being substantially as Figure 2 The XRPD pattern described in .

[0547] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0548] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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, Figure 3 The XRPD pattern described in .

[0549] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by being substantially as Figure 1 、 Figure 2 or Figure 3 The XRPD pattern described in .

[0550] 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 substantially Figure 5 The DSC curve described in .

[0551] 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 weight loss of about 5.6% from about 26.5° C. to about 160.0° C. as determined by thermogravimetric analysis (TGA). Figure 4 In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having substantially Figure 6 DVS diagram shown.

[0552] In some aspects, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline hydrochloride salt of a compound of Formula (I) as described herein, or a solvate thereof, and one or more pharmaceutically acceptable excipients.

[0553] Acetate

[0554] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is an acetate. In some embodiments, the acetate of the compound of formula (I) is crystalline. In some embodiments, the acetate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the acetate of the compound of formula (I) is a hydrate. In some other embodiments, the acetate of the compound of formula (I) is crystalline and is in the form of a solvate.

[0555] 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 two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. 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 two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. 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 two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0556] 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 two or more diffraction peaks at 2θ 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 2θ. 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 two or more diffraction peaks at 2θ 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 2θ. 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 two or more diffraction peaks at angles 2θ 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 2θ.

[0557] 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 a diffraction peak at 2θ 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 2θ. 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 a diffraction peak at 2θ 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 2θ. 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 a diffraction peak at angles 2Θ 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 2Θ.

[0558] 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 angles 2θ 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 2θ. 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 angles 2θ 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 2θ. 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 angles 2θ 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 2θ.

[0559] In some embodiments, the crystalline acetate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO: 1, or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline acetate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ.

[0560] In some embodiments, the crystalline acetate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline acetate salt of the peptide of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least two diffraction peaks at angles 2θ 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 2θ. 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 angles 2θ 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 2θ.

[0561] In some embodiments, the crystalline acetate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline acetate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO: 1, or a solvate thereof, is characterized by having an XRPD pattern having at least three diffraction peaks at angles 2θ 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 2θ.

[0562] 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 diffraction peaks at angles 2θ 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 2θ. 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 diffraction peaks at angles 2θ 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 2θ. 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 diffraction peaks at angles 2Θ 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 2Θ.

[0563] In some embodiments, the crystalline acetate salt of the peptide of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. 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 diffraction peaks at angles 2Θ 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 2Θ. 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 diffraction peaks at angles 2θ 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 2θ. 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 diffraction peaks at angles 2θ 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, Figure 7 The XRPD pattern described in .

[0564] 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 substantially Figure 9 The DSC curve described in .

[0565] 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 weight loss of about 5.8% from about 26.5°C to about 150.0°C as determined by TGA. Figure 8 In some embodiments, the crystalline acetate salt of the compound of formula (I) or a solvate thereof is characterized by having substantially Figure 10 DVS diagram shown.

[0566] 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) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0567] Fumarate

[0568] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a fumarate. In some embodiments, the fumarate of the compound of formula (I) is crystalline. In some embodiments, the fumarate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the fumarate of the compound of formula (I) is a hydrate. In some other embodiments, the fumarate of the compound of formula (I) is crystalline and is in the form of a solvate.

[0569] 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0570] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0571] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at angles 2θ 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 2θ.

[0572] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0573] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. ... Figure 15 The XRPD pattern described in .

[0574] 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 substantially 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 weight loss of about 4.4% from about 26.5°C to about 110.0°C as determined by TGA. Figure 16 TGA chart as described in .

[0575] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline fumarate salt of a compound of formula (I) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0576] Glutarate

[0577] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a glutarate. In some embodiments, the glutarate of the compound of formula (I) is crystalline. In some embodiments, the glutarate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the glutarate of the compound of formula (I) is a hydrate. In some other embodiments, the glutarate of the compound of formula (I) is crystalline and in the form of a solvate.

[0578] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0579] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0580] In some embodiments, the crystalline glutarate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at an angle 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at an angle 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at angles 2Θ 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 2Θ.

[0581] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0582] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In some embodiments, the crystalline glutarate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. ... Figure 18 The XRPD pattern described in .

[0583] 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 substantially 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 weight loss of about 6.4% from about 26.5°C to about 125.0°C as determined by SDT. Figure 20 DVS diagram shown.

[0584] 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) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0585] Glycolate salt of the peptide of SEQ ID NO: 1

[0586] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a glycolate. In some embodiments, the glycolate of the compound of formula (I) is crystalline. In some embodiments, the glycolate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the glycolate of the compound of formula (I) is a hydrate. In some other embodiments, the glycolate of the compound of formula (I) is crystalline and in the form of a solvate.

[0587] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0588] In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0589] In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at an angle 2θ 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 2θ. In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at an angle 2θ 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 2θ. In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at angles 2Θ 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 2Θ.

[0590] In some embodiments, the crystalline glycolate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glycolate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glycolate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0591] In some embodiments, the crystalline glycolate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline glycolate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In some embodiments, the crystalline glycolic acid salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. ... Figure 21 The XRPD pattern described in .

[0592] In some embodiments, the crystalline glycolate salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 237.0° 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 substantially Figure 22 SDT thermogram as described in .

[0593] 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 a weight loss of about 5.1% from about 26.5°C to about 100.0°C as determined by SDT. Figure 22 In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or a solvate thereof is characterized by having substantially Figure 23 DVS diagram shown.

[0594] In some aspects, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline glycolate salt of a compound of Formula (I) as described herein, or a solvate thereof, and one or more pharmaceutically acceptable excipients.

[0595] Sulfate salt of the peptide of SEQ ID NO: 1

[0596] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a sulfate. In some embodiments, the sulfate of the compound of formula (I) is crystalline. In some embodiments, the sulfate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the sulfate of the compound of formula (I) is a hydrate. In some other embodiments, the sulfate of the compound of formula (I) is crystalline and in the form of a solvate.

[0597] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0598] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2θ.

[0599] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0600] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. ... Figure 26 The XRPD pattern described in .

[0601] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having an endothermic peak at about 255.0° C. as determined by SDT. In certain embodiments, the crystalline sulfate salt of the compound of formula (I) or a solvate thereof is characterized by having substantially Figure 27 SDT thermogram as described in .

[0602] In some embodiments, the crystalline sulfate 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 80.0°C as determined by SDT. In certain embodiments, the crystalline sulfate 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 80.0°C as determined by SDT. Figure 27 SDT thermogram as described in .

[0603] 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) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0604] Methanesulfonate of the peptide of SEQ ID NO: 1

[0605] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a mesylate. In some embodiments, the mesylate of the compound of formula (I) is crystalline. In some embodiments, the mesylate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the mesylate of the compound of formula (I) is a hydrate. In some other embodiments, the mesylate of the compound of formula (I) is crystalline and is in the form of a solvate.

[0606] 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0607] In some embodiments, the crystalline methanesulfonate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees 2θ. In some embodiments, the crystalline methanesulfonate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees 2θ. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2θ.

[0608] In some embodiments, the crystalline methanesulfonate 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 2θ 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 2θ + / - 0.2 degrees 2θ. In some embodiments, the crystalline methanesulfonate 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 2θ 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 2θ + / - 0.3 degrees 2θ. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having at least two diffraction peaks at angles 2θ 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 2θ + / - 0.4 degrees 2θ.

[0609] In some embodiments, the crystalline methanesulfonate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ + / - 0.2 degrees 2θ. In some embodiments, the crystalline methanesulfonate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ + / - 0.3 degrees 2θ. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ + / - 0.4 degrees 2θ. ... Figure 24 The XRPD pattern described in .

[0610] 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 substantially Figure 25 In some embodiments, the crystalline methanesulfonate 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 methanesulfonate 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. Figure 25 SDT thermogram as described in .

[0611] 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) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0612] Citrate salt of the peptide of SEQ ID NO: 1

[0613] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a citrate. In some embodiments, the citrate of the compound of formula (I) is crystalline. In some embodiments, the citrate of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the citrate of the compound of formula (I) is a hydrate. In some other embodiments, the citrate of the compound of formula (I) is crystalline and is in the form of a solvate.

[0614] 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0615] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees 2θ.

[0616] In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least two diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least two diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having at least two diffraction peaks at angles 2Θ 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 2Θ.

[0617] In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2Θ 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 2Θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline citrate salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at 2θ 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, Figure 28 The XRPD pattern described in .

[0618] 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) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0619] Dihydrochloride of the peptide of SEQ ID NO: 1

[0620] In some embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a dihydrochloride salt. In some embodiments, the dihydrochloride salt of the compound of formula (I) is crystalline. In some embodiments, the dihydrochloride salt of the compound of formula (I) is in the form of a solvate. In certain embodiments, the solvate of the dihydrochloride salt of the compound of formula (I) is a hydrate. In some other embodiments, the dihydrochloride salt of the compound of formula (I) is crystalline and is in the form of a solvate.

[0621] In some embodiments, the crystalline dihydrochloride 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees 2θ. In some embodiments, the crystalline dihydrochloride 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees 2θ. In some embodiments, the crystalline dihydrochloride 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 2θ angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees 2θ.

[0622] In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having two or more diffraction peaks at angles 2θ 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 2θ.

[0623] In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having a diffraction peak at 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having a diffraction peak at angles 2Θ 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 2Θ.

[0624] In some embodiments, the crystalline dihydrochloride 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 angles 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride 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 angles 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride 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 angles 2θ 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 2θ.

[0625] In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I), or a solvate thereof, is characterized by having an XRPD pattern having diffraction peaks at angles 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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 2θ. In some embodiments, the crystalline dihydrochloride salt of the compound of Formula (I) or a solvate thereof is characterized by having an XRPD pattern having diffraction peaks at 2θ 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, Figure 29 The XRPD pattern described in .

[0626] In some embodiments, the crystalline dihydrochloride 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 dihydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having substantially Figure 31 The DSC curve described in .

[0627] In some embodiments, the crystalline dihydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 11.3% from about 26.5°C to about 190.0°C as determined by TGA. In certain embodiments, the crystalline dihydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having a weight loss of about 11.3% from about 26.5°C to about 190.0°C as determined by TGA. Figure 30 TGA chart as described in .

[0628] In some embodiments, the crystalline dihydrochloride salt of the compound of formula (I) or a solvate thereof is characterized by having substantially Figure 32DVS diagram shown.

[0629] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline dihydrochloride salt of a compound of formula (I) as described herein, or a solvate thereof, and a pharmaceutically acceptable excipient.

[0630] purity

[0631] In some embodiments, the crystalline salt of the compound of formula (I) or its solvate prepared 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-high performance liquid chromatography (UPLC), high performance liquid chromatography (HPLC), or other appropriate methods. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of between about 90% and 100%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9%, including any amount and fractions therebetween. In other embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level between about 95.0% and 99.9%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of at least 95%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate has a purity level of at least 96%. In some embodiments, the crystalline salt of the compound of formula (I) or its solvate 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%.

[0632] In some embodiments, the crystalline hydrochloride of the compound of formula (I) or its solvate has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9%, including any amount and fraction therebetween. In other embodiments, the crystalline hydrochloride of the compound of formula (I) or its solvate has a purity level between about 99.0% and 99.5%. In certain embodiments, the crystalline hydrochloride of the compound of formula (I) or its solvate has a purity level of at least 99.0%.

[0633] 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 fractions 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 between about 99.0% and 99.5%.

[0634] In some embodiments, the crystalline fumarate of the compound of formula (I) or its solvate has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97% or about 98% or about 99%, including any amount and fraction therebetween. In other embodiments, the crystalline fumarate of the compound of formula (I) or its solvate has a purity level between about 86% to 90%. In other embodiments, the crystalline fumarate of the compound of formula (I) or its solvate has a purity level between about 86% to 87%. In certain embodiments, the crystalline fumarate of the compound of formula (I) or its solvate has a purity level of at least 86%.

[0635] 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 fractions therebetween. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of between about 85% and 90%. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of between about 90% and 95%. In some embodiments, the crystalline glutarate salt of the compound of formula (I) or a solvate thereof has a purity level of between about 95% and 99%. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or a solvate thereof has a purity level of between about 99.0% and 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%.

[0636] In some embodiments, the crystalline methanesulfonate of the compound of formula (I) or its solvate has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97% or about 98% or about 99%, including any amount and fraction therebetween. In other embodiments, the crystalline methanesulfonate of the compound of formula (I) or its solvate has a purity level between about 90% to 95%. In other embodiments, the crystalline methanesulfonate of the compound of formula (I) or its solvate has a purity level between about 95% to 99%. In other embodiments, the crystalline methanesulfonate of the compound of formula (I) or its solvate has a purity level between about 90% to 92%. In certain embodiments, the crystalline methanesulfonate of the compound of formula (I) or its solvate has a purity level of at least 90%.

[0637] In some embodiments, the crystalline sulfate salt of the compound of formula (I) or its solvate has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97% or about 98% or about 99%, including any amount and fractions therebetween. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or its solvate has a purity level between about 90% and 95%. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or its solvate has a purity level between about 95% and 99%. In other embodiments, the crystalline sulfate salt of the compound of formula (I) or its solvate has a purity level between about 90% and 92%. In certain embodiments, the crystalline sulfate salt of the compound of formula (I) or its solvate has a purity level of at least 91%.

[0638] In some embodiments, the crystalline citrate salt of the compound of formula (I) or its solvate has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9%, including any amount and fractions therebetween. In other embodiments, the crystalline citrate salt of the compound of formula (I) or its solvate has a purity level between about 99.0% and 99.9%. In certain embodiments, the crystalline citrate salt of the compound of formula (I) or its solvate has a purity level of at least 99.5%.

[0639] In some embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.3%, including any amount and fractions therebetween. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 97.0%. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 98.0%. In certain embodiments, the crystalline free base of the compound of formula (I) or its solvate has a purity level of at least 99.0%. In other embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of between about 97.0% and 98.0%. In other embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of about 98.0%. In other embodiments, the crystalline free base of the compound of formula (I) or a solvate thereof has a purity level of about 99.0%.

[0640] The crystalline form of formula (II)

[0641] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of formula (II):

[0642] or

[0643] Its pharmaceutically acceptable salt, or the aforementioned solvate.

[0644] In another aspect, the present invention relates to a crystalline free base form of the compound of formula (II).

[0645] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO: 2.

[0646] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (II).

[0647] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the peptide of SEQ ID NO: 2.

[0648] 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: 2. The crystalline form of the pharmaceutically acceptable salt of the peptide of SEQ ID NO: 2 can be a crystalline hydrochloride, crystalline acetate, crystalline fumarate, crystalline glycolate, crystalline glutarate, crystalline methanesulfonate, crystalline sulfate, crystalline dihydrochloride, and crystalline citrate of the peptide of SEQ ID NO: 2.

[0649] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the compound of formula (II).

[0650] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a 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 methanesulfonate, crystalline sulfate, crystalline dihydrochloride and crystalline citrate of the compound of formula (II).

[0651] In some aspects, the crystalline hydrochloride salt form of the compound of Formula (II) has the following structure:

[0652] or

[0653] its solvates.

[0654] The crystalline form of formula (III)

[0655] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of formula (III):

[0656] or a pharmaceutically acceptable salt or solvate thereof.

[0657] In another aspect, the present invention relates to a crystalline free base form of the compound of formula (III).

[0658] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the peptide of SEQ ID NO: 3.

[0659] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of the compound of formula (III).

[0660] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the peptide of SEQ ID NO: 3.

[0661] 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 methanesulfonate, crystalline sulfate, crystalline dihydrochloride, and crystalline citrate of the peptide of SEQ ID NO: 3.

[0662] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of the compound of formula (III).

[0663] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a 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 methanesulfonate, crystalline sulfate, crystalline dihydrochloride and crystalline citrate of the compound of formula (III).

[0664] In some aspects, the crystalline hydrochloride salt form of the compound of formula (III) has the following structure:

[0665] or a solvate thereof.

[0666] VI. Particle Size of Crystalline Forms

[0667] In one embodiment, the method for crystallizing a compound of formula (I) provided herein provides a crystalline material characterized in that laser diffraction (LD) has an average particle size distribution (PSD) range of about 1 μm to 100 μm. In another embodiment, the characterized crystalline material has an average particle size distribution range of about 1 μm to 90 μm. In another embodiment, the crystalline material has a particle size distribution range of about 2 μm to 80 μm. In another embodiment, the crystalline material has a particle size distribution range of about 3 μm to 70 μm.

[0668] In an embodiment, the PSD of the crystalline compound of Formula (I) is characterized as having a Dv10 in the range of about 1 μm to 30 μm. In another embodiment, the PSD is characterized as having a Dv10 in the range of about 2 μm to 20 μm. In another embodiment, the PSD is characterized as having a Dv10 in the range of about 3 μm to 10 μm.

[0669] In one embodiment, the PSD of the crystallized 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 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 μm to 50 μm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 μm to 30 μm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 μm to 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.

[0670] In one embodiment, the PSD of the crystalline compound of Formula (I) is characterized as having a Dv90 in the range of 10 μm to 110 μm. In another embodiment, the PSD is characterized as having a Dv90 in the range of 20 μm to 100 μm. In yet another embodiment, the PSD is characterized as having a Dv90 in the range of 30 μm to 90 μm.

[0671] In certain embodiments, the crystalline compound of Formula (I) has PSD values ​​of: 4 μm to 6 μm (Dv10); 14 μm to 19 μm (Dv50); and 34 μm to 60 μm (Dv90).

[0672] In certain embodiments, the crystalline compound of Formula (I) has PSD values ​​of: 4.5 μm to 5.4 μm (Dv10); 14 μm to 19 μm (Dv50); and 34 μm to 60 μm (Dv90).

[0673] 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 crystallized compound of Formula (I) are as follows: about 9 μm (Dv10); about 26 μm (Dv50); and about 61 μm (Dv90). In another embodiment, the PSD values ​​of the crystallized compound of Formula (I) are as follows: about 3 μm (Dv10); about 11 μm (Dv50); and about 34 μm (Dv90).

[0674] In one embodiment, the methods provided herein for crystallizing a compound of formula (I) provide a crystalline material characterized by a particle size distribution (PSD) span of 1 to 3 by laser diffraction (LD). In certain embodiments, the span is from 1.5 to 3.5. In a certain embodiment, the crystalline hydrochloride salt of the compound of formula (I) has a PSD span of about 2.2. In some embodiments, the span of the particle size distribution is less than 5, 4, or 3. In some embodiments, the span of the particle size distribution is less than 3. In some embodiments, the span of the particle size distribution is less than 4. In some embodiments, the span of the particle size distribution is less than 5.

[0675] In one embodiment, the methods provided herein for crystallizing a compound of formula (I) provide a crystalline material characterized by a particle size distribution (PSD) span of 1.99 to 2.90 by laser diffraction (LD). In certain embodiments, the span is 1.99 to 2.47. In a certain embodiment, the crystalline hydrochloride salt of the compound of formula (I) has a PSD span of about 2.21.

[0676] In one embodiment, the above-mentioned PSD values ​​and ranges are measured for the crystalline hydrochloride salt of the compound of formula (I).

[0677] VII. Synthesis Methods

[0678] Compounds of formula (I') or pharmaceutically acceptable salts or solvates thereof can be prepared using solid phase peptide synthesis or by convergent liquid phase synthesis. For example, cyclic peptide molecules can be prepared in liquid phase by coupling a cyclic moiety with a linear moiety in a liquid reaction medium.

[0679] However, further processing is required to provide solid forms of the peptide inhibitors having characteristics that provide improved handleability, such as improving rheological (flow) properties, particle size, and hygroscopicity of the peptide inhibitors for use as pharmaceutical ingredients.

[0680] VIII. Pharmaceutical Compositions

[0681] In general, the present invention relates to pharmaceutical hydrochloride forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for the treatment of autoimmune inflammatory diseases and related disorders as defined herein.

[0682] 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.

[0683] In one aspect, the present invention relates to a pharmaceutical composition of the hydrochloride salt of a compound of formula (I):

[0684] Ac-[Pen]*-NT-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2 (wherein [Pen]*-[Pen]* forms a disulfide bond); and has the chemical structure shown below:

[0685] or

[0686] its corresponding solvates.

[0687] In some embodiments, the monocyclic peptide comprises the amino acid sequence of 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.

[0688] In some embodiments, the crystalline form of the compound of formula (I) or a solvate thereof has a water content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight. In some embodiments, the crystalline form of 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.

[0689] In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition ranges from about 0.1% to about 65%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition ranges from about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of Formula (I) or a solvate thereof in the composition is in the range of about 2% to about 65%, about 2% to about 60%, about 2% to about 55%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, or about 2% to about 5% by weight. In some embodiments, the amount of the crystalline form of the compound of formula (I) or a solvate thereof in the composition is in the range of about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10%. In some embodiments, the amount of the crystalline form of the compound of formula (I) or a solvate thereof in the composition is in the range of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% by weight.

[0690] In another aspect, the hydrochloride of the compound of formula (I) or its corresponding solvate can exist in any form (such as hydrate or other solvates). In some respects, the hydrochloride of the compound of formula (I) or its solvate can provide in crystalline form, amorphous form or semi-crystalline form. In some respects, the hydrochloride of the compound of formula (I) or its solvate is crystalline form. In some respects, the hydrochloride of the compound of formula (I) or its solvate is amorphous form. In some respects, the hydrochloride of the compound of formula (I) or its solvate is semi-crystalline form.

[0691] In one aspect, the hydrochloride of the compound of formula (I) or the composition of its solvate is hemihydrochloride.In some respects, hemihydrochloride has about 0.1 molar equivalent to about 0.9 molar equivalent compared with the compound of formula (I), such as about 0.2 molar equivalent to about 0.8 molar equivalent or about 0.3 molar equivalent to about 0.7 molar equivalent hydrogen chloride.In some respects, hemihydrochloride has about 0.1 molar equivalent, 0.2 molar equivalent, 0.3 molar equivalent, 0.4 molar equivalent, 0.5 molar equivalent, 0.6 molar equivalent, 0.7 molar equivalent, 0.8 molar equivalent or about 0.9 molar equivalent hydrogen chloride compared with the compound of formula (I).In some respects, hemihydrochloride has about 0.5 molar equivalent hydrogen chloride compared with the compound of formula (I).

[0692] In some respects, the hydrochloride form of the compound of formula (I) or its solvate can be a hydrate. In some respects, the hydrate of the hydrochloride of the compound of formula (I) has about 0.2 molar equivalents to about 100 molar equivalents of water compared with the compound of formula (I). In another aspect, the scope of hydrate can exist with about 2%w / w to about 10%w / w water compared with the hydrochloride of the compound of formula (I). The present invention relates to the hydrochloride composition of the present invention that can be liquid or solid composition.

[0693] In some embodiments, the hydrochloride salt form of the compound of formula (I) or a solvate thereof has a water content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight. In some embodiments, the 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.

[0694] The hydrochloride compositions of the present invention can be administered to a subject or patient by any means according to the therapeutic administration that achieves the intended purpose or pharmaceutical efficacy. Examples include administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, oral or ocular routes. In some aspects, the administration of the hydrochloride compositions of the present invention is suitable for oral administration.

[0695] In another aspect, the present invention provides a composition comprising: a hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, and one or more pharmaceutically acceptable excipients.

[0696] In another aspect, the present invention provides a composition comprising: a hydrochloride salt of a compound of formula (I) or a solvate thereof; and an approximately 50 mM phosphate buffer solution at pH 7.4.

[0697] In another aspect, the present invention is directed to a composition comprising: a hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 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.

[0698] 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%, about 0.1% to about 60%, about 0.1% to about 55%, about 0.1% to about 50%, about 0.1% to about 45%, about 0.1% to about 40%, about 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% to about 5% by weight. In some embodiments, 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%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% by weight. In some embodiments, the amount of the 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%, about 2% to about 60%, about 2% to about 55%, about 2% to about 50%, about 2% to about 45%, about 2% to about 40%, about 2% to about 35%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, or about 2% to about 5% by weight. In some embodiments, the amount of the 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%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10%. 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.

[0699] In another aspect, the present invention provides a composition comprising: a hydrochloride salt of a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 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.

[0700] In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist with any amount of about 0.1% to about 15% (w / w) of composition.For example, the hydrochloride of the compound of formula (I) or its solvate can exist with the amount of about 0.5% to about 15% (w / w) of composition 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).In another aspect, the hydrochloride of the compound of formula (I) or its solvate exists with the amount of about 1% to about 5% (w / w).

[0701] In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist with the amount of approximately 1% to approximately 5% (w / w).For example, the hydrochloride of the compound of formula (I) or its solvate can include about 1% of composition, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or about 15% (w / w) and the amount of any fraction therebetween to exist.In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist with the amount of approximately 1.8% (w / w).

[0702] In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in any amount, such as the amount of about 1mg to about 1000mg or about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 50mg, about 20mg to about 40mg or about 20mg to about 30mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can be about 1mg to about 1000mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can be about 5mg to about 300mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can be about 25mg to about 150mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can be about 25mg to about 100mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in the amount of about 1mg to about 100mg. In another aspect, the hydrochloride salt of the compound of formula (I) or a solvate thereof can be present in an amount of about 20 mg to about 40 mg. In another aspect, the hydrochloride salt of the compound of formula (I) or a solvate thereof can be present in an amount of about 20 mg to about 30 mg.

[0703] In yet another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 5mg, about 10mg, about 25mg, about 50mg, about 75mg, about 100mg or about 150mg, including any amount and fraction therebetween. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 5mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 10mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 25mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 50mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 75mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 100mg. In another aspect, the hydrochloride of the compound of formula (I) or its solvate can exist in an amount of about 150mg.

[0704] In another aspect, the amount of the crystalline form of the 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 amounts therebetween and fractions thereof.

[0705] Generally speaking, the pharmaceutical compositions of the present invention can be prepared into different dosage forms, which are prepared using conventional materials and techniques known in the art of medicine and formulation, which may include, but are not limited to, techniques such as mixing, blending, etc., as well as as described throughout this disclosure. In addition, the pharmaceutical compositions used to form the dosage forms may also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, and may be in solid or liquid form, such as solid or liquid dosage forms, which may include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions, etc. According to the present invention, the solid unit dosage form may be other conventional types known in the art.

[0706] Suitable compositions of the present invention can be in different forms, including but not limited to liquids, tablets, capsules, etc. In some aspects, the composition can be a tablet composition or a capsule composition.

[0707] In addition, suitable for use in the present invention are solutions, which may be, but are not limited to, water, saline, aqueous dextrose solutions and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol, buffer solutions, etc. are preferred liquid carriers, especially for injectable solutions. Under ordinary storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

[0708] The compositions of the present invention may include various other pharmaceutically acceptable components or excipients, such as, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients, etc. These components are described herein.

[0709] According to the present invention, the composition as described herein may include at least one filler. In some aspects, the composition of the present invention may include a filler 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, calcium phosphate, or calcium carbonate. In some aspects, the composition of the present invention may include mannitol. In other aspects, the composition of the present invention may include sorbitol.

[0710] Representative fillers for the compositions of the present invention may include, but are not limited to, starch, lactitol, lactose, inorganic calcium salts, microcrystalline cellulose, sucrose, combinations thereof, and the like. Additional fillers or diluents for the compositions of the present invention may include, but are not limited to, fillers or diluents conventionally known in the art, i.e., fillers or diluents commonly used in pharmaceutical compound formulations. Examples of such fillers or diluents used according to the present invention may include, but are not limited to, sugars such as lactose, dextrose, glucose, sucrose, cellulose, starch and carbohydrate derivatives, polysaccharides (including dextran binders and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, combinations thereof, and the like. In some aspects, such fillers or diluents suitable for use in the present invention may include, but are not limited to, lactose, microcrystalline cellulose, combinations thereof, and the like.

[0711] Additionally, in another aspect, fillers for use in the present invention can be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50% of the composition as defined in this specification, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w / w). Additionally, such fillers can also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10% (w / w) of the composition, which amount may include any fractional amount between those defined amounts.

[0712] In some embodiments, the filler is present in an amount of about 10% to about 95% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 25% to about 95% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 30% to about 90% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 10% to about 50% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 10% to about 40% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 10% to about 30% (w / w) of the composition as defined in this specification. In some embodiments, the filler is present in an amount of about 10% to about 20% (w / w) of the composition as defined in this specification. 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).

[0713] In some aspects, the composition may further include microcrystalline cellulose. Several types of microcrystalline cellulose may be suitable for use in the compositions described herein, for example, microcrystalline cellulose may be selected from but is not limited to MICROCE or Types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, etc., as well as other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one aspect, the composition for use in the present invention may include microcrystalline cellulose (AVICEL PH102). In another aspect, the composition suitable for use in the present invention may include microcrystalline cellulose (AVICEL PH101).

[0714] In another aspect, microcrystalline cellulose can be present in an amount of about 1% to about 99% (w / w) of composition, or about 1% to about 50% of composition as defined in this specification sheets, 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). In some aspects, microcrystalline cellulose can also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10% (w / w) of composition, which amount may include any fractional amount between those amounts defined. In some aspects, microcrystalline cellulose can also be present in an amount of about 3% to about 5% (w / w) of composition.

[0715] In some aspects, the composition may further include silicified microcrystalline cellulose. In some aspects, the silicified microcrystalline cellulose may be, but is not limited to, SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. In some aspects, the silicified microcrystalline cellulose may be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. Without being bound by theory, the silicified microcrystalline cellulose is understood to protect the enteric coating from premature erosion by the sodium caprate present in the composition. The silicified microcrystalline cellulose may be present in any suitable amount for use in the present invention. For example, SMCC may 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 aspects, the amount of silicified microcrystalline cellulose is about 30% to about 70% (w / w) of the composition. In some aspects, the amount of silicified microcrystalline cellulose is about 65% to about 85% (w / w) of the composition. In some aspects, the amount of silicified microcrystalline cellulose is about 66.5% to about 81.3% (w / w) of the composition. In some aspects, 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 may 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.

[0716] In some embodiments, SMCC is present in an amount of about 20% to about 90% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 25% to about 85% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 25% to about 45% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 30% to about 40% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 65% to about 90% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 70% to about 85% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 70% to about 75% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 80% to about 85% (w / w), including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 30%. In some embodiments, SMCC is present in an amount of about 40%, including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 50%, including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 60%, including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 70%, including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 80%, including but not limited to any fractional amount therebetween. In some embodiments, SMCC is present in an amount of about 90%, including but not limited to any fractional amount therebetween.

[0717] In some embodiments, SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0718] In some aspects, the composition may further include one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, calcium phosphate, or calcium carbonate. In some aspects, the composition may further include mannitol.

[0719] In some respects, compositions of the present invention may include sorbitol.For example, for use in the present invention, sorbitol can exist with the amount of about 1% to about 99% (w / w) of composition or about 1% to about 50% of composition or about 1% to about 25% or about 5% to about 25% or about 5% to about 20% or about 5% to about 15% or about 8% to about 12% (w / w).In yet another aspect, sorbitol can exist with the amount of about 5% (w / w) of 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 composition. In some aspects, the composition further comprises sorbitol in an amount of about 5% to about 15% (w / w) of the composition. In some aspects, the amount of sorbitol is about 10% to about 15% (w / w) of the composition. In some aspects, the composition comprises sorbitol in an amount of about 10.7% (w / w) of the composition.

[0720] In some embodiments, compositions of the present invention may include mannitol.For example, for use in the present invention, mannitol can exist with the amount of about 1% to about 99% (w / w) of 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 composition.In another embodiment, mannitol can exist with the amount of about 5% (w / w) of 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 composition, and this amount includes but is not limited to any fractional amount therebetween. In some embodiments, the composition further 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.

[0721] In one embodiment, the amount of sugar alcohol can exist with the scope of about 1% to about 50% (w / w) of composition or about 5% to about 50% or about 5% to about 30% or about 10% to about 30% (w / w) of composition.In some aspects, the amount of sugar alcohol can exist with the amount of about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5% or about 20% (w / w) of composition.In some aspects, the amount of sugar alcohol can exist with the amount of about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5% or about 20% (w / w) higher than composition.In some aspects, the amount of sugar alcohol can exist with the amount lower than about 5%, 7.5%, 10%, 12.5%, 15%, 17.5% or about 20% (w / w) of composition.

[0722] In some embodiments, the pharmaceutical compositions described herein do not include a sugar alcohol. In some embodiments, the pharmaceutical compositions described herein do not include sorbitol. In some embodiments, the pharmaceutical compositions described herein do not include mannitol.

[0723] The compositions of the present invention may include, but are not limited to, at least one effective therapeutic amount of a disintegrant determined for use according to the present invention. Representative disintegrants for use in the present invention include, but are not limited to, starches, clays, celluloses, alginates, and gums, as well as cross-linked starches, celluloses, and polymers, combinations thereof, and the like. Additional representative disintegrants for use in the present invention may include, but are not limited to, microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, 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, carboxymethyl cellulose, alginic acid, guar gum, combinations thereof, and the like.

[0724] In some aspects, the disintegrant is cross-linked carboxymethyl cellulose (crosslinked carboxymethyl cellulose), glycolic acid starch, polyvinyl pyrrolidone, sago starch, psyllium husk, silicate or soy polysaccharide. In some aspects, the disintegrant is cross-linked carboxymethyl cellulose sodium or crospovidone. In some aspects, the disintegrant for the present invention may include but is not limited to cross-linked carboxymethyl cellulose sodium. In some aspects, the disintegrant for the present invention may include crospovidone. In some aspects, the disintegrant can be present in an amount of about 1% to about 99% (w / w) of the composition of the present invention or about 1% to about 50% of the composition, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 4% to about 6% (w / w). Disintegrant for the present invention can also exist with the amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% or about 12% (w / w) of compositions, and this amount includes but is not limited to any fractional amount therebetween. In some respects, the amount of disintegrant can exist with the about 1% to about 10% (w / w) of compositions of the present invention. In some respects, the amount of disintegrant can exist with the about 8% to about 12% (w / w) of compositions of the present invention. In some respects, the amount of disintegrant can exist with the about 3% to about 8% (w / w) of compositions of the present invention.

[0725] In another aspect, for the purposes of the present invention, the compositions of the present invention may also include, but are not limited to, any amount of silicon dioxide. In particular, silicon dioxide is exemplified by Aerosil 200, which has a density of approximately 200 m 2 Alternatives to silica may include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silica, precipitated silica, sodium aluminosilicate, combinations thereof, and the like.

[0726] In some aspects, the compositions of the present invention may further comprise silicon dioxide. In one aspect, silicon dioxide can be present in the compositions of the present invention in an amount from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1.25%, or from about 0.5% to about 1.5%, or from about 1.0% to about 1.25%, or from about 0.1% to about 1%, or from about 0.3% to about 0.7% (w / w) of the composition. For example, the silicon dioxide used in the present invention 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%, 1.1%, 1.2%, 1.3%, 1.4% or about 1.5% (w / w) of the composition, including any fractional amount as defined therein. In another aspect, the composition of the present invention may also include an amount of silicon dioxide accounting for about 0.1% to about 1.5% (w / w) of the composition. In another aspect, the composition of the present invention may also include an amount of silicon dioxide accounting for about 0.5% to about 2% (w / w) of the composition. In another aspect, the composition of the present invention may also include an amount of silicon dioxide accounting for about 0.3% to about 0.7% (w / w) of the composition. In other aspects, the composition of the present invention may also include an amount of silicon dioxide accounting for about 0.5% (w / w) of the composition. In some aspects, the composition may further comprise silicon dioxide in an amount of about 1% (w / w) of the composition. Examples of suitable silicon dioxide materials include, but are not limited to, colloidal silicon dioxide, aerosols, colloidal silicon dioxide, fumed silicon dioxide, pyrogenic silicon dioxide, colloidal anhydrous silicon dioxide, colloidal silicon dioxide, and the like. In some embodiments, the silicon dioxide is colloidal silicon dioxide.

[0727] Compositions may also include a binding agent. The binding agent used for compositions of the present invention includes a binding agent commonly used in pharmaceutical preparations. Examples of binding agents used for the present invention include, but are not limited to, cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and sodium carboxymethyl cellulose), ethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including gum arabic, tragacanth, guar gum, alginate, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinyl pyrrolidone, polyethylene glycol, combinations thereof, and the like.

[0728] In some embodiments, the binder is hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder for use in the present invention can 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 fractional amount therebetween.

[0729] In the present invention, the composition may include any suitable amount of lubricant used as described herein. Examples of suitable lubricants for use in the present invention may include, but are not limited to, magnesium carbonate, magnesium lauryl sulfate, calcium silicate, talc, fumed silica, combinations thereof, and the like. 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, and the like.

[0730] In some respects, lubricant may include but is not limited to magnesium stearate. In one aspect, the amount of lubricant can exist in the range of about 0.1% to about 10% (w / w) of the composition or about 0.1% to about 5% of the composition, or about 0.1% to about 2.5% of the composition, or about 0.1% to about 1%, or about 0.1% to about 0.5% (w / w). In some respects, the amount of lubricant can exist in the range of about 0.5% to about 2.5% of the composition or about 0.5% to about 2.0% (w / w). In some respects, the amount of lubricant can exist in the range of about 0.1% to about 0.5% (w / w) of the composition. In some respects, the amount of lubricant is about 0.3% to about 0.7% (w / w) of the composition. In some respects, 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 aspects, the lubricant can be present in an amount of about 0.25% (w / w).

[0731] In some aspects, the composition comprises: (i) the hydrochloride salt of a 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) silicon dioxide 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.

[0732] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically acceptable salt of a 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) silicon dioxide 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.

[0733] In some embodiments, the pharmaceutical composition includes: (i) a crystalline form of a pharmaceutically acceptable salt of a 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) silicon dioxide 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.

[0734] 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 a compound of formula (I) or a solvate thereof in an amount of about 0.1% to about 15% (w / w) of the composition, and (iii) silicified microcrystalline cellulose in an amount of about 10% to about 50% (w / w) of the composition.

[0735] In some embodiments, a 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 10% (w / w) of the composition; and (iii) a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I) or a solvate thereof in an amount of about 0.5% to about 15% (w / w) of the composition; (iv) silicified microcrystalline cellulose in an amount of about 30% to about 40% (w / w) of the composition; (v) silicon dioxide 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.

[0736] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically acceptable salt of a 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) (w / w) of the composition; (vii) silicified microcrystalline cellulose in an amount of about 34.8% to about 39.7% (w / w) of the composition; (viii) mannitol in an amount of about 10.7% (w / w) of the composition; (ix) crospovidone in an amount of about 5% (w / w) of the composition; (x) silicon dioxide 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.

[0737] 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 a compound of Formula (I) or a solvate thereof in an amount of 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) silicon dioxide 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.

[0738] In some embodiments, the pharmaceutical composition comprises: (i) a crystalline form of a pharmaceutically acceptable salt of a 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) (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) silicon dioxide 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.

[0739] In some aspects, the composition comprises: (i) the hydrochloride salt of a 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) silicon dioxide 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.

[0740] In some aspects, the composition comprises: (i) the hydrochloride salt of a 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) silicon dioxide 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.

[0741] In some aspects, the composition comprises: (i) a hydrochloride salt of a 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) silicon dioxide 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 further comprise one or more coatings.

[0742] The compositions described herein may include various other pharmaceutically acceptable components or excipients, such as, but not limited to, glidants, lubricants, disintegrants, binders, desiccants, fillers, and other components or excipients.

[0743] According to the present invention, the compositions described herein may include at least one disintegrant in any suitable amount. Representative disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starches, clays, other algins, other celluloses, gums (such as gellan gum), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one aspect, the disintegrant may include cross-linked sodium carboxymethyl cellulose. In one aspect, the disintegrant may include crospovidone. In another aspect, suitable disintegrants may be, but are not limited to, present in an amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any fractional amount therebetween as defined herein. In another aspect of the invention, the disintegrant may be, but are not limited to, present in an amount of about 1% to 10% (w / w) of the composition. In other aspects, the disintegrant can be present in an amount of about 5.0% (w / w) of the composition.

[0744] In some aspects, the microcrystalline cellulose can be present in an amount of about 1% to about 10% (w / w) of the composition. In some aspects, the microcrystalline cellulose can be present in an amount of about 3.9% (w / w) of the composition.

[0745] In some aspects, the composition may also include silicon dioxide. In some aspects, the composition may also include silicon dioxide in an amount of about 0.1% to about 1.5% (w / w) of the composition. For example, silicon dioxide can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0% or about 1.5% (w / w) of the composition, including any fractional amount therebetween as defined herein. In some aspects, the composition may also include silicon dioxide in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some aspects, the composition may also include silicon dioxide in an amount of about 0.5% to about 2% (w / w) of the composition. In some aspects, the composition may also include silicon dioxide in an amount of about 0.5% (w / w) of the composition.

[0746] In another aspect, 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; silicon dioxide 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.

[0747] In yet another aspect, the composition can 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; silicon dioxide 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.

[0748] In some aspects, 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 silicon dioxide in an amount of about 0.5% (w / w).

[0749] In some aspects, the composition can 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 silicon dioxide in an amount of about 0.5% (w / w).

[0750] In some aspects, the composition can 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).

[0751] The microcrystalline cellulose can include any microcrystalline cellulose known in the art. In some aspects, the microcrystalline cellulose can comprise silicified microcrystalline cellulose (SMCC).

[0752] In some aspects, for use in the present invention, the microcrystalline cellulose can be silicified microcrystalline cellulose (SMCC) and can have any particle size. In some aspects, the composition comprises silicified microcrystalline cellulose in an amount of about 25% to about 45% (w / w) of the composition. In some aspects, the composition comprises silicified microcrystalline cellulose in an amount of about 36.6% (w / w) of the composition.

[0753] According to the present invention, the composition may include at least one disintegrant in any suitable amount. Representative disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clay, other algins, other celluloses, gums (such as gellan gum), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one aspect, the disintegrant may include cross-linked sodium carboxymethyl cellulose. In one aspect, the disintegrant may include crospovidone. The disintegrant for use in the present invention may be, but is not limited to, present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50% of the composition, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 4% to about 6% (w / w). In another aspect, suitable disintegrant can be but is not limited to exist with the amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or about 10% (w / w) of composition, including any fractional amount therebetween as defined in the present invention. In another aspect of the invention, disintegrant can be but is not limited to exist with the amount of about 1% to about 10% (w / w) of composition. In other aspects, disintegrant can exist with the amount of about 5.0% (w / w) of composition.

[0754] In another aspect, the composition may further include any amount of silicon dioxide according to the present invention. An example of silicon dioxide is Aerosil 200, which has a density of about 200 m 2 / g specific surface area. Alternatives to silica include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silica, 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% to 10% (w / w) of the composition, or about 0.1% to 5%, or about 0.1% to 2%, or about 0.1% to 1.5%, or about 0.1% to 1%, or about 0.3% to 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 fractional amount therebetween.

[0755] In some aspects, the composition may also include silicon dioxide (e.g., Aerosil 200). In some aspects, the composition may also include silicon dioxide (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% (w / w) of the composition. For example, silicon dioxide can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0% or about 1.5% (w / w) of the composition, including any fractional amount therebetween as defined herein. In some aspects, the composition may also include silicon dioxide (e.g., Aerosil 200) in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some aspects, the composition may also include silicon dioxide (e.g., Aerosil 200) in an amount of about 0.5% to about 2% (w / w) of the composition. In some aspects, the composition can further comprise silicon dioxide in an amount of about 0.5% (w / w) of the composition. In some aspects, the composition can further comprise silicon dioxide (eg, Aerosil 200) in an amount of about 1% (w / w) of the composition.

[0756] The compositions described herein may include a variety of other pharmaceutical excipients or components, which may include but are not limited to lubricants, disintegrants, binders, desiccants, fillers and other components. For use in the present invention, disintegrants 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% of the composition, or about 0.1% to about 2% of the composition, or about 0.1% to about 1.5% of the composition, or about 0.1% to about 1% of the composition, or about 0.1% to about 0.4% (w / w). In some aspects, the composition may also include a disintegrant. In some aspects, the composition may also include silicon dioxide (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% (w / w) of the composition. In some aspects, the composition may also include a disintegrant in an amount of about 0.25% (w / w) of the composition.

[0757] In some aspects, the compositions disclosed herein may further comprise at least one of: a lubricant measured at about 0.1% to about 0.5% by weight of the composition, a disintegrant measured at about 1% to about 10% by weight of the composition, or silicon dioxide (e.g., Aerosil 200) measured at about 0.1% to about 1.5% by weight of the composition.

[0758] In some aspects, the composition can further include: a lubricant measured at about 0.1% to about 0.5% by weight of the composition; a disintegrant measured at about 1% to about 10% by weight of the composition; and silicon dioxide (e.g., Aerosil 200) measured at about 0.1% to about 1.5% by weight of the composition.

[0759] In some aspects, the compositions disclosed herein may further comprise at least one of: a disintegrant in an amount of about 5.0% (w / w); silicon dioxide (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).

[0760] In some aspects, 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); silicon dioxide (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).

[0761] In some aspects, the composition can include: 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).

[0762] In some aspects, the compositions of the present invention may not include or may exclude the use of absorption enhancers, depending on their intended delivery or use and / or for the treatment of a specific indication as defined herein.

[0763] In some embodiments described herein, such as those involving pharmaceutical compositions, tablets, methods, processes, etc., absorption enhancers are excluded. In some embodiments described herein, such as those involving compositions, tablets, methods, processes, etc., absorption enhancers are included.

[0764] In other aspects, suitable compositions of the present invention may exhibit improved bioavailability when administered in conjunction with an absorption enhancer.

[0765] In some respects, the compositions of the present invention may include an absorption enhancer. When present, the absorption enhancer may be amphoteric, cationic, anionic or nonionic. In one aspect, the absorption enhancer is an intestinal permeability enhancer. In some respects, 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) etc.

[0766] Other absorption enhancers may include, but are not limited to, citric acid or a salt of a citrate (such as sodium citrate), tartaric acid or a salt of a tartrate, salicylic acid or a derivative thereof or a salt of a salicylate, fatty acid acylated amino acids, alkyl sugars, C8-o-alkyl polysaccharides, n-octyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, n-tetradecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monolaurate, sucrose monotridecanoate, sucrose monotetradecanoate, coco-glucoside, cyclodextrins, alkanoylcarnitines (such as lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine, lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride), fatty acid acylated amino acids,Including but not limited to sodium lauroyl alanine, N-lauroyl-L-alanine, sodium lauroyl asparagine, N-lauroyl-L-asparagine, sodium lauroyl aspartate, N-lauroyl-L-aspartic acid, sodium lauroyl cysteine, N-lauroyl-L-cysteine, sodium lauroyl glutamate, N-lauroyl-L-glutamate, sodium lauroyl glutamine, N-lauroyl-L-glutamine, sodium lauroyl glycinate, N-lauroyl-L-glycine, sodium lauroyl histidine, N-lauroyl-L-histidine, sodium lauroyl isoleucine, N-lauroyl L-Isoleucine, Sodium Lauroyl Leucine, N-Dodecanoyl-L-Leucine, Sodium Lauroyl Methionine, N-Dodecanoyl-L-Methionine, Sodium Lauroyl Phenylalanine, N-Dodecanoyl-L-Phenylalanine, Sodium Lauroyl Propionate, N-Dodecanoyl-L-Proline, Sodium Lauroyl Serine, N-Dodecanoyl-L-Serine, Sodium Lauroyl Threonine, N-Dodecanoyl-L-Threonine, Sodium Lauroyl Tryptophan, N-Dodecanoyl-L-Tryptophan, Sodium Lauroyl Tyrosine, N-Dodecanoyl-L-Tyrosine, Sodium Lauroyl Valine, N-Dodecanoyl-L-Valine , Sodium Lauroyl Sarcosinate, N-Lauroyl-L-Sarcosine, Sodium Decanoate Alanine, N-Decanoyl-L-Alanine, Sodium Decanoate Asparagine, N-Decanoyl-L-Asparagine, Sodium Decanoate Aspartate, N-Decanoyl-L-Aspartic Acid, Sodium Decanoate Cysteine, N-Decanoyl-L-Cysteine, Sodium Decanoate Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Decanoate Glutamine, N-Decanoyl-L-Glutamine, Sodium Decanoate Glycinate, N-Decanoyl-L-Glycine, Sodium Decanoate Histidine, N-Decanoyl-L-Histidine, Sodium Decanoate Isoleucine, N-Decanoyl-L-Isoleucine, Sodium Decanoate Leucine, N-Decanoyl decanoate, N-decanoyl-L-leucine, sodium decanoate methionine, N-decanoyl-L-methionine, sodium decanoate phenylalanine, N-decanoyl-L-phenylalanine, sodium decanoate propionate, N-decanoyl-L-proline, sodium serine, N-decanoyl-L-serine, sodium decanoate threonine, N-decanoyl-L-threonine, sodium decanoate tryptophan, N-decanoyl-L-tryptophan, sodium decanoate tyrosine, N-decanoyl-L-tyrosine, sodium decanoate valine, N-decanoyl-L-valine, sodium decanoate 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-11), 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 glycinate and pharmaceutically acceptable salts of any of the foregoing compounds; or alkanoyl sarcosinate (e.g., lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or with C8-C, 20 one of the 20 standard proteinogenic α-amino acids acylated with an alkanoic acid), an alkyl sugar (e.g., C1-C 20 Alkyl sugars, such as Multitrope TM 1620-LQ-(MV); or n-octyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, n-tetradecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-myristate, coco-glucoside, alkyl sugars, cyclodextrins (e.g., α- cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino]caprylic acid, N-[8-(2-hydroxybenzoyl)amino]caprylate, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also known as "SNAC"), calcium chelating compounds (e.g., ethylenediaminetetraacetic acid (EDTA), polyoxyethyl castor oil (also known as "Kolliphor EL"; or CAS No. 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin or an alkanol (e.g., ethanol, decanol), caprylocaproyl polyoxylglycerides (such as caprylocaproyl polyoxy-8 glyceride; trade name or ACCON MC8-2), ethyl caprylate, monolaurin, lysophosphatidylcholine, menthol, C8-C 20 Alkylamine, C8-C 20 Alkenylamine (e.g., oleylamine), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (e.g., polysorbate 80), cholic acid (or a cholate salt, e.g., sodium cholate), sodium deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauroyl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, or decyldimethylaminopropanesulfonate, and the like.

[0767] In some aspects, absorption enhancers may include, but are not limited to, sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium saporin (SNAC), polyethylene glycol (PEG)-modified medium chain fatty acid triglycerides of capric and caprylic acid (such as those available from Gattefosse, USA). ), sucrose laurate, or lauroyl-L-carnitine (LC, such as available from Enteris BioPharma, NJ, USA ) etc. In some aspects, the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, saprolactam sodium (SNAC), polyethylene glycol (PEG) modified medium chain fatty acid triglycerides of capric and caprylic acid, sucrose laurate or lauroyl-L-carnitine (LC).

[0768] Absorption enhancer can be present in said composition in an amount of about 1% to about 99% (w / w) of composition or about 5% to about 50% (w / w) of composition, 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 aspects, the amount of absorption enhancer exists with about 5% to about 50% (w / w). In some aspects, the amount of absorption enhancer exists with about 5% to about 40% (w / w). In some aspects, the amount of absorption enhancer exists with about 30% to about 40% (w / w). For example, the absorption enhancer can be present in an amount of about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or about 40% (w / w) of the composition, including any fractional amounts therebetween. In some aspects, the absorption enhancer is present in an amount of about 30% to about 40% (w / w). In some aspects, the absorption enhancer is present in an amount of about 32% to about 38% (w / w). In some aspects, the absorption enhancer is present in an amount of about 35.7% (w / w).

[0769] In some aspects, the absorption enhancer used in the compositions of the present invention can be sodium caprate.

[0770] Sodium caprate can be present in the composition in an amount of about 1% to about 99% (w / w) of the composition, or about 5% to about 50% (w / w) of the composition, 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 aspects, sodium caprate is present in an amount o...

Claims

1. A method for preparing 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, wherein the method comprises the following steps: (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 seed crystals 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 hydrochloride from the mixture obtained in step (d) and removing the residual solvent.

2. A method for improving the rheological properties of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, wherein the method comprises the following steps: (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 seed crystals 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 hydrochloride from the mixture obtained in step (d) and removing the residual solvent.

3. The method of claim 1 or 2, wherein step (a) is performed at a temperature of about 25°C 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 method according to any one of claims 1 to 5, wherein the first solvent comprises methanol and H2O.

7. The method according to any one of claims 1 to 6, wherein the first solvent comprises an alkyl alcohol and H2O in a volume ratio of 9:1 to 5:

5.

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% w / v to 25% w / v.

9. The method according to any one of claims 1 to 8, wherein the first solvent comprises methanol and H2O in a volume ratio of 3:1 to 3:

2.

10. The process according to any one of claims 1 to 9, wherein step (a) is performed at a pH between 5.0 and 6.

5.

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

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

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

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 claim 1 , wherein the amount of the seed crystal added is 0.005 to 0.1 molar equivalents based on the amount of the monocyclic peptide compound in step (a).

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

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. 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 sodium chloride aqueous solution.

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 the monocyclic peptide compound in step (a).

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

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

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

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

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

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

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

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

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

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

31. The method of any one of claims 1 to 29, further comprising preparing the monocyclic peptide compound by liquid 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. A method for preparing a crystalline form of a monocyclic peptide compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of: (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); and (iv) isolating the crystalline monocyclic peptide compound or its salt from the mixture obtained in step (iii), And remove the residual solvent.

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

35. The method of any one of claims 33 to 34, wherein the first solvent comprises an alkyl alcohol.

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

37. The method of any one of claims 33 to 36, wherein the first solvent comprises methanol and H2O.

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 method of any one of claims 33 to 38, wherein the first solvent comprises methanol and H2O in a volume ratio of 9:1 to 5:

5.

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

3.

42. The method of any one of claims 33 to 41, wherein the second solvent comprises H2O.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

58. The process according to any one of claims 1 to 32, wherein the seed crystals of the crystalline monocyclic peptide compound are obtained by the process according to any one of claims 33 to 51.

59. The method according to any one of claims 1 to 32, further comprising the steps of: (f) dissolving the hydrochloride 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; and (h) isolating the crystalline monocyclic peptide compound in free base form from the mixture obtained in step (g).

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

61. The method of any one of claims 59 to 60, wherein the buffer solution is a phosphate buffer having a pH between pH 7 and pH 9.

62. The method according to any one of claims 59 to 61, further comprising: (i) dissolving the crystalline free base of the monocyclic peptide compound in a second solvent; (j) adding a solution comprising a counterion to the mixture obtained in step (i); (k) adding an antisolvent; (1) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained in step (k).

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

64. The method of any one of claims 62 to 63, wherein the anti-solvent is selected from tert-butyl methyl ether (TBME), acetonitrile and isopropyl alcohol (IPA).

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

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

67. The method of any one of claims 1 to 66, further comprising passing the isolated crystalline single cyclic 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 using a dynamic drying step, wherein the dynamic drying step comprises agitating the crystalline monocyclic peptide compound.

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

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

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

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

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 pharmaceutical excipient and a crystalline form of a monocyclic peptide compound prepared by the method of any one of the preceding claims.

75. The method of any one of claims 1 to 73, wherein 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') in X3 does not exist or is any amino acid; X4 is Abu, Cys, (D)Cys, α-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, β-Ala, Ala, Lys, Asn, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, Lys(Ac), α-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln or Asp; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, α-MeGln, α-MeLys, α-MeLeu, α-MeAsn, α-MeThr, α-MeSer or Val; X7 is substituted or unsubstituted Trp; X8 is Gln, α-MeLys, α-MeLeu, α-MeLys(Ac), β-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, α-MeGln, α-MeAsn, Lys(Ac), D ab(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, α-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is Tyr or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 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, hydroxyl, or alkoxy; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, α-MeLys, α-MeLeu, α-MeArg, α-MePhe, α-MeLeu, α-MeLys, α-MeAsn, α-MeTyr, Ala, cyclohexylAla, Lys or Aib; X13 is any amino acid; X14 is any amino acid; and 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 is any amino acid; and wherein X4 and X9 form a disulfide bond or a thioether bond.

76. The method of any one of claims 1 to 75, wherein 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 by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal; Wherein Pal is 2Pal, 3Pal or 4Pal; in, 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 method of any one of claims 1 to 76, wherein 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 by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal; Wherein Pal is 2Pal, 3Pal or 4Pal; 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 method of any one of claims 1 to 77, wherein 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 by cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal; Wherein Pal is 2Pal, 3Pal or 4Pal; in, 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 method of any one of claims 1 to 78, wherein 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-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; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal; Wherein Pal is 2Pal, 3Pal or 4Pal; in, 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 method of any one of claims 1 to 79, wherein 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; wherein Phe is unsubstituted Phe or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxyl, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal; Wherein Pal is 2Pal, 3Pal or 4Pal; in, 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. The method of any one of claims 1 to 80, wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

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

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

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

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

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

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

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

89. The method according to any one of claims 1 to 88, wherein the monocyclic peptide compound is a compound having the following structure: or or a pharmaceutically acceptable salt thereof.

90. A method for preparing a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the following structure: The method comprises the following steps: (a) dissolving the monocyclic peptide compound comprising 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 seed crystals 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 the hydrochloride salt from the mixture and removing the residual solvent.

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

92. A method for preparing a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the following structure: The method comprises the following steps: (a) mixing the monocyclic peptide compound in a first solvent; (b) heating the mixture to between 30° C. and 40° C.; (c) adding a second solvent to the solution obtained in step (b); (d) cooling the mixture to between 20° C. and 30° C.; (e) adding seed crystals of the crystalline monocyclic peptide compound to the mixture obtained in step (d); (f) stirring the mixture at 20° C. to 30° C. for 1 to 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 the residual solvent.

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

94. A method for preparing a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the following structure: The method comprises the following steps: (a) mixing a crude monocyclic peptide compound in a first solvent; (b) heating the mixture to 30° C. to 50° C.; (c) filtering the suspension obtained in step (b) to obtain a solution; (d) cooling the solution obtained in step (c) to 10° C. to 20° C.; (e) adding seed crystals 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 3 to 5 hours; (i) stirring the mixture at 0°C to 5°C for 12 to 18 hours; (j) isolating the crystalline monocyclic peptide compound from the mixture and removing the residual solvent.

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

96. A method for preparing a crystalline form of an acetate salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the following structure: The method comprises the following steps: (a) dissolving the monocyclic peptide compound comprising the hydrochloride salt of the monocyclic peptide compound in a first solvent; (b) diafiltration of 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 a dry solid.

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

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

99. The method of any one of claims 75 to 98, further comprising passing the isolated crystalline single cyclic 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 using a dynamic drying step, wherein the dynamic drying step comprises agitating the crystalline monocyclic peptide compound.

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

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

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

104. The method according to any one of claims 75 to 103, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized in that Dv90 is in the following ranges: 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 pharmaceutical excipient and a crystalline form of a monocyclic peptide compound prepared by the method of any one of claims 75 to 105.

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

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