Methods for preparing crystalline peptide inhibitors of interleukin-23 receptor

Abstract

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

Description

METHODS FOR PREPARING CRYSTALLINE PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR SEQUENCE LISTING The contents of the electronic sequence listing (747883-NTT-4258PC_SL.xml; Size: 13,484 bytes; and Date of Creation: January 30, 2024) is herein incorporated by reference in its entirety. RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Patent Application no.63 / 482,512, filed January 31, 2023, as well as US Provisional Patent Application no.63 / 517,307, filed Augst 2, 2023. The contents of both of these applications are incorporated herein by reference in their entireties. FIELD

[0002] The present invention relates to methods for preparing crystalline monocyclic peptide compounds, and salts or solvates thereof, which are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystalline monocyclic peptide compounds, and salts or solvates thereof, have favorable rheological (flow) properties making them suitable for pharmaceutical processing. The peptide inhibitors are useful for treatment of autoimmune inflammation diseases and related disorders. BACKGROUND

[0003] The interleukin-23 (IL-23) cytokine has been implicated as playing a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBD revealed a primary role of IL-23R and downstream effector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 mediates this effect by promoting the development of a pathogenic CD4+T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).

[0004] Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell-independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17- associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis.

[0005] Psoriasis (PsO), a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms. IL-23 has one of several interleukins implicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL- 23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0006] IL-23 is a heterodimer composed of a unique p19 subunit and the p40 subunit shared with IL-12, which is a cytokine involved in the development of interferon-γ (IFN-γ)-producing T helper 1 (TH1) cells. Although IL-23 and IL-12 both contain the p40 subunit, they have different phenotypic properties. For example, animals deficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 deficient animals are resistant, presumably due to a reduced number of CD4+T cells producing IL-6, IL-17, and TNF in the CNS of IL-23- deficient animals. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL- 12Rβ1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat 3, Stat 4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with Stat3. In contrast to IL-12, which acts mainly on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0007] Efforts have been made to identify therapeutic moieties that inhibit the IL-23 pathway, for use in treating IL-23-related diseases and disorders. A number of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, an antibody that binds the p40 subunit of IL-23, which has been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderately to severely active Crohn’s disease and moderately to severely active ulcerative colitis. More recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified (see, e.g., US Patent Application Publication No. US2013 / 0029907). Clinical trials in Crohn’s Disease or psoriasis withbriakinumab (which also target 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 treatment of human inflammatory diseases. While these findings are promising, challenges remain with respect to successful delivery of such therapeutics to their target. Effective delivery can improve the treatment of intestinal inflammation, such as intestinal bowel diseases, including Crohn’s disease, ulcerative colitis and related disorders.

[0008] An inhibitor of IL-23R was described as Peptide #104 in PCT publication WO 2021 / 146441 and US 2021 / 0261622, the disclosures of which are incorporated herein by reference in their entireties.

[0009] Peptide compounds such as those described in PCT publication WO 2021 / 146441 and US 2021 / 0261622 may be manufactured using solid phase peptide synthesis (SPPS). In solid phase peptide synthesis, an amino acid or peptide is bound, usually via the C-terminus, to a solid support. New amino acids are added to the bound amino acid or peptide via coupling reactions. Though solid phase peptide synthesis has been widely used, the process is laborious and often requires purification of the reaction products by chromatography, resulting in high cost, slow process and difficulties in scale-up.

[0010] Alternative methods to synthesis the peptides described herein are therefore required, particularly those that provide improved handleability, such as improved rheological (flow) properties, particle size and hygroscopicity, of the peptide inhibitors for use as pharmaceutical ingredients.

[0011] There remains a need in the art to develop methods for preparing the peptide inhibitors of the interleukin-23 receptor (IL-23R) in forms which are suitable for large scale commercial development, and which provide solid forms of the peptide inhibitors with characteristics which improve handleability of the peptide inhibitors for use as pharmaceutical ingredients. For example, there remains a need to develop methods for preparing and isolating forms of peptide inhibitors of IL-23R which have good rheological properties. The present invention addresses these needs. BRIEF SUMMARY

[0012] Provided herein are methods for preparing crystalline forms of a peptide inhibitor of the interleukin-23 receptor (IL-23R). Crystalline forms have advantageous properties such as ease of isolation, processibility, handleability, enhanced purity, and greater physical and chemical stability compared to analogous amorphous forms. These attributes can be particularly important for pharmaceutical agents where large-scale production, reproducibility, andcompound purity are required. Crystalline forms of peptides may be uniquely advantageous as the corresponding amorphous forms are often unsuitable for formulating, such as tableting.

[0013] In general, the present invention relates to methods for the preparation of monocyclic peptide compounds or hydrochloride salt, solvates or forms thereof having rheological (flow) properties suitable for pharmaceutical processing. The methods of the invention include methods for improving the rheological properties of monocyclic peptide compounds, and methods for the preparation of monocyclic peptide compounds having rheological properties suitable for manufacturing pharmaceutical compositions.

[0014] In particular, the present invention relates to a method for the preparation of a crystalline form of the peptide of SEQ ID NO: 1: Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3- Pal]-Sarc-NH2 (in which [Pen]*-[Pen]* form a disulfide bond); or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, having the structure of Formula (I):

[0015] Inpreparation of a crystalline hydrochloride salt form of a compound of Formula (I) that has the structure:(I), or a solvate thereof.

[0016] The present invention also relates to a method for the preparation of a crystalline form of the peptide of SEQ ID NO: 2: 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 of the foregoing, having the structure of a compound of Formula (II):

[0017] In another embodiment, the present invention provides a method for the preparation of a crystalline acetate salt form of a compound of Formula (II) that has the structure: (II), or a solvate

[0018] In another embodiment, the present invention relates to a method for the preparation of a crystalline form of the peptide of SEQ ID NO: 3: Ac-[Pen]*-Asn-Thr-Trp(7Me)-Lys(Ac)-[Pen]*-Tyr(2-ea)-2Nal-αMe-Lys-Lys(Ac)-Asn-D-Leu- NH2(in which [Pen]*-[Pen]* form a disulfide bond); or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, having the structure of a compound of Formula (III):(III).

[0019] The present invention also provides a method for the preparation of a crystalline hydrochloride salt form of a compound of Formula (III) that has the structure:or a solvate thereof.

[0020] The present invention also provides methods for the preparation of crystalline forms of a peptide compound of any one of Formula (I’), (IIa)-(IId), (IIIa)-(IIIf), (IVa)-(IVd), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, as described herein. The pharmaceutically acceptable salts of the compound of any one of Formula (I’), (IIa)-(IId), (IIIa)- (IIIf), (IVa)-(IVd) provided herein include hydrochloride salts, bis-hydrochloride salts, acetate salts, fumarate salts, glutarate salts, glycolate salts, mesylate salts, sulfate salts, and citrate salts.

[0021] The present invention also provides a method for the preparation of a crystalline form of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing. The pharmaceutically acceptable salts of the compound of Formula (I) provided herein include hydrochloride salt, bis-hydrochloride salt, acetate salt, fumarate salt, glutarate salt, glycolate salt, mesylate salt, sulfate salt, and citrate salt.

[0022] Further provided herein is a crystalline form of a free base of a peptide of a compound of Formula (I), or of any one of Formula (I’), (IIa)-(IId), (IIIa)-(IIIf), (IVa)-(IVd), or a solvate thereof of any of the foregoing, prepared according to the methods of the present invention.

[0023] Further provided herein is a crystalline form of a free base of a compound of Formula (I), or of any one of Formula (I’), (IIa)-(IId), (IIIa)-(IIIf), (IVa)-(IVd), or a solvate thereof of any of the foregoing, prepared according to the methods of the present invention.

[0024] The present invention also provides methods for the preparation of crystalline forms of a peptide compound of any one of Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, as described herein. The pharmaceutically acceptable salts of the compound of any one of Formula (II) or Formula (III), provided herein may include hydrochloride salts, bis-hydrochloride salts, acetate salts, fumarate salts, glutarate salts, glycolate salts, mesylate salts, sulfate salts, and citrate salts.

[0025] Further provided herein is a crystalline form of a free base of a compound of Formula (I), or of any one of Formula (II) or (III), or a solvate thereof of any of the foregoing, prepared according to the methods of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG.1 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0027] FIG.2 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0028] FIG.3 shows an XRPD pattern of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0029] FIG.4 shows a thermogravimetric analysis (TGA) graph of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0030] FIG.5 shows a differential scanning calorimetry (DSC) graph of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0031] FIG.6 shows a dynamic vapor sorption (DVS) curve of a crystalline form of a hydrochloride salt of a compound of Formula (I).

[0032] FIG.7 shows an XRPD pattern of a crystalline form of an acetate salt of a compound of Formula (I).

[0033] FIG.8 shows a TGA graph of a crystalline form of an acetate salt of a compound of Formula (I).

[0034] FIG.9 shows a DSC graph of a crystalline form of an acetate salt of a compound of Formula (I).

[0035] FIG.10 shows a DVS curve of a crystalline form of an acetate salt of a compound of Formula (I).

[0036] FIG.11 shows an XRPD pattern of a crystalline form of a free base of a compound of Formula (I).

[0037] FIG.12 shows a TGA graph of a crystalline form of a free base of a compound of Formula (I).

[0038] FIG.13 shows a DSC graph of a crystalline form of a free base of a compound of Formula (I).

[0039] FIG.14 shows a DVS curve of a crystalline form of a free base of a compound of Formula (I).

[0040] FIG.15 shows an XRPD pattern of a crystalline form of a fumarate salt of a compound of Formula (I).

[0041] FIG.16 shows a TGA graph of a crystalline form of a fumarate salt of a compound of Formula (I).

[0042] FIG.17 shows a DSC graph of a crystalline form of a fumarate salt of a compound of Formula (I).

[0043] FIG.18 shows an XRPD pattern of a crystalline form of a glutarate salt of a compound of Formula (I).

[0044] FIG.19 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a glutarate salt of a compound of Formula (I).

[0045] FIG.20 shows a DVS curve of a crystalline form of a glutarate salt of a compound of Formula (I).

[0046] FIG.21 shows an XRPD pattern of a crystalline form of a glycolate salt of a compound of Formula (I).

[0047] FIG.22 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a glycolate salt of a compound of Formula (I).

[0048] FIG.23 shows a DVS curve of a crystalline form of a glycolate salt of a compound of Formula (I).

[0049] FIG.24 shows an XRPD pattern of a crystalline form of a mesylate salt of a compound of Formula (I).

[0050] FIG.25 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a mesylate salt of a compound of Formula (I).

[0051] FIG.26 shows an XRPD pattern of a crystalline form of a sulfate salt of a compound of Formula (I).

[0052] FIG.27 shows a simultaneous thermal analysis (SDT) thermogram of a crystalline form of a sulfate salt of a compound of Formula (I).

[0053] FIG.28 shows an XRPD pattern of a crystalline form of a citrate salt of a compound of Formula (I).

[0054] FIG.29 shows an XRPD pattern of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I).

[0055] FIG.30 shows a TGA graph of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I).

[0056] FIG.31 shows a DSC graph of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I).

[0057] FIG.32 shows a DVS curve of a crystalline form of a bis-hydrochloride salt of a compound of Formula (I).

[0058] FIG.33 is a process flow chart for the preparation of a crystalline form of a compound of Formula (I).

[0059] FIG.34 shows PLM images of a crystalline form of a hydrochloride salt of a compound of Formula (II).

[0060] FIG.35 shows PLM images of a crystalline form of a sulfate salt of a compound of Formula (II).

[0061] FIG.36 shows PLM images of a crystalline form of an acetate salt of a compound of Formula (II).

[0062] FIG.37 shows a PSD data plot comparing material isolated from SPPS, LPPS, and material recovered after tabulation of a crystalline form of a compound of Formula (I).

[0063] FIG.38 shows a PSD data plot comparing statically dried versus dynamically dried material of a crystalline form of a compound of Formula (I).

[0064] FIG.39 shows a PSD data plot comparing sieved versus not sieved material of a crystalline form of a compound of Formula (I).

[0065] FIG.40 shows a PSD data plot comparing milling and sieving versus a control of material of a crystalline form of a compound of Formula (I). DETAILED DESCRIPTION I. GENERAL

[0066] The present invention relates to methods for the preparation of crystalline forms of monocyclic peptide compounds, or pharmaceutically acceptable salts thereof, or solvates of thereof, which are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystallineforms of monocyclic peptide compounds, or pharmaceutically acceptable salts thereof, or solvates of thereof, have rheological (flow) properties suitable for manufacturing pharmaceutical compositions. The present invention also relates to crystalline forms of a monocyclic peptide compound, or pharmaceutically acceptable salts thereof, or solvates of thereof, which is a peptide inhibitor of IL-23R, prepared by the methods of the invention.

[0067] The present invention provides methods for the preparation of crystalline forms of monocyclic peptide compounds from monocyclic peptide compounds such as those obtained via a liquid phase peptide synthesis (LPPS). The methods of the present invention provide crystalline forms of the peptide compounds with improved handleability, rheological properties and purity suitable for large scale commercial manufacture without the need for chromatography. The monocyclic peptide compounds may be thixotropic materials. The methods of the present invention allow the isolation of crystalline forms of monocyclic peptide compounds which are thixotropic.

[0068] In particular, the present invention provides methods for the preparation of crystalline forms of a hydrochloride salt of a monocyclic peptide compound having the structure of Formula (I) (SEQ ID NO: 1): (I).

[0069] of crystalline forms of a peptide compound having the structure of Formula (II) (SEQ ID NO: 2):(II).

[0070] The pr ration of crystalline forms of a hydrochloride salt of a peptide compound having the structure of Formula (III) (SEQ ID NO: 3): .

[0071] Theof crystalline forms of an acetate salt of a peptide compound having the structure of Formula (III).II. DEFINITIONS

[0072] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0073] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0074] “A,” “an,” or “a(n)”, is an indefinite article when used in reference to a group of substituents or “substituent group” herein, mean at least one.

[0075] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3. In some embodiments, reference to about a value or parameter includes a description of that value or parameter per se. For example, reference to about 20 molar equivalents includes and describes 20 molar equivalents per se.

[0076] As used in the specification and in the claims, the “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named features, groups, ingredients, or steps and does not exclude the presence of additional features, groups, ingredients, or steps. For example, the language “a peptide of Formula (I’), comprising the amino acid sequence: X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15- X16 (I’),” means that in addition to amino acids X3 through X16, the peptide may include but is not limited to additional amino acids attached to the N-terminus, additional amino acids attached to the C-terminus, N-terminal or C-terminal capping groups, chemical or biological moieties (including but not limited to, for example, lipophilic substituents, antibodies, imaging agents, etc.) conjugated to the peptide at any location, and the like. The term “comprise(s),” “comprising,” “include(s),” “having,” “has,” “can,” or “contain(s),” can include embodiments encompassed by the term "consisting essentially of" or "consisting of."

[0077] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and typically refer to a molecule 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.).

[0078] Unless otherwise indicated, naturally-occurring L-amino acids and D-amino acids are both represented by either conventional three-letter, or capitalized one-letter, amino aciddesignations of Table A1. In some embodiments, naturally-occurring L-amino acids are represented by either conventional three-letter, or capitalized one-letter, amino acid designations of Table 1. In some embodiments, D-amino acids, are represented by lower-case one-letter amino acid designations corresponding to one-letter designations of Table A1, i.e., g, a, l, m, f, w, k, q, e, s, p, v, i, c, y, h, r, n, d, and t. Table A1: Naturally-occurring amino acids GGlycine Gly P Proline ProA Alanine Ala V Valine ValL Leucine Leu I Isoleucine IleM Methionine Met C Cysteine CysF Phenylalanine Phe Y Tyrosine TyrW Tryptophan Trp H Histidine HisK Lysine Lys R Arginine ArgQ Glutamine Gln N Asparagine AsnE Glutamic Acid Glu D Aspartic Acid AspS Serine Ser T Threonine Thr

[0079] The term “L-amino acid,” as used herein, refers to the “L” isomeric form of an amino acid, and conversely the term “D-amino to the “D” isomeric form of an amino acid(e.g., (D)Asp or D-Asp; (D)Phe or D-Phe). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired function is retained by the peptide. D-amino acids may be indicated as customary in lower case when referred to using single-letter abbreviations. 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 of the D isomeric form, for example D-lysine can be represented by dK.

[0080] Less common or non-naturally occurring amino acids are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently employed three- or four-character codes employed for such residues, including, Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α- aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ- Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and Abu (2-aminobutyric acid) or as defined below.

[0081] Some abbreviations useful in describing the invention are defined below in the following Table 1.Table 1. Abbreviations of Non-Natural Amino Acids and Chemical Moieties Abbreviation DefinitionAbbreviation DefinitionAbbreviation Definition NεtlNεbtlLL i L N tlNAbbreviation Definition

[0082] One of skill in the art will appreciate that certain amino acids and other chemical moieties may be modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogen may be removed or replaced by the bond. Accordingly, as used herein, reference to an amino acid or modified amino acid present in a peptide dimer of the present invention (e.g., at position X4 or position X9) is meant to include the form of such amino acid or modified amino acid present in the peptide both before and after forming the intramolecular bond.

[0083] The term “NH2,” as used herein, can refer to a free amino group present at the amino terminus of a polypeptide. The term “OH,” as used herein, can refer to a free carboxy group present at the carboxy terminus of a peptide. Further, the term “Ac,” or “Ac-“ as used herein, refers to Acetyl protection through acylation of the C- or N-terminus of a polypeptide. In certain peptides shown herein, the NH2located at the C-terminus of the peptide indicates an amino group.

[0084] The term “carboxy,” as used herein, refers to –CO2H.

[0085] The term “cyclized,” as used herein, refers to one part of a polypeptide molecule being linked to another part of the polypeptide molecule to form a closed ring, such as by forming a disulfide bridge or thioether bond.

[0086] The term “subunit,” as used herein, refers to one of a pair of polypeptide monomers that are joined to form a dimer peptide composition.

[0087] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the peptides or compounds of the present invention which are water or oil- soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit / risk ratio, and which are effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds 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-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds ofthe present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci.66: 2 (1977). Also, for a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0088] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

[0089] "Halo" or "halogen" refers to bromo (Br), chloro (Cl), fluoro (F) or iodo (I) substituents.

[0090] The terms “haloalkyl” includes alkyl structures in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0091] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0092] “Aminocarbonyl” or “carboxamido” refers to a -CONH2radical.

[0093] “2-Aminoethoxy” refers to -OCH2CH2-NH2 radical.

[0094] “2-Acetylaminoethoxy” refers to -OCH2CH2-N(H)C(O)Me radical.

[0095] The term “mammal” refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0096] An “analog” of an amino acid, e.g., a “Phe analog” or a “Tyr analog” means an analog of the referenced amino acid. A variety of amino acid analogs are known and available inthe art, including Phe and Tyr analogs. In certain embodiments, an amino acid analog, e.g., a Phe analog or a Tyr analog comprises one, two, three, four or five substitutions as compared to Phe or Tyr, respectively. In certain embodiments, the substitutions are present in the side chains of the amino acids. In certain embodiments, a Phe analog has the structure Phe(R2), wherein R2is a Hy, OH, CH3, CO2H, CONH2, CONH2OCH2CH2NH2, t-Bu, OCH2CH2NH2, phenoxy, OCH3, OAllyl, Br, Cl, F, NH2, N3, or guanadino. In certain embodiments, R2is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3or 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-guanadino), Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH2), BhPhe(4-F), Phe(4-F), Phe(3,5 DiF), Phe(CH2CO2H), Phe(penta-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: hTyr, N-Me-Tyr, Tyr(3-tBu), Tyr(4-N3) and βhTyr.

[0097] Substituents are those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0098] “Absorption enhancer” refers to a component that improves or facilitates the mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, permeation enhancers (PEs) are agents aimed to improve oral delivery of therapeutic drugs with poor bioavailability. PEs are capable of increasing the paracellular and / or transcellular passage of drugs. Pharmaceutical excipients that can increase permeation have been termed ‘absorption modifying excipients' (AMEs). AMEs may be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g. EDTA), and emulsifiers (e.g. macrogol glycerides), and may be specifically included in compositions as PEs to improve bioavailability. PEs can be categorized as to how they alter barrier integrity via paracellular or transcellular routes.

[0099] “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, acyl carnitine and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, and chitosans, other mucoadhesive polymers and the like. For example, a suitable IPE for use in the present invention may be sodium caprate.

[0100] “Administering” refers to administration of the composition of the present invention to a subject.

[0101] “Composition” or “Pharmaceutical Composition” as used herein is intended to encompass an invention or product comprising the specified active product ingredient (API), which may include pharmaceutically acceptable excipients, carriers or diluents as described herein, such as in specified amounts defined herein, which results from combination of specific components, such as specified ingredients in the specified amounts as described herein.

[0102] “Granulated mixture” refers to a mixture of two or more agents made by mixing the two or more agents and granulating them together in a particulate form. Such a mixture provides particulate material that is composed of two or more agents. For example, in the present invention, the compositions may include, but are not limited to granulated mixtures of a hydrochloride salt form of the peptide of SEQ ID NO: 1 or solvate thereof and absorption or permeation enhancer, such as sodium caprate. Such a granulated mixture is formed into a particle or tablet forms, which contain a hydrochloride salt form of a compound of Formula (I) or solvate thereof and sodium caprate. In some embodiments, the compositions may include granulated mixtures comprising sodium caprate.

[0103] In an embodiment, provided herein is a pharmaceutical tablet comprising a crystalline form of a monocyclic peptide compound prepared by the methods described herein, and a pharmaceutical excipient.

[0104] “Disintegrant” refers to a pharmaceutical excipient that is incorporated into a composition to promote their disintegration when they come into contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent, used in preparation of tablets, which causes tablets to disintegrate and release medicinal substances on contact with moisture. Examples of disintegrants include, without limitation, crosslinked polymers, including crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and modified starch sodium starch glycolate and the like. Representative disintegrants for use in the present invention, may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low- substituted hydroxypropyl cellulose, or mixtures thereof and the like. In some aspects, disintegrants for use in the present invention, may include, but are not limited to croscarmellosesodium. Additional representative disintegrants for use in the present invention, may include, but are not limited to microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like. Representative disintegrants for use in the present invention, include, but are not limited to, starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like.

[0105] “Disposed over” refers to the placement of one phase or coating on top of another phase or coating. Such placement can conform to the shape of the underlying phase or coating such that the layering of phases and coatings do not leave substantial gaps there between.

[0106] “Enteric coating” refers to any of the commonly applied polymeric coatings employed for delayed release of active ingredients. As conventionally understood in the art, an enteric coating generally is a polymer barrier applied to oral medication that prevents its dissolution or disintegration in the gastric environment. This helps by either protecting drugs from the acidity of the stomach, the stomach from the detrimental effects of the drug, or to release the drug after the stomach (usually in the upper tract of the intestine). Some drugs are unstable at the pH of gastric acid and need to be protected from degradation. An enteric coating is also an effective method to obtain drug targeting (such as gastro-resistant drugs). Such delayed release is typically pH dependent and allows for release of the active ingredient further in the intestinal tract where the pH differs from that in the stomach. In general, suitable materials used for enteric coatings may include, but is not limited to fatty acids, waxes, shellac, plastics, and plant fibers, where such enteric materials, may include, but is not limited to cellulose acetate phthalate, polyvinylalcohol phthalate, shellac, zein, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimaleate, film resins, etc and the like. Additional examples of enteric coating for use in the present invention, may include, without limitation, those based on esters of aleurtic acid, cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), poly(vinyl acetate phthalate) (PVAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP) and the like. Other suitable materials used for enteric coatings may also include, but is not limited to methacrylic acid copolymers, poly(methacrylic acid ethyl acrylate) 1:1, poly(methacrylic acid methyl methacrylate) 1:2, poly(methacrylic acid ethyl acrylate) (L100D-55), combinations of methyl acrylate, methyl methacrylate, hydroxypropyl methylcellulose (HPMC), methacrylic acid (FS30D), Eudragit®, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), and Type L, M or H of HPMC-AS. In some embodiments, the enteric coating is disposed over a subcoating.

[0107] “Glidant” refers to a substance that is added to a powder to improve its flowability and / or lubricity. Examples of glidants, may include, but is not limited to, magnesium stearate, fumed silica, starch, talc and the like.

[0108] “Silica” refers to a pharmaceutical excipient that can be employed as flow agent (anti-caking), adsorbent and desiccant in solid product forms. It can also be used to increase the mechanical stability and the disintegration rate of the compositions. The silica can be fumed, i.e., referring to its production through a pyrogenic process to generate fine particles of silica. Particles of fumed silica can vary in size such as from 5 nm to 100 nm, or from 5 to 50 nm. The particles can be non-porous and have a surface area from 50–1,000 m2 / g or from 50–600 m2 / g. Examples of silicas include Aerosil 200, having a specific surface area of about 200 m2 / g. 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, silicon dioxide fumed, colloidal anhydrous silica, colloidal silicon dioxide, and the like.

[0109] “Lubricant” refers to a substance added to a formulation to reduce friction. Compounds that serve as lubricants can also have properties as glidants. Examples of lubricants may include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate or stearic acid and the like.

[0110] “Microcrystalline cellulose,” or “MCC,” refers to a pharmaceutical grade of cellulose manufactured from a refined wood pulp. The MCC can be unmodified or chemically modified, such as silicified microcrystalline cellulose (SMCC). MCC can serve the function of a bulking agent and aid in tablet formation due to its favorable compressibility characteristics.

[0111] “Patient” or “subject” refers to a living organism, which includes, but is not limited to a human subject suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Further non-limiting examples may include, but is not limited to humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, horse, and other mammalian animals and the like. In some aspects, the patient is human.

[0112] By “pharmaceutically acceptable” it is meant the carrier(s), diluent(s) or excipient(s) must be compatible with the other components or ingredients of the compositions of the present invention, i.e., that which is useful, safe, non-toxic acceptable for pharmaceutical use. In accordance with the present invention pharmaceutically acceptable means approved orapprovable as is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0113] “Hemi” hydrochloride salts refer to salts having a substoichiometric amount of hydrochloride. For example, a hemi hydrochloride salt can have from about 0.1 to about 0.9 molar equivalents of hydrogen chloride associated with the peptide of SEQ ID NO: 1. Representative, non-limiting hemi hydrochloride salts, include, but are not limited to 0.2, 0.3, 0.4, 0.50.6 and 0.7 equivalents HCl associated with peptide of SEQ ID NO: 1. With regard to the present invention, the terms “hemi” hydrochloride salt shall be indistinguishable from the term “partial” hydrochloride. In some embodiments, “hemi” refers to other pharmaceutically acceptable salt forms of the peptide of SEQ ID NO: 1, such as an acetate salt of the peptide of SEQ ID NO: 1, a fumarate salt of the peptide of SEQ ID NO: 1, a glutarate salt of the peptide of SEQ ID NO: 1, a glycolate salt of the peptide of SEQ ID NO: 1, a mesylate salt of the peptide of SEQ ID NO: 1, a bis-hydrochloride salt of the peptide of SEQ ID NO: 1, a citrate salt of the peptide of SEQ ID NO: 1, or a sulfate salt of the peptide of SEQ ID NO: 1.

[0114] “Free base of compound of formula (I)” refers to the peptide of SEQ ID NO: 1 with the following structure: in a salt-free form.

[0115] base of compound of Formula (III)” refer to the peptide of SEQ ID NO: 2 and the peptide of SEQ ID NO: 3 in a salt free form respectively .

[0116] “Crystalline salt of 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 hydrochloridesalt 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 mesylate salt of the compound of Formula (I), a crystalline citrate salt of a compound of Formula (I) , a crystalline bis-hydrochloride 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 may include, but are not limited to, the salts described herein.

[0117] Compositions or pharmaceutical compositions of the present invention may be in different pharmaceutically acceptable forms, which may include, but are not limited to a liquid composition, a tablet or matrix composition, a capsule composition, etc. and the like. When the composition is a tablet composition, the tablet may include, but is not limited to different layers. The tablet composition can also include, but is not limited to one or more coatings.

[0118] “Silicified microcrystalline cellulose,” or “SMCC,” refers to a particulate agglomerate of coprocessed microcrystalline cellulose and silicon dioxide. Suitable for use in the present invention, SMCC may include, but is not limited to amounts from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, where the silicon dioxide can have a particle size from about 1 nanometer (nm) to about 100 microns (μm), based on average primary particle size. For example, the silicon dioxide can contain from about 0.5% to about 10% of the silicified microcrystalline cellulose, or from about 1.25% to about 5% by weight relative to the microcrystalline cellulose. Moreover, the silicon dioxide can have a particle size from about 5 nm to about 40 μm, or from about 5 nm to about 50 μm. The silicon dioxide can have a surface area from about 10 m2 / g to about 500 m2 / g, or from about 50 m2 / g to about 500 m2 / g, or from about 175 m2 / g to about 350 m2 / g. Silicified microcrystalline cellulose is commercially available from a number of suppliers known to one of skill in the art, Including Penwest Pharmaceuticals, Inc., under the trademark PROSOLV®. PROSOLV®is available in a number of grades, including, for example, PROSOLV®SMCC 50, PROSOLV®SMCC 90, and PROSOLV®HD. Other products include, without limitation, SMCC 50LD, SMCC HD90 and SMCC 90LM and the like.

[0119] “Sodium caprate” or “NaC10” refers to the IUPAC compound sodium decanoate having molecular formula C10H19NaO2 and the structural formula:

[0120] In some embodiments, sodium caprate functions as either an absorption enhancer or an excipient in tablet formulation. Sodium caprate is approved by the European Union and Food and Drug Administration (FDA) as a direct food additive for human consumption.

[0121] “Solvate” as used herein, means a physical association of the peptide of SEQ ID NO: 1 of the present invention with one or more solvent molecules. This physical association involves varying degrees bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include hydrates.

[0122] “Sorbitol” refers to the sugar alcohol D-glucitol and which may serve as a binder promoting adhesion of ingredients in tablet compositions.

[0123] “Sugar alcohol” as used herein refers to compounds derived from sugars and containing one or more hydroxyl groups. Sugar alcohol may contain multiple –OH groups and be classified as polyols. Examples of sugar alcohol include but not limited to sorbitol, mannitol, xylitol.

[0124] “Subcoating” refers to any number of film layers disposed over the core tablet that can provide one or more benefits such as, providing a smooth tablet surface to ease swallowing of compositions, accommodate pigmentation to aid in pill identification, provide a moisture barrier, and provide a high tensile strength outer layer of the tablet. Such subcoatings can comprise, but is not limited to graft co-polymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG). Commercial products that provide subcoatings include the line of products under the trade names OPADRY®, OPAGLOS®, and the like. A subcoating may be further covered by one or more additional coatings.

[0125] In some embodiments, the subcoating refers to any number of film layers disposed over the core tablet. Examples of suitable materials for cosmetic subcoatings include a polyvinyl alcohol—polyethylene glycol (PVA-PEG) graft co-polymer (e.g., OPADRY®QX). Other coatings include, without limitation, HPMC, HPC, PVA, Eudragit E based coatings and the like.

[0126] In some embodiments, a subcoating may be further covered by one or more additional coatings, such as an enteric coating or a functional coating. In certain embodiments, a subcoating comprises one or more of a plasticizer, anti-tacking agent, coloring agent, HPMC, HPC, PVA, and Eudragit E based coatings. In some embodiments, a subcoating is covered with one or more additional coatings. In certain embodiments, the one or more additional coatings over the subcoating is an enteric coating. In other embodiments, the one or more additional coatings over the subcoating is a functional coating.

[0127] In some aspects, a subcoating is not covered by one or more additional coatings and is referred to as a cosmetic subcoating. For example, in certain embodiments, a core tablet is covered by a cosmetic coating and the cosmetic coating is not further covered with an enteric coating or a functional coating. In some embodiments, a cosmetic coating can serve as a smooth surface to aid in swallowing the tablet. In some embodiments, a cosmetic coating can provide a vehicle for pigmentation for tablet identification. serve as a smooth surface to aid in swallowing the tablet.

[0128] “Core tablet” refers to a mixture of the components of the core tablet. In some embodiments, the components are one or more of a crystalline form of the peptide of SEQ ID NO: 1, a pharmaceutically acceptable salt thereof, or a solvate of the foregoing, and suitable excipients. In some embodiments, the suitable excipient is one or more of the following, but not limited to, a filler, a disintegrant, a glidant, a lubricant, and an absorption enhancer. A subcoating, a cosmetic coating, an enteric coating, or any combination thereof may be disposed over the core tablet.

[0129] “Therapeutically effective amount” refers to an amount of a compound (i.e., a peptide of SEQ ID NO: 1) or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. "Therapeutically effective amount” further includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient’s general health, the patient’s age, etc. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0130] “Treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation.

[0131] Abbreviation, “(V / V)” refers to the phrase “volume for volume”, i.e., the proportion of a particular substance within a mixture, as measured by volume or a volume amount of a component of the composition disclosed herein relative to the total volume amount of the composition. Accordingly, the quantity is unit less and represents a volume percentage amount of a component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture can indicate 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0132] Abbreviation, “(w / w)” refers to the phrase “weight for weight”, i.e., the proportion of a particular substance within a mixture, as measured by weight or mass or a weight amount of a component of the composition disclosed herein relative to the total weight amount of the composition. Accordingly, the quantity is unit less and represents a weight percentage amount of a component relative to the total weight of the composition. For example, a 2% (w / w) solution can indicate 2 grams of solute is dissolved in 100 grams of solution.

[0133] Systemic routes of administration as conventionally understood in the medicinal or pharmaceutical arts, refer to or are defined as a route of administration of drug, a pharmaceutical composition or formulation, or other substance into the circulatory system so that various body tissues and organs are exposed to the drug, formulation or other substance. As conventionally understood in the art, administration can take place orally (where drug or oral preparations are taken by mouth, and absorbed via the gastrointestinal tract), via enteral administration (absorption of the drug also occurs through the gastrointestinal tract) or parenteral administration (generally injection, infusion, or implantation, etc).

[0134] “Systemically active” peptide drug therapy as it relates to the present invention generally refers to treatment by means of a pharmaceutical composition comprising a peptide active ingredient, wherein said peptide resists immediate metabolism and / or excretion resulting in its exposure in various body tissues and organs, such as the cardiovascular, respiratory, gastrointestinal, nervous or immune systems.

[0135] Systemic drug activity in the present invention also refers to treatment using substances that travel through the bloodstream, reaching and affecting cells in various body tissues and organs. Systemic active drugs are transported to their site of action and work throughout the body to attack the physiological processes that cause inflammatory diseases.

[0136] Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action. Bioavailability of a drug is impacted by the properties of the dosage form, which depend partly on its design and manufacture.

[0137] “Digestive tract tissue” as used herein refers to all the tissues that comprise the organs of the alimentary canal. For example only, and without limitation, “digestive tract tissue” includes tissues of the mouth, esophagus, stomach, small intestine, large intestine, and anus.

[0138] “Amorphous” refers to a solid material having no long range order in the position of its molecules. “Partially amorphous” refers to a solid material having little or no long range order in the position of its molecules. For example, amorphous and partially amorphous materials have 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% crystallinity.

[0139] The term, “Dv50” (or “volume D50” or “volume weighted D50”), as used herein refers to the median particle size based on a volume weighted particle size distribution. Dv50 thus typically describes the particle size (based on a volume weighted distribution), preferably the diameter of a particle in micrometers ( ^m), with 50% of the particles in the distribution having a larger size and 50% of the particles in the distribution having a smaller size than Dv50. In a volume weighted distribution, the parameter “Dv50” typically relates to the diameter (e.g., in micrometers (µm)) of a hypothetical spherical particle, which has the volume of the corresponding actual particle in the distribution (which may or may not be spherical).

[0140] The term “Dv10” as used herein refers to the cut-oft size (preferably in µm) of the particles in a volume weighted distribution, which represent 10% of the total volume of the sample, and which have a particle size equal to or smaller than the Dv10 value.

[0141] The term “Dv50” (or “volume D50” or “volume weighted D50”) refers to the median particle size based on a volume weighted particle size distribution. Dv50 thus typically describes the particle size (based on a volume weighted distribution), preferably the diameter of a particle in micrometers ( ^m), with 50% of the particles in the distribution having a larger size and 50% of the particles in the distribution having a smaller size than Dv50. In a volume weighted distribution, the parameter “Dv50” typically relates to the diameter (e.g., in micrometers (µm)) of a hypothetical spherical particle, which has the volume of the corresponding actual particle in the distribution (which may or may not be spherical).

[0142] The term “Dv90” as used herein refers to the cut-off size (preferably in µm) of the particles in a volume weighted distribution, which represent 90% of the total volume of the sample, and which have a particle size equal to or smaller than the Dv90 value.

[0143] “Span,” “particle size distribution span,” or “span of particle size distribution,” as used herein, refers to a parameter used to describe the general width of the size distribution of particles observed by laser diffraction. The span of a volume-based size distribution is defined asSpan = (Dv90 – Dv10) / Dv50 and gives an indication of how far the 10 percent and 90 percent points are apart, normalized with the midpoint.

[0144] The Dv10, Dv50, Dv90 and span of particle size distribution described herein can be measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer in combination and an Aero S dry dispersion unit is used for the determination of the particle size distribution. III. METHODS FOR PREPARING CRYSTALLINE FORMS

[0145] In general, the present invention relates to methods for the preparation of crystalline forms of monocyclic peptide compounds, or pharmaceutically acceptable salts, or solvates thereof. The peptide compounds are peptide inhibitors of the interleukin-23 receptor (IL-23R). The crystalline compounds and crystalline salts, or solvates, are useful in the preparation of pharmaceutical compositions as defined herein, and in methods and / or uses for the treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0146] According to the present invention, it is possible to provide monocyclic peptide compounds having excellent rheological properties (flowability) useful for manufacturing pharmaceutical compositions. According to the present invention, it is possible to suppress agglomeration which reduces flowability of a pharmaceutical preparation. As a result, the crystalline forms of the monocyclic peptide compound has excellent rheological properties (flowability is realized) making the crystalline forms suitable for the manufacture of pharmaceutical formulations.

[0147] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt, or solvate thereof, having rheological properties suitable for manufacturing pharmaceutical compositions, wherein the method comprises the following steps: (a) dissolving the monocyclic peptide compound, or 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing residual solvent.

[0148] In another aspect, the present invention provides a method for improving the rheological properties of a monocyclic peptide compound, or salt or solvate thereof, wherein the method comprises the following steps: (a) dissolving the monocyclic peptide compound, or 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing residual solvent.

[0149] In another aspect the present invention provides a method for the preparation of a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the structure: ,steps: (a) dissolving the 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 a Liquid Phase Peptide Synthesis; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing residual solvent.

[0150] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt, or solvate thereof, having rheological properties suitable for manufacturing pharmaceutical compositions, wherein the method comprises the following steps: (a) dissolving the monocyclic peptide compound, or salt or solvate thereof, in a first solvent; (b’) adding a second portion of solvent to the mixture obtained in step (a); (c) adding seeds of the crystalline monocyclic peptide compound to the mixture obtained in step (b’) to obtain a slurry; (d’) adding a third portion of solvent to the mixture obtained in step (c); (e) isolating a crystalline monocyclic peptide compound from the mixture obtained in step (d’) and removing residual solvent.

[0151] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt, or solvate thereof, having rheological properties suitable for manufacturing pharmaceutical compositions, wherein the method comprises the following steps: (a) dissolving the monocyclic peptide compound, or salt or solvate thereof, in a first solvent; (h) percolating the mixture obtained in step (a) through an ion exchange resin; (e) isolating a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (h) and removing residual solvent. Step (a)

[0152] In step (a) the monocyclic peptide compound, or salt or solvate thereof, is dissolved in a first solvent. In one embodiment, the monocyclic peptide compound, or salt or solvate thereof, which is dissolved in step (a) is an amorphous or partially amorphous form of the monocyclic peptide compound, or salt or solvate thereof. In one embodiment, the monocyclic peptide compound, or salt or solvate thereof, which is dissolved in step (a) comprises the hydrochloride salt of the monocyclic peptide compound. In one embodiment, the monocyclic peptide compound, or salt or solvate thereof, which is dissolved in step (a) comprises an amorphous or partially amorphous form of the hydrochloride salt of the monocyclic peptidecompound. In one embodiment, the hydrochloride salt of the monocyclic peptide compound comprises the crude product isolated from synthesis of the monocyclic peptide compound.

[0153] 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.

[0154] In some embodiments, step (a) is carried out at a pH of between 5.0 and 6.5. In some embodiments, step (a) is carried out at a pH of between 5.5 and 6.0.

[0155] In some embodiments, the first solvent in step (a) comprises an alkyl alcohol, such as a C1-C12 alkyl alcohol. In some embodiments, the first solvent in step (a) comprises one or more solvents selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the first solvent in step (a) comprises one or more solvents selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the first solvent in step (a) comprises methanol and water

[0156] 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 a C1-C12 alkyl alcohol and H2O. 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 H2O. In some embodiments, the first solvent in step (a) consists of methanol and H2O.

[0157] In some embodiments, the first solvent in step (a) comprises methanol and H2O in a ratio of from 9:1 to 5:5 by volume. In some embodiments, the first solvent in step (a) comprises methanol and H2O in a ratio of from 8:2 to 13:7, or about 7:3 by volume. In some embodiments, the first solvent in step (a) comprises methanol and H2O in a ratio of from by volume.

[0158] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (a) is from 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 from 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 from 15% w / v to 20% w / v.

[0159] 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.

[0160] In some embodiments, the mixture obtained in step (a) is stirred at about 35 °C – 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.

[0161] In some embodiments, the mixture obtained in step (a) is stirred until all of the hydrochloride salt of the monocyclic peptide compound is dissolved.

[0162] In some embodiments, the first solvent in step (a) comprises methanol and H2O in a ratio of from 3:1 and 3:2 by volume.

[0163] In some embodiments, the mixture obtained in step (a) is filtered to provide a solution.

[0164] In some embodiments, step (a) comprises adjusting pH of the solution to be in the range of about 4.5-6.5, about 5-6.5, about 5.5-6.1, or about 5.5-6. In some embodiments, step (a) comprises adjusting pH of the solution to be about 5.8. In some embodiments, step (a) comprises adjusting pH of the solution to be about 5.5-6.1. In some embodiments, adjusting pH can be performed before filtration in step (a). In some embodiments, adjusting pH can be performed after the filtration in step (a).

[0165] In an 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.

[0166] Step (b)

[0167] In step (b) a first portion of sodium chloride is added to the mixture obtained in step (a).

[0168] In some embodiments, in step (b) the sodium chloride is an aqueous solution of sodium chloride. In some embodiments, in step (b) the sodium chloride is a 0.1M to 2M aqueous solution of sodium chloride. In some embodiments, in step (b) the sodium chloride is a 0.5M to 1.5M aqueous solution of sodium chloride. In some embodiments, in step (b) the sodium chloride is about a 1M aqueous solution of sodium chloride. In some embodiments, in step (b) the sodium chloride is about a 0.96 M aqueous solution of sodium chloride.

[0169] In some embodiments, in step (b) the sodium chloride is added over a period of time of at least 10 minutes. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least 30 minutes. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least 45 minutes. In some embodiments, in step (b) the sodium chloride is added over a period of time of about 60 minutes. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least about 90 minutes. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least about 2 hours. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least about 3 hours. In some embodiments, in step (b) the sodium chloride is added over a period of time of at least about 4 hours.

[0170] In some embodiments, in step (b) the sodium chloride is added at a temperature of between about 25°C to about 55 °C. In some embodiments, in step (b) the sodium chloride is added at a temperature of between about 35°C to about 45 °C. In some embodiments, in step (b) the sodium chloride is added at a temperature of about 40 °C.

[0171] In some embodiments, in step (b) from 1.0 to 13.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 5.0 to 12.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 7.0 to 12.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 10.0 to 12.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 10.5 to 11.5 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 1.0 to 13.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 11.0 to 11.5 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) is about from 11.05 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) from 1.5 to 2.5 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (b) about 2.3 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. Step (c)

[0172] In step (c) seeds of crystalline hydrochloride salt of the monocyclic peptide compound are added to the mixture obtained in step (b) to obtain a slurry.

[0173] In some embodiments, the seeds of crystalline monocyclic peptide compound are obtained by a method comprising the following steps: (i) dissolving the monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, in a first solvent; (ii) adding a second solvent to the mixture obtained in step (i); (iii) cooling the mixture obtained in step (ii); and (iv) isolating the crystalline monocyclic peptide compound, or salt or solvate thereof, from the mixture obtained from step (iii) and removing residual solvent.

[0174] In some embodiments, the amount of seeds added is from 0.005 to 0.1 mole equivalents based on the amount of monocyclic peptide compound in step (a). In some embodiments, the amount of seeds added is from 0.008 to 0.08 equivalents based on the amount of monocyclic peptide compound in step (a). In some embodiments, the amount of seeds added is about 0.01 equivalents based on the amount of monocyclic peptide compound in step (a).

[0175] In some embodiments, the slurry obtained in step (c) is allowed to age for a period of at least 1 hour. In some embodiments, the slurry obtained in step (c) is allowed to age for a period of at least 3 hours. In some embodiments, the slurry obtained in step (c) is allowed to age for a period of at least 5 hours. In some embodiments, the slurry obtained in step (c) is allowed to age for a period of about 8 hours.

[0176] In some embodiments, prior to step (c), the slurry is allowed to age at a temperature of about 25°C to about 55 °C. In some embodiments, prior to step (c), the slurry is allowed to age at a temperature of about 35°C to about 45 °C. In some embodiments, prior to step (c) the slurry is allowed to age at a temperature of about 40 °C.

[0177] In some embodiments, the seeds of crystalline monocyclic peptide compound are free-base crystals of the monocyclic peptide compound.

[0178] 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 mins-4h. In some embodiments, the slurry obtained in step (c) is stirred for about 1h-4h. In some embodiments, the slurry obtained in step (c) is stirred for about 1h-3h. In some embodiments, the slurry obtained in step (c) is stirred for about 2h. In some embodiments, the slurry obtained in step (c) is stirred for less than 4h. 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 obtainedin 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. Step (d)

[0179] In step (d), a second portion of sodium chloride is added to the slurry obtained in step (c). Optionally, prior to, or after, the addition of the second portion of sodium chloride, the slurry may be cooled.

[0180] In some embodiments, in step (d) the slurry obtained in step (c) is cooled to a temperature of between about 0° and about 10°C. In some embodiments, in step (d) the slurry obtained in step (c) is cooled to a temperature of between about 3° 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.

[0181] In some embodiments, in step (d) the slurry is cooled to a temperature of between about 0° 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 of between about 0° 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 of between about 0° 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 of between about 3° 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 of between about 3° and about 7°C at a rate of about 0.1°C / min.

[0182] In some embodiments, in step (d) the slurry is cooled to a temperature of about 5°C at a rate of less than 0.5°C / min. In some embodiments, in step (d) the slurry is cooled to a temperature of about 5°C at a rate of about 0.1°C / min.

[0183] In some embodiments, in step (d) the sodium chloride is an aqueous solution of sodium chloride.

[0184] In some embodiments, in step (d) the sodium chloride is added at a temperature of between about 25°C to about 55 °C. In some embodiments, in step (d) the sodium chloride is added at a temperature of between about 35°C to about 45 °C.

[0185] In some embodiments, in step (d) the sodium chloride is a 0.1M to 2M aqueous solution of sodium chloride. In some embodiments, in step (d) the sodium chloride is a 0.5 to 1.5 M aqueous solution of sodium chloride. In some embodiments, in step (d) the sodium chloride is about a 1M aqueous solution of sodium chloride.

[0186] In some embodiments, in step (d) at least 4.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) at least 6.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) at least 8.0 mole equivalents, based onthe amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) at least 7.6 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) at least 2.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) at least 3.0 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) about 2-4 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) about 3-4 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) about 3-3.5 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added. In some embodiments, in step (d) about 3.34 mole equivalents, based on the amount of monocyclic peptide compound in step (a), of NaCl is added.

[0187] In some embodiments, in step (d) the sodium chloride is added over a period of time of at least 30 minutes. In some embodiments, in step (d) the sodium chloride is added over a period of time of at least 1 hour. In some embodiments, in step (d) the sodium chloride is added over a period of time of at least 2 hours. In some embodiments, in step (d) the sodium chloride is added over a period of time of about 4 hours.

[0188] In some embodiments, the slurry obtained in step (d) is allowed to age for a period of at least 1 hour. In some embodiments, the slurry obtained in step (d) is allowed to age for a period of at least 2 hours. In some embodiments, the slurry obtained in step (d) is allowed to age for a period of at least 3 hours. In some embodiments, the slurry obtained in step (d) is allowed to age for a period of about 5 hours. Step (e)

[0189] In step (e) the crystalline monocyclic peptide compound is isolated and residual solvent is removed. In order to isolate the crystalline material, it is important to remove residual solvent. The residual solvent left on the isolated crystalline peptide compound could lead to the crystalline peptide turning thixotropic. The thixotropicity of the peptide compound results in crystalline particle breakage making the particles unsuitable for later processing steps such as tableting. Therefore, removal of the residual solvent in step (d) is needed for maintaining the crystalline form and avoiding thixotropicity of the particles. In some embodiments, removing residual solvent comprises one or more washing steps. In some embodiments, removing residual solvent comprises two washing steps. In some embodiments, removing residual solvent comprises washing the isolated crystalline peptide compound and then drying in vacuum.

[0190] In some embodiments, the residual solvent is removed by washing with a second solvent. In some embodiments, step (e) comprises first washing the isolated crystalline peptide with a mixture of water and 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 isopropyl alcohol. In some embodiments, step (e) comprises washing with a mixture of water and methanol (e.g., water / methanol: 65% / 35% v / v), washing with isopropyl alcohol, and then drying in vacuum.

[0191] Some embodiments relate to a first washing step of washing of the isolated crystalline peptide with a mixture of water and alkyl alcohol helps to remove the residual NaCl. The amount of solvent used for the washing step needs to be sufficient for removing residual NaCl and at the same time not leading to substantial loss in yield. In some embodiments, the amount of washing solvent is in the range of 1 L to 3L of water / alkyl alcohol per 1 mole of the crystalline peptide compound. In some embodiments, the amount of washing solvent is in the range of 1.5 L to 2L of water / alkyl alcohol per 1 mole of the crystalline peptide compound. In some embodiments, the amount of washing solvent is about 1.93L of water / alkyl alcohol per 1 mole of the 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).

[0192] Some embodiments relate to a second washing step of removing the mixture of water and alkyl alcohol (e.g., methanol) by washing with isopropyl alcohol so that the solvent used in the first washing step is replaced with isopropyl alcohol. The washing displacement with isopropyl alcohol is needed to avoid thixotropicity. The amount of solvent used for the second washing step needs to be sufficient for removing the residual water and at the same time not leading to substantial loss in yield. In some embodiments, the amount of washing solvent is in the range of 1 L to 3L of the second solvent per 1 mole of the crystalline peptide compound. In some embodiments, the amount of washing solvent is in the range of 1.5 L to 2L of the second solvent per 1 mole of the crystalline peptide compound. In some embodiments, the amount of washing solvent is about 1.93L of isopropanol per 1 mole of the crystalline peptide compound. In some embodiments, the second washing solvent is isopropanol.

[0193] In some embodiments, in step (e) the precipitate is isolated by filtration and then washed and dried.

[0194] In some embodiments, in step (e) the second solvent comprises an alkyl alcohol. In some embodiments, in step (e) the second solvent is an alkyl alcohol other than methanol. In some embodiments, in step (e) the second solvent comprises 2-propanol (isopropyl alcohol,IPA). In some embodiments, in step (e) the second solvent consists essentially of 2-propanol (isopropyl alcohol).

[0195] In some embodiments, in step (e) the precipitate is washed with the second solvent in a ratio of 1.5 – 2.5 L per mole of the monocyclic peptide compound of step (a). In some embodiments, in step (e) the precipitate is washed with the second solvent in a ratio of about 2 L per mole of the monocyclic peptide compound of step (a).

[0196] In some embodiments, in step (e) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried. In some embodiments, in step (e) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried at a temperature below about 20°C under vacuum. In some embodiments, the crystalline peptide compound is dried at a temperature in the range of about 10°C -50°C. In some embodiments, the crystalline peptide compound is dried at a temperature in the range of about 20°C - 40°C. In some embodiments, the crystalline peptide compound is dried under vacuum.

[0197] This drying step can remove residual solvent from the crystallization process, such as removing isopropyl alcohol. The drying step can take place at, for example, about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C. In another embodiment, the drying step takes place at about 20°C-45°C. In yet another embodiment, the drying step takes place 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 takes place at 50% - 70% RH, e.g., about 65% RH.

[0198] In some embodiments, the amount of residual IPA is l in the crystalline peptide compound ess than 9000ppm, 8000 ppm, 7000 ppm, 6000 ppm, 5000ppm, or 4000ppm after the drying step. In some embodiments, the amount of residual IPA is less than 5000 ppm after the drying step. In some embodiments, the amount of residual methanol in the crystalline peptide compound is less than 8000 ppm, 7000 ppm, 6000 ppm, 5000ppm, 4000ppm, 3000ppm, 2000ppm after the drying step. In some embodiments, the amount of residual methanol is less than 3000ppm after the drying step.

[0199] In some embodiments, the amount of water in the crystalline peptide compound is in the range of about 3-10%, 4-8%, or 4-6% by weight after the drying step. In some embodiments, the amount of water in the crystalline peptide compound is in the range of about 4-6% after the drying step. In some embodiments, the drying step comprises drying the crystalline peptide compound under relative humidity in the range of 50-70% under vacuum while the humidity is provided with humidified nitrogen flow, and the drying continues until the water content of the crystalline peptide compound is in the range of about 3-10% by weight.

[0200] In some embodiments, in step (e) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried under relative humidity of between about 45% and about 75%. In some embodiments, in step (e) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried under relative humidity of between about 50% and about 70%.

[0201] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of the hydrochloride salt.

[0202] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of the acetate salt.

[0203] In some embodiments, the crystalline monocyclic peptide compound is obtained in step (e) in the form of free-base crystalline solid.

[0204] In some embodiments, the crystalline monocyclic peptide compound obtained in step (e) is dissolved in a solvent, which is removed by freeze-drying. Step (b’)

[0205] In step (b’) a second portion of a solvent is added to the mixture obtained in step (a).

[0206] In some embodiments, the second solvent in step (b’) comprises an alkyl alcohol, such as a C1-C12 alkyl alcohol. In some embodiments, the second solvent in step (b’) comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the second solvent in step (b’) comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the second solvent in step (b’) comprises methanol.

[0207] 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 a C1-C12alkyl alcohol and H2O. 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.

[0208] In some embodiments, the second solvent in step (b’) comprises methanol and H2O in a ratio of from 9:1 to 5:5 by volume. In some embodiments, the second solvent in step (b’) comprises methanol and H2O in a ratio of from 8:2 to 13:7, or about 7:3 by volume.

[0209] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (b’) is from 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 from 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 from 15% w / v to 20% w / v.

[0210] 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.

[0211] In some embodiments, the mixture obtained in step (b’) is stirred at about 35 °C – about 55 °C. In some embodiments, the mixture obtained in step (b’) is stirred at about 45 °C.

[0212] In some embodiments, the second portion of a solvent is omitted.

[0213] In some embodiments, the mixture obtained in step (b’) is cooled to about 10 °C – about 25 °C. In some embodiments, the process of cooling mixture obtained in step (b’) is completed in 15 – 60 minutes. In some embodiments, the process of cooling the mixture obtained in step (b’) is completed in 45 minutes. In some embodiments, the process of cooling the mixture obtained in step (b’) is completed in 20 minutes. Step (d’) In step (d’) a third portion of a solvent is added to the mixture obtained in step (c). In some embodiments, the third solvent in step (d’) comprises an alkyl alcohol, such as a C1-C12 alkyl alcohol. In some embodiments, the third solvent in step (d’) comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1- butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1-heptanol, and combinations thereof. In some embodiments, the third solvent in step (d’) comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the third solvent in step (d’) comprises methanol.

[0216] 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 a C1-C12 alkyl alcohol and H2O. 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.

[0217] In some embodiments, the third solvent in step (d’) comprises methanol and H2O in a ratio of from 9:1 to 5:5 by volume. In some embodiments, the third solvent in step (d’) comprises methanol and H2O in a ratio of from 8:2 to 13:7, or about 7:3 by volume.

[0218] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (d’) is from 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 from 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 from 15% w / v to 20% w / v.

[0219] 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.

[0220] In some embodiments, the mixture obtained in step (d’) is stirred at about 35 °C – about 55 °C. In some embodiments, the mixture obtained in step (d’) is stirred at about 45 °C.

[0221] In some embodiments, the third portion of a solvent is omitted.

[0222] In some embodiments, the third portion of a solvent is added of the course of 1–5 hours. In some embodiments, the third portion of a solvent is added of the course of 3 hours. In some embodiments, the third portion of a solvent is added of the course of 1–5 hours.

[0223] In some embodiments, the mixture obtained in step (d’) is cooled to -10–10 °C.

[0224] In some embodiments, the mixture obtained in step (d’) is cooled to -10–10 °C and the mixture stirred for 6–18 hours.

[0225] In some embodiments, the mixture obtained in step (d’) is cooled to -10–10 °C and stirred for 6–18 hours, then warmed to 20–30 °C and stirred for 2–6 hours.

[0226] In some embodiments, the mixture obtained in step (d’) is cooled to -10–10 °C and stirred for 6–18 hours, then warmed to 20–30 °C and stirred for 2–6 hours, then cooled to -10– 10 °C and stirred for 6–18 hours. Step (h)

[0227] 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.

[0228] 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 a C1-C12 alkyl alcohol and H2O. 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 H2O. In some embodiments, the wash solvent in step (h) comprises methanol and H2O. Starting material

[0229] In some embodiments, the method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, further comprises preparing the monocyclic peptide compound by a Solid Phase Peptide Synthesis or a Liquid Phase Peptide Synthesis. In some embodiments, the method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, further comprises preparing the monocyclic peptide compound by a Liquid Phase Peptide Synthesis.

[0230] The method of the present invention provides a method for improving the rheological properties of the monocyclic peptide compound obtained by Liquid Phase Peptide Synthesis.

[0231] Accordingly, in another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: (a) dissolving the monocyclic peptide compound, or salt or solvate thereof, in a first solvent; wherein the monocyclic peptide compound is obtained by a liquid phase peptide synthesis; (b) adding a first portion of sodium chloride to the mixture obtained in step (a); (c) adding seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture, and removing residual solvent. Methods for obtaining the crystalline free base

[0232] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) dissolving a 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (e) and washing with a second solvent;(f) dissolving the hydrochloride salt obtained in step (e) in aqueous hydrochloric acid; (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; and (h) isolating a crystalline monocyclic peptide compound in the form of the free base from the mixture.

[0233] 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.

[0234] In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of between pH 7.0 and pH 9.0. In some embodiments, the buffer solution in step (g) is a phosphate buffer having a pH of 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. Methods for preparing alternative salts

[0235] In another aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps: (a) dissolving the monocyclic peptide compound, or 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d) and removing residual solvent; (f) dissolving the hydrochloride salt obtained in step (e) in aqueous hydrochloric acid; (g) adding a buffer solution to the mixture obtained in step (f) over a period of at least 10 hours; and (h) isolating a crystalline monocyclic peptide compound in the form of the free base from the mixture;(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 (a); (k) adding an anti-solvent; (l) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained from step (k).

[0236] In some embodiments, the second solvent in step (j) comprises methanol and / or water.

[0237] In some embodiments, the antisolvent is an organic solvent. In some embodiments, the antisolvent is a solvent selected from an alkyl alcohol, such as a C1-C12alkyl alcohol, 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 the group consisting of tert- butyl methyl ether (TBME), acetonitrile, and isopropanol (2-propanol).

[0238] In some embodiments, the solution comprising a counterion is a solution comprising a counterion selected from the group consisting of fumarate, glutarate, glycolate, mesylate, sulfate, and citrate. Methods for obtained crystalline seeds

[0239] The present invention further provides methods for the preparation of seeds of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof.

[0240] Accordingly, in a further aspect, the present invention provides a method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, comprising the following steps: (i) dissolving the monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, in a first solvent; (ii) adding a second solvent to the mixture obtained in step (i); (iii) cooling the mixture obtained in step (ii); and (iv) isolating the crystalline monocyclic peptide compound, or salt thereof, from the mixture obtained from step (iii) and removing residual solvent. Step (i)

[0241] In some embodiments, step (i) is carried out at a temperature of from about 15°C to about 80°C. In some embodiments, step (i) is carried out at a temperature of from about 25°C to about 55°C. In some embodiment, step (i) is carried out at a temperature of from about 30°C toabout 50 °C, or from about 35°C to about 45 °C. In some embodiments, step (i) is carried out at a temperature of about 40 °C.

[0242] In some embodiments, the first solvent comprises an alkyl alcohol, such as a C1-C12alkyl alcohol. In some embodiments, the first solvent comprises a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- 1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-pentanol, cyclopentanol, 1-hexanol, and 1- heptanol, and combinations thereof. In some embodiments, the first solvent comprises a solvent selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 2- methyl-1-propanol, 2-methyl-2-propanol, and combinations thereof. In some embodiments, the first solvent comprises methanol.

[0243] In some embodiments, the first solvent comprises H2O. In some embodiments, the first solvent comprises an alkyl alcohol, such as a C1-C12 alkyl alcohol and H2O. 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.

[0244] In some embodiments, the first solvent comprises methanol and H2O in a ratio of from 9:1 to 5:5 by volume. In some embodiments, the first solvent comprises methanol and H2O in a ratio of from 8:2 to 13:7, or about 7:3 by volume.

[0245] In some embodiments, the concentration of the monocyclic peptide compound in the mixture obtained in step (i) is from 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 from 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. Step (ii)

[0246] In some embodiments, in step (ii) the second solvent is added over a period of time of at least 1 hour. In some embodiments, in step (ii) the second solvent is added over a period of time 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 time of about 10 hours.

[0247] In some embodiments, in step (ii) the ratio of the first solvent to second solvent is from 3:1 to 1:3 by volume. In some embodiments, in step (ii) the ratio of the first solvent to second solvent is from 6:4 to 4:6 by volume. In some embodiments, in step (ii) the ratio of the first solvent to second solvent is about 1:1 by volume.

[0248] In some embodiments, the second solvent comprises H2O. In some embodiments, the second solvent consists essentially of H2O.Step (iii)

[0249] Optionally, the mixture obtained in step (ii) is cooled prior to step (iv).

[0250] In some embodiments, in step (iii) the mixture obtained in step (ii) is cooled to a temperature of between about 0° and about 10°C. In some embodiments, in step (iii) the mixture obtained in step (ii) is cooled to a temperature of 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.

[0251] In some embodiments, in step (iii) the mixture obtained in step (ii) is cooled to a temperature of between about 0° 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 of between about 0° and about 10°C at a rate of less than 0.5°C / min. In some embodiments, in step (iii) the rate of cooling is less than 0.1°C / min, or about 0.05 °C / min.

[0252] In some embodiments, prior to step (iii) and after the addition of the second solvent the temperature of the mixture is maintained for a period of time of at least 1 hour. In some embodiments, prior to step (iii) and after the addition of the second solvent the temperature of the mixture is maintained for a period of time of at least 4 hours. In some embodiments, prior to step (iii) and after the addition of the second solvent the temperature of the mixture is maintained for a period of time of at least 7 hours. In some embodiments, prior to step (iii) and after the addition of the second solvent the temperature of the mixture is maintained for a period of time of about 9 hours.

[0253] In some embodiments, after step (iii) the temperature is maintained for a period of time of at least 30 mins. In some embodiments, after step (iii) the temperature is maintained for a period of time of at least 60 mins. In some embodiments, after step (iii) the temperature is maintained for a period of time of at least 90 mins. In some embodiments, after step (iii) the temperature is maintained for a period of time of about 2 hours.

[0254] In some embodiments, after step (iii) the mixture is warmed to a temperature of from about 25 °C to about 55°C, and then cooled to a temperature of between about 0° and about 10°C. In some embodiments, after step (iii) the mixture is warmed to a temperature of from about 35 to about 45 °C, and then cooled to a temperature of between about 3 °C and about 7 °C.

[0255] 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. Step (iv)

[0256] 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. Insome embodiments, in step (iv) the third solvent comprises 2-propanol (isopropyl alcohol). In some embodiments, in step (iv) the third solvent consists essentially of 2-propanol (isopropyl alcohol).

[0257] In some embodiments, in step (iv) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried. In some embodiments, in step (iv) the crystalline monocyclic peptide compound is isolated by filtration and then washed and dried at a temperature below about 20°C under vacuum.

[0258] In some embodiments, the monocyclic peptide compound isolated in step (iv) is in the form of the hydrochloride salt. Milling / Sieve

[0259] In an embodiment, to obtain the crystalline form of a monocyclic peptide compound in a particle form having the particle size and or and / or the particle size distribution as described herein, one skilled in the art may use methods such as a milling process or a sieve process. For example, after the isolation step, the monocyclic peptide compound can be treating with a sieve step. The subsequent sieve step can remove the finest and biggest particles, which could impair achieving the proper rheological properties for pharmaceutical processing. In an embodiment, the isolated crystalline monocyclic peptide is passed through a suitable sieve. In some embodiments, the size of the sieve mesh 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 mesh is about 2 mm. In some embodiments, the size of the sieve mesh is about 4 mm. Drying Step

[0260] In an embodiment, to obtain the crystalline form of a monocyclic peptide compound, one skilled in the art can dry the isolated crystalline monocyclic peptide. This drying step can, for example, remove residual solvent from the crystallization process, such as removing isopropyl alcohol. The drying step can take place at, for example, about 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C. In another embodiment, the drying step takes place at about 20°C- 45°C. In yet another embodiment, the drying step takes place 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 takes place at 50% - 70% RH, e.g., about 65% RH. In some embodiments, the humidity is provided using nitrogen as the carrier gas.

[0261] The drying step can, for example, comprise static drying or dynamic drying. The static drying step occurs with little to no agitation of the crystalline form during the drying process. The dynamic drying step comprises agitating the crystalline monocyclic peptidecompound during the drying step. The dynamic drying step can further comprise heating, exposure to vacuum, or exposure to nitrogen gas. Rheological properties (Flowability)

[0262] Using the methods of the present invention it is possible to improve the rheological properties of the monocyclic peptide compounds, particularly those obtained using a Liquid Phase Peptide Synthesis.

[0263] Accordingly, the present invention provides methods for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, having rheological properties suitable for manufacturing pharmaceutical compositions.

[0264] To be suitable for pharmaceutical processing factors such as definite size and shape of particles; uniformity of particle size; homogeneity of mixing; flowability (flow); moisture content; ability to be compactly formed under pressure are important.

[0265] Rheological properties are those which are used to characterize the flowability of a material. In particular, rheological properties suitable for manufacturing pharmaceutical compositions can be selected from Conditioned Bulk Density, Compressibility, Basic Flow Energy, Stability Index, Cohesion, Flow Function, Angle of Internal Friction, Effective Angle of Internal Friction, and Wall Friction Angle, and combinations thereof. Flow properties are measured according to standardized methods known in the art. IV. PEPTIDE INHIBITORS OF THE INTERLEUKIN-23 RECEPTOR (IL-23R)

[0266] 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 such peptides and compounds. Illustrative peptides of the invention comprise an amino acid sequence or structure described in any of the accompanying tables.

[0267] In a first aspect, the monocyclic peptide compound, or a pharmaceutically acceptable salt thereof, or solvate thereof, comprises an amino acid sequence of Formula (I’): X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I’) wherein X3 is absent or any amino acid;X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha- MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is substituted or unsubstituted Trp; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, 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; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha- MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is any amino acid; X14 is any amino acid; 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 any amino acid; wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyl substituted alanine, and 4Pal is 4-pyridyl substituted alanine O andnd orm a disulfide bond or a thioether bond.

[0068] n certa n embodiments, the peptide compound inhibits the binding of interleukin 23 (IL 23) and an IL 23 receptor.

[0269] 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.

[0270] In certain embodiments, X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy.

[0271] In certain embodiments, X11 is 2-Nal, 2-Nal substituted by alkyl or hydroxy, Phe(2- Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal.

[0272] In certain embodiments, X11 is 2-Nal, or 1-Nal.

[0273] In certain embodiments, X11 is 2-Nal, or 2-Nal substituted by alkyl or hydroxy.

[0274] In certain embodiments, X11 is 2-Nal.

[0275] 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.

[0276] In certain embodiments, X15 is 5-Pyal, His, (D)His, (1-Me)His, (3-Me)His, (D)Lys, (D)Leu, 2Pal, 3Pal, 4Pal; and X16 is absent or Sarc.

[0277] In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is absent.

[0278] In certain embodiments, X16 is any D-amino acid.

[0279] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IIa), (IIb), (IIc) or (IId): X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16 (IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16 (IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16 (IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16 (IId) wherein Trp is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal.wherein Pal is 2Pal, 3Pal, or 4Pal; wherein, unless otherwise indicated, X3-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 a Abu-Cys or Abu-Pen thioether bond.

[0280] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IIa), (IIb), (IIc) or (IId): X3-X4-X5-X6-[Trp]-X8-X9-X10-X11-X12-X13-X14-X15-X16 (IIa), X3-X4-X5-X6-X7-X8-X9-[Phe]-X11-X12-X13-X14-X15-X16 (IIb), or X3-X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-X15-X16 (IIc), or X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-[Pal]-X16 (IId) wherein Trp is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, 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-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 a Abu-Cys or Abu-Pen thioether bond.

[0281] In certain embodiments, 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]-X10-X11-X12-X13-X14-[Pal]-X16 (IIIe), or X4-X5-X6-X7-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16 (IIIf); wherein Trp is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal;wherein, unless otherwise indicated, X4-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 a Abu-Cys or Abu-Pen thioether bond.

[0282] In certain embodiments, the peptide compound comprises an amino acid sequence of Formula (IVa), (IVb), (IVc), (IVd), or (IVe): X4- X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-X15-X16 (IVa), X4-X5-X6-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16 (IVb), X4- X5-X6-X7-X8- X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVc), X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVd); or X4-X5-X6-[Trp]-X8-X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVe) wherein Trp is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal; wherein, unless otherwise indicated, X4-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 a Abu-Cys or Abu-Pen thioether bond.

[0283] In certain embodiments, the monocyclic peptide is a peptide where the peptide is cyclized via a Pen-Pen disulfide bond, or via Abu-Cys or Abu-Pen thioether bond.

[0284] In certain embodiments, X4 is (D)Pen, Pen, or Pen(sulfoxide)

[0285] In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp.

[0286] In certain embodiments, X4 or X9 is independently Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond.

[0287] In certain embodiment, X5 is Asn, Ser, Gln, or Glu.

[0288] In certain embodiments, X5 is Asn.

[0289] In certain embodiments, X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val.

[0290] In certain embodiments, X6 is Thr.

[0291] In certain embodiments, X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac),Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp. In certain embodiments, X8 is Lys(Gly) or Lys(bAla).

[0292] In certain embodiments, X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), Lys(Ac), or Glu.

[0293] In certain embodiments, X8 is Gln. In certain embodiments, X8 is Lys(Ac).

[0294] In certain embodiments, X9 is Pen, (D)Pen, Cys, (D)Cys, or alpha-MeCys. In certain embodiments, X9 is Pen or (D)Pen.

[0295] 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.

[0296] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4- CONH2).

[0297] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)]. In certain embodiments, X10 is Phe[4-(2-aminoethoxy)].

[0298] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha- MeLys, alpha-MeLeu, Ala, cyclohexylAla, Lys, or Aib.

[0299] In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha- MeLys, or alpha-MeLeu.

[0300] In certain embodiments, X12 is alpha-MeLeu. In certain embodiments, X12 is THP.

[0301] In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha- MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac); wherein Y2 is an amino acid. In certain embodiments, X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha- MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or b- homoGlu.

[0302] In certain embodiments, X13 is Glu, Gln, Lys(Ac), or Lys.

[0303] In certain embodiments, X13 is Lys(Ac), or Lys.

[0304] In certain embodiments, X13 is Lys(Ac). In certain embodiments, X13 is Glu.

[0305] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is unsubstituted Trp.

[0306] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamide, cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and X11 is as described for Formula (I).

[0307] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamide, cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and the substitution is at 4-, 5-, 6- or 7- position.

[0308] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with N-phenylacetamide, cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxy, OMe, or OEt; and the substitution is at 4-, 5-, 6- or 7- position.

[0309] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(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.

[0310] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(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.

[0311] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-( N-phenylacetamide),7-Me, 6-Me, 4-OMe, or 6- Cl.

[0312] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-( N-phenylacetamide),7-Me.

[0313] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with phenyl, substituted phenyl, or thienyl.

[0314] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, substituted phenyl, or thienyl.

[0315] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with i) phenyl, unsubstituted or substituted with cyano, halo, alkyl, haloalkyl, aryl hydroxy, alkoxy, or haloalkoxy; or ii) thienyl.

[0316] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with phenyl, unsubstituted or substituted with Me, Et, n- Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl, or amido.

[0317] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Me.

[0318] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X7 is Trp substituted with 7-Ph.

[0319] In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X16 is absent. In certain embodiments, particularly with respect to Formula (IIa)-(IId), (IIIa)-(IIIf), and (IVa)-(IVe), X16 is Sarc.

[0320] In one particular embodiment, particularly with respect to Formula (IIa)-(IId), (IIIa)- (IIIf), and (IVa)-(IVe), X3 is absent.

[0321] In certain embodiments, the peptide compound is Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]- [Sarc]-NH2(SEQ ID NO:1), wherein the peptide compound is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable salt thereof.

[0322] In certain embodiments, the peptide compound is Ac-[Pen]-N-T-[W(7-Me)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2; (SEQ ID NO:1) , or a

[0323] 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):. or a pharm

[0324] 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 (in which [Pen]*-[Pen]* form a disulfide bond); (SEQ ID NO:3): , or a.V. CRYSTALLINE FORMS

[0325] Provided herein are crystalline forms of a peptide inhibitor of the interleukin-23 receptor (IL-23R). Crystalline forms of compounds of Formula (I) were unexpectedly obtained and isolated. Crystalline forms of pharmaceutically acceptable salts of a compound of Formula (I) were prepared, isolated, and found suitable for use in pharmaceutical formulations. As such, crystalline forms of peptides may be uniquely advantageous as the corresponding amorphous forms are often unsuitable for formulating, such as tableting.

[0326] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of Formula (I) : , or a pharmaceutically

[0327] In another aspect, the present invention relates to a crystalline free base form of a compound of Formula (I) .

[0328] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a peptide of SEQ ID NO: 1.

[0329] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (I).

[0330] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a peptide of SEQ ID NO: 1.

[0331] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 1. The crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 1 may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystallineglycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a peptide of SEQ ID NO: 1.

[0332] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a compound of Formula (I).

[0333] 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) may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a compound of Formula (I).

[0334] In some aspects, the crystalline hydrochloride salt form of a compound of Formula (I) has the structure: , or a solvate thereof.

[0335] In other aspects, the crystalline hydrochloride salt form of a compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG.1. In some aspects, the crystalline hydrochloride salt form or solvate thereof is a hemi hydrochloride salt. In some embodiments, the crystalline hydrochloride salt form of a compound of Formula (I) is characterized by an XRPD pattern substantially as set forth in FIG.1 or FIG. 2.

[0336] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a crystalline hydrochloride salt or solvate thereof described herein and one or more pharmaceutically acceptable excipients.

[0337] In other aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of a crystalline salt or solvate thereof described herein and one or more pharmaceutically acceptable excipients. Free Base Form

[0338] In some embodiments, the compound of Formula (I) is a free base of the compound of Formula (I). In some embodiments, the free base of the compound of Formula (I) is crystalline. In some embodiments, the free base of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the free base of the compound of Formula (I) is a hydrate. In some other embodiments, the free base of the compound of Formula (I) is crystalline and in the form of a solvate.

[0339] In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.2 degrees two theta. In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.3 degrees two theta. In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 7.7, 9.1, 9.6, and 13.3 + / - 0.4 degrees two theta.

[0340] In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees two theta.

[0341] In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two thetaangles 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 two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.9, 13.3, 14.0, 14.8, 15.4, 16.0, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees two theta.

[0342] In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees two theta.

[0343] In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.2 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.3 degrees two theta. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.3, 5.8, 6.5, 6.8, 7.7, 8.3, 9.1, 9.6, 10.2, 11.1, 12.4, 12.8, 13.3, 14.0, 14.8, 15.4, 16.0, 16.8, 17.3, 18.0, 18.5, 18.9, 19.4, 20.0, and 20.5 + / - 0.4 degrees two theta. In some embodiments, the crystalline free base salt ofthe compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.11.

[0344] In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as having endotherm 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 solvate thereof is characterized as having substantially a DSC curve as shown in FIG.13.

[0345] In some embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having a TGA graph substantially as shown in FIG.12. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.14.

[0346] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline free base of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients. Salt Ratios

[0347] 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, a crystalline pharmaceutically acceptable salt of a compound of Formula (I) comprises a cationic form of the compound of Formula (I) and a pharmaceutically acceptable anion. For example, a crystalline hydrochloride salt of a compound of Formula (I) comprises the compound of Formula (I) in its cationic form and a chloride anion. The salt compositions described herein include a salt of a compound of Formula (I) wherein the salt is a pharmaceutically acceptable salt chosen from an acetate salt, a fumarate salt, a glycolate salt, a glutarate salt, a mesylate salt, a sulfate salt, a citrate salt, a bis-hydrochloride salt, and the like.

[0348] In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt and the anion is chloride. In some embodiments, the salt of a compound of Formula (I) is an acetate salt and the anion is acetate. In some embodiments, the salt of a compound of Formula (I) is a fumarate salt and the anion is fumarate. In someembodiments, the salt of a compound of Formula (I) is a glutarate salt and the anion is glutarate. In some embodiments, the salt of a compound of Formula (I) is a glycolate salt and the anion is glycolate. In some embodiments, the salt of a compound of Formula (I) is a mesylate salt and the anion is mesylate. In some embodiments, the salt of a compound of Formula (I) is a sulfate salt and the anion is sulfate. In some embodiments, the salt of a compound of Formula (I) is a citrate salt and the anion is citrate. In some embodiments, the salt of a compound of Formula (I) is a bis-hydrochloride salt and the anion is chloride.

[0349] In some embodiments, the molar equivalents of an anion of a crystalline salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of an anion of a salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0, including any amount in between and fractions thereof.

[0350] In some embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.6 to about 0.7.

[0351] In some embodiments, the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of an acetate anion of a crystalline acetate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In certain embodiments, the molar equivalents of an acetate of a crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.6 to about 0.7. In certainembodiments, the molar equivalents of an acetate of a crystalline acetate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.65.

[0352] In some embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In other embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 1.5. In other embodiments, the molar equivalents of a fumarate anion of a crystalline fumarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.

[0353] In some embodiments, the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 1.0. In other embodiments, the molar equivalents of a glutarate anion of a crystalline glutarate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of a glutarate anion of a crystalline glutarate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.5.

[0354] In some embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 1.0. In other embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.3 to about 0.6. In certain embodiments, the molar equivalents of a glycolate anion of a crystalline glycolate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 0.5.

[0355] In some embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I)is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0. In other embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.8 to about 1.9. In certain embodiments, the molar equivalents of a mesylate anion of a crystalline mesylate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 1.8.

[0356] In some embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0. In other embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 1.7. In certain embodiments, the molar equivalents of a sulfate anion of a crystalline sulfate salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is about 1.6.

[0357] In some embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.4 to about 1.5. In other embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 0.5 to about 1.0. In other embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 1.5. In other embodiments, the molar equivalents of a citrate anion of a crystalline citrate salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0.

[0358] In some embodiments, the molar equivalents of a chloride anion of a crystalline bis- hydrochloride salt of a compound of Formula (I) relative to one mole of the compound ofFormula (I) is from about 0.2 to about 2.0. In some embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.0 to about 2.0. In other embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.5 to about 2.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline hydrochloride salt of the compound of Formula (I) relative to one mole of the compound of Formula (I) is from about 1.9 to about 2.0. In certain embodiments, the molar equivalents of a chloride anion of a crystalline bis-hydrochloride salt of a compound of Formula (I) relative to one mole of the compound of Formula (I) is about 2.0. Salt Forms Hydrochloride Salt

[0359] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt. In some embodiments, a hydrochloride salt of the compound of Formula (I) is crystalline. In some embodiments, the hydrochloride salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate. In some other embodiments, the hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0360] In certain embodiments, the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate, having a water content of about 1-20%, 2-15%, 3-10%, 4-8%, 4-6%, or about 5%.

[0361] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a hydrochloride salt. In some embodiments, a hydrochloride salt of the compound of Formula (I) is crystalline. In some embodiments, the hydrochloride salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the hydrochloride salt of the compound of Formula (I) is a hydrate. In some other embodiments, the hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0362] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at twotheta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0363] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0364] In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees two theta. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees two theta. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees two theta.

[0365] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees two theta. In some embodiments,the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.1. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.2.

[0366] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees two theta.

[0367] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4,17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees two theta. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.3.

[0368] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.1, FIG.2, or FIG.3.

[0369] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks 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 solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.5.

[0370] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.4. In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.6.

[0371] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients. Acetate Salt

[0372] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is an acetate salt. In some embodiments, the acetate salt of the compound of Formula (I) is crystalline. In some embodiments, the acetate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the acetate salt of the compound of Formula(I) is a hydrate. In some other embodiments, the acetate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0373] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0374] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0375] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0376] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6,10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees two theta.

[0377] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees two theta.

[0378] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1. + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the peptide of compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.3 degrees two theta.In some embodiments, the crystalline acetate salt of compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees two theta.

[0379] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1. + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at three theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the peptide of SEQ ID NO: 1 or solvate thereof is characterized as having an XRPD pattern having at least three diffraction peaks at two theta angles selected from 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees two theta.

[0380] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, and 19.4 + / - 0.4 degrees two theta.

[0381] In some embodiments, the crystalline acetate salt of the peptide of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4 and 20.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.8, 7.0, 7.6, 7.7, 8.5, 8.6, 9.2, 9.9, 10.1, 10.4, 10.6, 10.7, 11.2, 11.4, 11.8,12.1, 12.8, 13.1, 13.8, 14.3, 14.5, 15.2, 15.5, 15.9, 17.2, 17.4, 18.0, 18.4, 19.1, 19.4, and 20.1 + / - 0.4 degrees two theta. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.7.

[0382] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm 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 solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.9.

[0383] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.8. In some embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.10.

[0384] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline acetate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Fumarate Salt

[0385] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a fumarate salt. In some embodiments, the fumarate salt of the compound of Formula (I) iscrystalline. In some embodiments, the fumarate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the fumarate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the fumarate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0386] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0387] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0388] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0389] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.4 degrees two theta.

[0390] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0, 12.8, 13.3, 14.0, 14.7, 15.7,17.0, 17.6, 19.1, 20.4, 21.7, 23.1, 24.2, 25.4, and 27.1 + / - 0.4 degrees two theta. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.15.

[0391] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 65.3 °C, as determined by DSC. In certain embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve substantially as set forth in FIG.17. In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof is characterized as 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 thecompound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.16.

[0392] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline fumarate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Glutarate Salt

[0393] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a glutarate salt. In some embodiments, the glutarate salt of the compound of Formula (I) is crystalline. In some embodiments, the glutarate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the glutarate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the glutarate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0394] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0395] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0396] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at twotheta 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 two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0397] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.2 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles of 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 two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.4 degrees two theta.

[0398] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.2 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.3 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.6, 8.5, 9.2, 9.9, 10.8, 11.9, 13.0, 13.9, 15.7, 17.0, 17.6, 18.6, 19.2, 20.3, 20.7, 21.4, 23.3, and 25.3 + / - 0.4 degrees two theta. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.18.

[0399] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm 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 solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.19. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having a DVS graph substantially as shown in FIG.20.

[0400] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline glutarate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Glycolate Salt of a Peptide of SEQ ID NO: 1

[0401] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a glycolate salt. In some embodiments, the glycolate salt of the compound of Formula (I) is crystalline. In some embodiments, the glycolate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the glycolate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the glycolate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0402] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0403] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern havingtwo or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0404] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0405] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.2 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.4 degrees two theta.

[0406] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.2 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5+ / - 0.3 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.7, 8.5, 9.2, 10.0, 10.7, 11.5, 12.0,13.1, 14.0, 15.8, 17.1, 17.7, 19.2, 20.2, 20.8, 21.6, 25.4, and 29.5 + / - 0.4 degrees two theta. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.21.

[0407] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 237.0 °C, as determined by SDT. In certain embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having and SDT thermogram substantially as set forth in FIG.22.

[0408] In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.22. In some embodiments, the crystalline glycolate salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.23.

[0409] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline glycolate salt of the compound of Formula (I) or solvate thereof described herein and one or more pharmaceutically acceptable excipients. Sulfate Salt of a Peptide of SEQ ID NO: 1

[0410] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a sulfate salt. In some embodiments, the sulfate salt of the compound of Formula (I) is crystalline. In some embodiments, the sulfate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the sulfate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the sulfate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0411] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof ischaracterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0412] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees two theta.

[0413] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.2 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.3 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.4 degrees two theta.

[0414] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.2 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.3 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized ashaving an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 10.3, 11.3, 12.5, 13.7, 16.8, 17.9, 18.4, 19.8, 20.7, 21.3, and 22.7 + / - 0.4 degrees two theta. In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.26.

[0415] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 255.0 °C, as determined by SDT. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG. 27.

[0416] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof is characterized as 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 solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.27.

[0417] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline sulfate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Mesylate Salt of a Peptide of SEQ ID NO: 1

[0418] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a mesylate salt. In some embodiments, the mesylate salt of the compound of Formula (I) is crystalline. In some embodiments, the mesylate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the mesylate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the mesylate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0419] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0420] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees two theta.

[0421] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.2 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.3 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.4 degrees two theta.

[0422] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.2 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.3 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 4.1, 6.8, 7.6, 9.2, 9.6, 11.3, 12.5, 13.7, 15.5, 16.6, 18.4, 19.8, 20.6, 22.8 and 27.8 degrees two theta + / - 0.4 degrees two theta. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.24.

[0423] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an endotherm peak at about 242.1 °C, as determined by SDT. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG. 25. In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having a weight loss of about 5.4% from about 26.5 °C to about 80.0 °C, as determined by SDT. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof is characterized as having an SDT thermogram substantially as set forth in FIG.25.

[0424] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline mesylate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Citrate Salt of a Peptide of SEQ ID NO: 1

[0425] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a citrate salt. In some embodiments, the citrate salt of the compound of Formula (I) is crystalline. In some embodiments, the citrate salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the citrate salt of the compound of Formula (I) is a hydrate. In some other embodiments, the citrate salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0426] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0427] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.2 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaksat two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.3 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, 9.2, 9.6, 11.3, 12.5, 16.7, and 18.4 + / - 0.4 degrees two theta.

[0428] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.2 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.3 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.4 degrees two theta.

[0429] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.2 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.3 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.3, 6.9, 7.0, 7.6, 8.4, 9.3, 10.0, 10.8, 12.2, 13.1,13.9, 14.1, 15.3, 15.9, 16.3, 17.0, 17.4, 17.9, 19.0, 19.5, 19.8, 20.5, 22.0, 23.1, 24.4, 24.8, 25.2, 26.5, 29.1, 30.5, 32.1, 33.1, and 33.5 + / - 0.4 degrees two theta. In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.28.

[0430] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline citrate salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Bis-Hydrochloride Salt of a Peptide of SEQ ID NO: 1

[0431] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (I) is a bis-hydrochloride salt. In some embodiments, the bis-hydrochloride salt of the compound of Formula (I) is crystalline. In some embodiments, the bis-hydrochloride salt of the compound of Formula (I) is in the form of a solvate. In certain embodiments, the solvate of the bis- hydrochloride salt of the compound of Formula (I) is a hydrate. In some other embodiments, the bis-hydrochloride salt of the compound of Formula (I) is crystalline and in the form of a solvate.

[0432] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.2 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.3 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 4.2, 6.9, 7.6, and 9.2 + / - 0.4 degrees two theta.

[0433] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having two or more diffraction peaks at two theta angles selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0434] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or17.1 + / - 0.2 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.3 degrees two theta. In some embodiments, the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1 + / - 0.4 degrees two theta.

[0435] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.2 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.3 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having at least two diffraction peaks at two theta angles selected from 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.4 degrees two theta.

[0436] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.2 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.3 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having an XRPD pattern having diffraction peaks at two theta angles of at least 3.4, 4.6, 6.1, 8.3, 8.7, 9.1, 9.4, 9.8, 10.1, 11.1, 11.4, 12.0, 12.4, 13.6, 15.1, 15.9, 16.1, 16.7, 17.8, 18.4, 18.7, 19.4, 19.9, and 20.8 + / - 0.4 degrees two theta. In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized by an XRPD pattern substantially as set forth in FIG.29.

[0437] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having endotherm peaks at about 79.5 °C and / or about 235.3 °C, as determined by DSC. In certain embodiments, the crystalline bis- hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DSC curve as substantially set forth in FIG.31.

[0438] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as 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 bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a TGA graph substantially as set forth in FIG.30.

[0439] In some embodiments, the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof is characterized as having a DVS graph substantially as shown in FIG.32.

[0440] In some aspects, the present invention relates to a pharmaceutical composition which comprises a therapeutically effective amount of the crystalline bis-hydrochloride salt of the compound of Formula (I) or solvate thereof described herein and a pharmaceutically acceptable excipient. Purity

[0441] In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof produced by the methods described herein has a purity level of at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least 98%, or at least about 99% as determined by ultra-performance liquid chromatography (UPLC), high-performance liquid chromatography (HPLC), or other appropriate methods. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 100%. In some embodiments, the crystalline salt of the compound of Formula (I) or 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 in between and fractions thereof. In other embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95.0% and 99.9%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 95%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a puritylevel of at least 96%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 97%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 98%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99%. In some embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.5%.

[0442] In some embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or 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 in between and fractions thereof. In other embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.5%. In certain embodiments, the crystalline hydrochloride salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%.

[0443] In some embodiments, the crystalline acetate salt of the compound of Formula (I) or 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 in between and fractions thereof. In certain embodiments, the crystalline acetate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%. In other embodiments, the crystalline salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.5%.

[0444] In some embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount in between and fractions thereof. In other embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 86% and 90%. In other embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 86% and 87%. In certain embodiments, the crystalline fumarate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 86%.

[0445] In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or 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%, about99.6%, about 99.7%, about 99.8%, or about 99.3%, including any amount in between and fractions thereof. In some embodiments, the crystalline glutarate salt of the compound of Formula (I) or 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 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 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 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 solvate thereof has a purity level of at least 99.0%.

[0446] In some embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount in between and fractions thereof. In other embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 95%. In other embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95% and 99%. In other embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 92%. In certain embodiments, the crystalline mesylate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 90%.

[0447] In some embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, or about 98%, or about 99%, including any amount in between and fractions thereof. In other embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 95%. In other embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 95% and 99%. In other embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 90% and 92%. In certain embodiments, the crystalline sulfate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 91%.

[0448] In some embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof. In other embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0% and 99.9%. In certain embodiments, the crystalline citrate salt of the compound of Formula (I) or solvate thereof has a purity level of at least 99.5%.

[0449] In some embodiments, the crystalline free base of the compound of Formula (I) or 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 in between and fractions thereof. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 97.0%. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 98.0%. In certain embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of at least 99.0%. In other embodiments, the crystalline free base of the compound of Formula (I) or 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 solvate thereof has a purity level of between about 98.0%. In other embodiments, the crystalline free base of the compound of Formula (I) or solvate thereof has a purity level of between about 99.0%. Crystalline Forms of Formula (II)

[0450] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of Formula (II): , or a

[0451] In another aspect, the present invention relates to a crystalline free base form of a compound of Formula (II).

[0452] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a peptide of SEQ ID NO: 2.

[0453] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (II).

[0454] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a peptide of SEQ ID NO: 2.

[0455] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 2. The crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 2 may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a peptide of SEQ ID NO: 2.

[0456] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a compound of Formula (II).

[0457] 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 a pharmaceutically acceptable salt of a compound of Formula (II) may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a compound of Formula (II).

[0458] In some aspects, the crystalline hydrochloride salt form of a compound of Formula (II) has the structure: , or a solvate thereof.Crystalline Forms of Formula

[0459] In one aspect, the present invention relates to a pharmaceutical composition of a crystalline salt of a compound of Formula (III): , or a

[0460] In another aspect, the present invention relates to a crystalline free base form of a compound of Formula (III).

[0461] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a peptide of SEQ ID NO: 3.

[0462] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (III).

[0463] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a peptide of SEQ ID NO: 3.

[0464] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 3. The crystalline form of a pharmaceutically acceptable salt of a peptide of SEQ ID NO: 3 may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a peptide of SEQ ID NO: 3.

[0465] In another aspect, the present invention relates to a pharmaceutical composition of a crystalline form of the hydrochloride salt of a compound of Formula (III).

[0466] 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 a pharmaceutically acceptable salt of a compound of Formula (III) may be a crystalline hydrochloride salt, a crystalline acetate salt, a crystalline fumarate salt, a crystalline glycolate salt, a crystalline glutarate salt, a crystalline mesylate salt, a crystalline sulfate salt, a crystalline bis-hydrochloride salt, and a crystalline citrate salt of a compound of Formula (III).

[0467] In some aspects, the crystalline hydrochloride salt form of a compound of Formula (III) has the structure: , or a solvateVI. PARTICLE SIZE OF THE CRYSTALLINE FORMS

[0468] In an embodiment, the method provided herein for the crystallization of the compound of Formula (I) provides a crystalline material characterized by laser diffraction (LD) as having an average particle size distribution (PSD) range of about 1–100 µm. In another embodiment, the crystalline material characterized has an average particle size distribution range of about 1–90 µm. In yet another embodiment, the crystalline material has a particle sizedistribution range of about 2–80 µm. In still another embodiment, the crystalline material has a particle size distribution range of about 3–70 µm.

[0469] In embodiment, the PSD of the crystalline compound of Formula (I) is characterized as having a Dv10 within the range of about 1 µm to 30 µm. In another embodiment, the PSD is characterized as having a Dv10 within the range of about 2 µm to 20 µm. In yet another embodiment, the PSD is characterized as having a Dv10 within the range of about 3 µm to 10 µm.

[0470] In an embodiment, the PSD of the crystalline compound of Formula (I) is characterized as having a Dv50 within the range of 3 µm to 80 µm. In another embodiment, the PSD is characterized as having a Dv50 within the range of 5 µm to 60 µm. In yet another embodiment, the PSD is characterized as having a Dv50 within the range of 10 µm to 40 µm. In some embodiments, the crystalline compound has a Dv50 in the range of about 8 to 50 µm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 to 30 µm. In some embodiments, the crystalline compound has a Dv50 in the range of about 10 to 25 µm. In an embodiment, the PSD of the crystalline compound is characterized as having a Dv50 within 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.

[0471] In an embodiment, the PSD of the crystalline compound of Formula (I) is characterized as having a Dv90 within the range of 10 µm to 110 µm. In another embodiment, the PSD is characterized as having a Dv90 within the range of 20 µm to 100 µm. In yet an embodiment, the PSD is characterized as having a Dv90 within the range of 30 µm to 90 µm.

[0472] In certain embodiments, the PSD values of the crystalline compound of Formula (I) are as follows: 4 µm to 6 µm (Dv10); 14 µm to 19 µm (Dv50); and 34 µm to 60 µm (Dv90).

[0473] In certain embodiments, the PSD values of the crystalline compound of Formula (I) are as follows: 4.5 µm to 5.4 µm (Dv10); 14 µm to 19 µm (Dv50); and 34 µm to 60 µm (Dv90).

[0474] In another embodiment, the PSD includes Dv10 within the range of about 3.0 µm to 11 µm; Dv50 within the range of 11 µm to 33 µm; and Dv90 within the range of 34 µm to 90 µm. In another embodiment, the PSD values of the crystalline compound of Formula (I) are as follows: about 9 µm (Dv10); about 26 µm (Dv50); and about 61 µm (Dv90). In yet other embodiment, the PSD values of the crystalline compound of Formula (I) are as follows: about 3 µm (Dv10); about 11 µm (Dv50); and about 34 µm (Dv90).

[0475] In an embodiment, the method provided herein for the crystallization of the compound of Formula (I) provides a crystalline material characterized by laser diffraction (LD) as having a particle size distribution (PSD) span of 1 to 3. In certain embodiments, span is 1.5 to3.5. In a certain embodiment, the span of the PSD of crystalline hydrochloride salt of the compound of Formula (I) is 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.

[0476] In an embodiment, the method provided herein for the crystallization of the compound of Formula (I) provides a crystalline material characterized by laser diffraction (LD) as having a particle size distribution (PSD) span of 1.99 to 2.90. In certain embodiments, span is 1.99 to 2.47. In a certain embodiment, the span of the PSD of crystalline hydrochloride salt of the compound of Formula (I) is about 2.21.

[0477] In an embodiment, the PSD values and ranges described above are measurements of the crystal hydrochloride salt of the compound of Formula (I). VII. METHOD OF SYNTHESIS

[0478] Compounds of Formula (I’) or a pharmaceutically acceptable salt, or solvate thereof may be prepared using solid phase peptide synthesis or through a convergent liquid phase synthesis. For instance, the cyclic peptide molecule can be made in a liquid phase by coupling the cyclic portion with a linear portion in a liquid phase reaction media.

[0479] However, further processing is required to provide solid forms of the peptide inhibitors with characteristics that provide improved handleability, such as improved rheological (flow) properties, particle size and hygroscopicity, of the peptide inhibitors for use as pharmaceutical ingredients. VIII. PHARMACEUTICAL COMPOSITIONS

[0480] In general, the present invention relates to pharmaceutical hydrochloride salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0481] Further, the present invention relates to pharmaceutical crystalline salt forms and compositions of peptide inhibitors of the interleukin-23 receptor (IL-23R) or solvates thereof, corresponding pharmaceutical compositions, methods and / or uses for treatment of autoimmune inflammation and related diseases and disorders as defined herein.

[0482] In one aspect, the present invention relates to a pharmaceutical composition of a hydrochloride salt of a compound of Formula (I):Ac-[Pen]*-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]*-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E- N-[3-Pal]-Sarc-NH2 (in which ([Pen]*-[Pen]* form a disulfide bond); and having the chemical structure shown below: , or a corresponding

[0483] In some embodiments, the monocyclic peptide comprises an amino acid sequence of Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-(2-aminoethoxy))]-[2-Nal]-[THP]-E-N- [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 is in the L configuration. In certain embodiments, all amino acids are in the L configuration.

[0484] In some embodiments, the crystalline form of a compound of formula (I) or solvate thereof has a moisture content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight. In some embodiments, the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%m 9%, or 10% by weight. In some embodiments, the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of greater than about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5% by weight. In some embodiments, the crystalline form of a compound of formula (I) or solvate thereof has a moisture content level of lower than about 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight.

[0485] In some embodiments, the amount of a crystalline form of a compound of formula (I) or 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 a crystalline form of a compound of formula (I) or 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. n some embodiments, the amount of a crystalline form of a compound of formula (I) or 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 a crystalline form of a compound of formula (I) or 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% by weight. In some embodiments, the amount of a crystalline form of a compound of formula (I) or 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.

[0486] In another aspect, the hydrochloride salt of a compound of Formula (I) or corresponding solvate thereof may be present in any form, such as a hydrate or other solvate. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be provided in crystalline form, in an amorphous form, or a semi-crystalline form. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof is a crystalline form. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof is an amorphous form. In some aspects, the hydrochloride salt of a compound of Formula (I) or solvate thereof is a semi-crystalline form.

[0487] In one aspect, the composition of a hydrochloride salt of a compound of Formula (I) or solvate thereof is a hemi hydrochloride salt. In some aspects, the hemi hydrochloride salt has from about 0.1 to about 0.9, such as from about 0.2 to about 0.8 or from about 0.3 to about 0.7,molar equivalents of hydrogen chloride compared to the compound of Formula (I). In some aspects, the hemi hydrochloride salt has about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or about 0.9 molar equivalents of hydrogen chloride compared to the compound of Formula (I). In some aspects, the hemi hydrochloride salt has about 0.5 molar equivalents of hydrogen chloride compared to the compound of Formula (I).

[0488] In some aspects, the hydrochloride salt form of a compound of Formula (I) or solvate thereof may be a hydrate. In some aspects, the hydrate of the hydrochloride salt of a compound of Formula (I) has from about 0.2 to about 100 molar equivalents of water compared to the compound of Formula (I). In another aspect, the hydrate may be present in a range of about 2% w / w to about 10% w / w water compared to the hydrochloride salt of the compound of Formula (I). The present invention relates to hydrochloride salt compositions of the present invention, which may be in a liquid or a solid composition.

[0489] In some embodiments, the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content in the range of about 0.1% to about 20%, 0.5% to about 15%, about 1% to about 10%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 0.1% to about 5%, about 0.1% to about 4%, or about 0.1% to about 3% by weight. In some embodiments, the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%m 9%, or 10% by weight. In some embodiments, the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of greater than about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5% by weight. In some embodiments, the hydrochloride salt form of a compound of formula (I) or solvate thereof has a moisture content level of lower than about 1%, 1.5%, 2%, 2.7%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 7%, 8%, 9%, or 10% by weight.

[0490] The hydrochloride salt compositions of the present invention can be administered to a subject or patient by any means in accordance with therapeutic administration, which accomplishes intended purpose or pharmaceutical efficacy. Examples include administration by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. In some aspects, the administration of the hydrochloride salt composition of the present invention is adapted for oral administration.

[0491] In another aspect, the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w / w) of the composition and one or more pharmaceutically acceptable excipients.

[0492] In another aspect, the present invention provides a composition, which comprises: a hydrochloride salt of a compound of Formula (I) or solvate thereof; and about 50 mM pH 7.4 phosphate buffered aqueous solution.

[0493] In another aspect, the present invention relates to a composition, which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w / w) of the composition; an absorption enhancer in an amount from about 10% to about 60% (w / w); and one or more pharmaceutically acceptable excipients.

[0494] In some embodiments, the amount of hydrochloride salt of a compound of formula (I) or 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 hydrochloride salt of a compound of formula (I) or 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. n some embodiments, the amount of hydrochloride salt of a compound of formula (I) or 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 hydrochloride salt of a compound of formula (I) or 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% by weight. In some embodiments, the amount of hydrochloride salt of a compound of formula (I) or 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.

[0495] In another aspect, the present invention provides a composition which comprises a hydrochloride salt of a compound of Formula (I) or solvate thereof in an amount of from about 0.1% to about 15% (w / w) of the composition, sodium caprate in an amount of from about 20% to about 45% (w / w) of the composition, and a microcrystalline cellulose.

[0496] In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof, may be present in any amount from about 0.1% to about 15% (w / w) of the composition. For example, the hydrochloride salt of a compound of Formula (I) or solvate thereof, may be present in an amount of from about 0.5% to about 15% (w / w), or from about 1% to about 10%, or from about 0.5% to about 5%, or from about 0.5% to about 3%, or from about 1% to about 3%, or from about 1.5% to about 2.5%, or from about 1.5% to about 2.0% (w / w) of the composition. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof is present in an amount of from about 1% to about 5% (w / w).

[0497] In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 1 to about 5% (w / w). For example, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in amounts including about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition, and any fractional amount in between. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof maybe present in an amount of about 1.8% (w / w).

[0498] In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in any amount, such as an amount of from about 1 mg to about 1000 mg, or from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, or from about 20 mg to about 30 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 1 mg to about 1000 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 5 mg to about 300 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof is from about 25 mg to about 150 mg. In another aspect, the amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be from about 25 mg to about 100 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 1 mg to about 100 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 20 mg to about 40 mg. In another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of from about 20 mg to about 30 mg.

[0499] In yet another aspect, the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, or about 150 mg, including any amount in between and fractionsthereof. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 5 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 10 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 25 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 50 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 75 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 100 mg. In another aspect, an amount of the hydrochloride salt of a compound of Formula (I) or solvate thereof may be present in about 150 mg.

[0500] In another aspect, the amount of the crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I) or solvate thereof may be present in an amount of about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg, including any amount in between and fractions thereof

[0501] In general, pharmaceutical compositions of the present invention may be formed into different dosage forms prepared using conventional materials and techniques known in the pharmaceutical and formulary arts, which may include, but is not limited to techniques, such as mixing, blending and the like and as set forth throughout the instant disclosure. Moreover, pharmaceutical composition used to form dosage forms may also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, etc. and can be in solid or liquid form such as, solid or liquid dosage forms, which may include, but are not limited to tablets, capsules, powders, solutions, suspensions, or emulsions and the like, etc. In accordance with the present invention, solid unit dosage forms may be other conventional types known in the art.

[0502] Suitable compositions of the present invention may be in different forms, including, but are not limited to a liquid, a tablet, a capsule, etc. and the like. In some aspects, the composition may be a tablet composition or a capsule composition.

[0503] Further, suitable for use in the present invention are solutions, which may, but are not limited to, such as in water, saline, aqueous dextrose and related sugar solutions, and glycols such as, propylene glycol or polyethylene glycol, buffered solutions and the like, etc., are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0504] The compositions of the present invention may include a variety of other pharmaceutically acceptable components or excipients, such as, including, but is not limited to, a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like. These components are described within.

[0505] In accordance with the present invention, compositions as described herein may include at least one filler. In some aspects, a composition of the present invention may comprise a filler including, but is not limited to, one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate and the like. In some aspects, a composition of the present invention may include mannitol. In other aspects, a composition of the present invention may include sorbitol.

[0506] Representative fillers for use in the compositions of the present invention may include, but are not limited to, starch, lactitol, lactose, an inorganic calcium salt, microcrystalline cellulose, sucrose, combinations thereof and the like. Additional fillers or diluents for use in the compositions of the present invention, may include, but are not limited to fillers or diluents conventionally known in the art, i.e., which are typically used in formulation of pharmaceutical compounds. Examples of such fillers or diluents for use in accordance with the present invention may include, but are not limited to sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In some 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.

[0507] Moreover, in another aspect, a filler for use in the present invention may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w / w) of a composition as defined in the instant specification. Moreover, such a filler may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, which may include any fractional amount in between those as defined.

[0508] In some embodiments, the filler is present in an amount from about 10% to about 95% (w / w) of the composition as defined in the instant specification. In some embodiments,the filler is present in an amount from about 25% to about 95% (w / w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 30% to about 90% (w / w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 50% (w / w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 40% (w / w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 30% (w / w) of the composition as defined in the instant specification. In some embodiments, the filler is present in an amount from about 10% to about 20% (w / w) of the composition as defined in the instant specification. In certain embodiments, the filler is present in an amount from about 10% to about 15% (w / w). In certain embodiments, the filler is present in an amount of about 12% (w / w).

[0509] In some aspects, the composition further can include microcrystalline cellulose. Several types of microcrystalline cellulose may be suitable for use in compositions described herein, for example, microcrystalline cellulose may be selected from, but is not limited to MICROCEL® or AVICEL®types: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, and the like and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one aspect, a composition for use in the present invention may include microcrystalline cellulose (AVICEL PH102). In another aspect, a composition suitable for use in the present invention may include microcrystalline cellulose (AVICEL PH101).

[0510] In another aspect, a microcrystalline cellulose may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 3% to about 5% (w / w) of a composition as defined in the instant specification. In some aspects, a microcrystalline cellulose may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, which may include any fractional amount in between those as defined. In some aspects, a microcrystalline cellulose may also be present in an amount of from about 3% to about 5% (w / w) of a composition.

[0511] In some aspects, the composition further can include a silicified microcrystalline cellulose. In some aspects, silicified microcrystalline cellulose may be, but is not limited to SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM and the like. In some aspects, silicified microcrystalline cellulose may be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90 or SMCC 90LM. Without being bound by theory, the silicified microcrystalline celluloseis understood to protect an enteric coating from premature erosion by 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, the SMCC can be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 10% to about 50%, or from about 20% to about 50%, or from about 25% to about 45%, or from about 30% to about 40%, or from about 35% to about 37% (w / w) of the composition. In some aspects, the amount of the silicified microcrystalline cellulose is from about 30% to about 70% (w / w) of the composition. In some aspects, the amount of the silicified microcrystalline cellulose is from about 65% to about 85% (w / w) of the composition. In some aspects, the amount of the silicified microcrystalline cellulose is from about 66.5% to about 81.3% (w / w) of the composition. In some aspects, the amount of the silicified microcrystalline cellulose is about 31.3%, about 36.6%, about 37.7%, about 50.9%, about 52%, about 65.2%, about 71.5%, about 79%, or about 80.5% of the composition. The SMCC can be present in an amount of about 30% (w / w) of the composition, or about 31%, 32%, 33%, 34%, 35%, 36%, 36.1%, 36.2%, 36.3%, 36.4%, 36.5%, 36.6%, 36.7%, 36.8%, 36.9%, 37%, 38%, 39%, or about 40% (w / w) of the composition.

[0512] In some embodiments, SMCC is present in an amount of from about 20% to about 90% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 25% to about 85% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 25% to about 45% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 30% to about 40% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 65% to about 90% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 70% to about 85% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 70% to about 75% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of from about 80% to about 85% (w / w), which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 30%. In some embodiments, SMCC is present in an amount of about 40%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 50%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 60%, whichincludes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 70%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 80%, which includes, but is not limited to any fractional amount in between. In some embodiments, SMCC is present in an amount of about 90%, which includes, but is not limited to any fractional amount in between.

[0513] In some embodiments, SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0514] In some aspects, the composition further can include one or more of alpha cellulose, beta cellulose, gamma cellulose, starch, modified-starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate. In some aspects, the composition further can include mannitol.

[0515] In some aspects, a composition of the present invention may include sorbitol. For example, for use in the present invention, sorbitol may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w / w) of the composition. In another aspect, sorbitol can be present in an amount of about 5% (w / w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition. In some aspects, the composition also includes sorbitol in an amount of from about 5% to about 15% (w / w) of the composition. In some aspects, the amount of the sorbitol is from about 10% to about 15% (w / w) of the composition. In some aspects, the composition includes sorbitol in an amount of about 10.7% (w / w) of the composition.

[0516] In some embodiments, a composition of the present invention may include mannitol. For example, for use in the present invention, mannitol may be present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 5% to about 25%, or from about 5% to about 20%, or from about 5 to about 15%, or from about 8 to about 12% (w / w) of the composition. In another embodiment, mannitol can be present in an amount of about 5% (w / w) of the composition, or about 6%, 7%, 8%, 9%, 10%, 10.1%, 10.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11%, 12%, 13%, 14%, or about 15% (w / w) of the composition, which includes, but is not limited to any fractional amount in between. In some embodiments, the composition also includes mannitol in an amount of from about 5% to about 15% (w / w) of the composition. Insome embodiments, the amount of the mannitol is from about 10% to about 15% (w / w) of the composition. In some embodiments, the composition includes mannitol in an amount of about 10.7% (w / w) of the composition.

[0517] In one embodiment, the amount of the sugar alcohol can be present in range from about 1% to about 50% (w / w) of the composition, or from about 5% to about 50%, or from about 5% to about 30%, or from about 10% to about 30% (w / w) of the composition. In some aspects, the amount of the sugar alcohol can be present in an amount of about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some aspects, the amount of the sugar alcohol can be present in an amount higher than about 1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition. In some aspects, the amount of the sugar alcohol can be present in an amount lower than about 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, or about 20% (w / w) of the composition.

[0518] In some embodiments, the pharmaceutical composition described herein does not include an sugar alcohol. In some embodiments, the pharmaceutical composition described herein does not include sorbitol. In some embodiments, the pharmaceutical composition described herein does not include mannitol.

[0519] The composition of the invention may include, but is not limited to at least one disintegrant in an effective therapeutic amount for use as determined in accordance with the present invention. Representative disintegrants for use in the present invention, include, but are not limited to, starches, clays, celluloses, alginates and gums and crosslinked starches, celluloses and polymers, combinations thereof and the like. Additional representative disintegrants for use in the present invention, may include, but are not limited to microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like.

[0520] In some aspects, the disintegrant is a cross-linked carboxymethyl cellulose (croscarmellose), a starch glycolate, a polyvinyl pyrrolidone, a sago starch, psyllium husk, a silicate, or a soy polysaccharide. In some aspects, the disintegrant is croscarmellose sodium or crospovidone. In some aspects, disintegrants for use in the present invention, may include, but are not limited to croscarmellose sodium. In some aspects, a disintegrant for use in the present invention can include crospovidone. In some aspects, a disintegrant may be present in an amount of from about 1% to about 99% (w / w) of a composition of the present invention, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to about 20%, orfrom about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w / w) of the composition. Disintegrants for use in the present invention may also be present in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w / w) of the composition, which include, but is not limited to any fractional amount in between. In some aspects, an amount of the disintegrant may be present in from about 1% to about 10% (w / w) of a composition of the present invention. In some aspects, an amount of the disintegrant may be present in from about 8% to about 12% (w / w) of a composition of the present invention. In some aspects, an amount of the disintegrant may be present in from about 3% to about 8% (w / w) of a composition of the present invention.

[0521] In another aspect, a composition of the present invention may also include, but is not limited to silica in any amount for purposes of the present invention. In particular, silica is exemplified by Aerosil 200, having a specific surface area of about 200 m2 / g. Alternatives to silica may include, but are not limited to talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, combinations thereof and the like.

[0522] In some aspects, a composition of the present invention may further comprise a silica. In one aspect, silica may be present in compositions of the present invention in an amount of from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1.25%, or from about 0.5% to about 1.5%, or from about 1.0% to about 1.25%, or from about 0.1% to about 1%, or from about 0.3% to about 0.7% (w / w) of the composition of the present invention. For example, silica as used in the present invention may be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or about 1.5% (w / w) of the composition, including any fraction amount in between as defined. In another aspect, a composition of the present invention may further include an amount of silica in from about 0.1% to about 1.5% (w / w) of the composition. In another aspect, a composition of the present invention may further include an amount of silica in from about 0.5% to about 2% (w / w) of the composition. In another aspect, a composition of the present invention may further include an amount of silica in from about 0.3% to about 0.7% (w / w) of the composition. In further aspects, a composition of the present invention may further include an amount of silica in about 0.5% (w / w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 1% (w / w) of the composition. Examples of suitable silica materials include, but are not limited to colloidal silicon dioxide, aerosol, colloidalsilica, fumed silica, silicon dioxide fumed, colloidal anhydrous silica, colloidal silicon dioxide, and the like. In some embodiments, the silica is colloidal silica.

[0523] The composition can also include a binder. Binders for use in the compositions of the present invention include binders commonly used in the formulation of pharmaceuticals. Examples of binders for use in the present invention include but are not limited to cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and sodium carboxymethyl cellulose), glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, targacanth, guar, alginates and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like.

[0524] In some embodiments, the binder is hydroxypropyl methylcellulose (HPMC).In some embodiments, binders for use in the present invention may also be present in an amount of about 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, or about 12% (w / w) of the composition, which include, but is not limited to any fractional amount in between.

[0525] In the present invention, the composition may include a lubricant in any suitable amount for use as described herein. Examples of suitable lubricants for use in the present invention, may include, but are not limited to magnesium carbonate, magnesium lauryl sulphate, calcium silicate, talc, fumed silicon dioxide, combinations thereof, and the like. Other useful suitable lubricants, may include, but are not limited to magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like.

[0526] In some aspects, lubricant may include, but is not limited to magnesium stearate. In one aspect, an amount of the lubricant can be present in from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2.5%, or from about 0.1% to about 1%, or from about 0.1% to about 0.5% (w / w) of the composition. In some aspects, an amount of the lubricant can be present in from about 0.5% to about 2.5% or about 0.5% to about 2.0% (w / w) of the composition. In some aspects, an amount of the lubricant can be present in from about 0.1% to about 0.5% (w / w) of the composition. In some aspects, the amount of the lubricant is from about 0.3% to about 0.7% (w / w) of the composition. In some aspects, the amount of the lubricant is about 0.5% (w / w) of the composition. The lubricant can also be present in an amount of about 0.10% (w / w) of the composition, or about 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%,0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or about 0.30% (w / w) of the composition. The lubricant can also be present in an amount of about 0.5% (w / w) of the composition, or about 0.75%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, or about 2.5% (w / w) of the composition. In some aspects, the lubricant may be present in an amount of about 0.25% (w / w).

[0527] In some aspects, the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of from about 0.2% to about 15% (w / w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of from 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) a silica in an amount of about 0.5% (w / w) of the composition; and (vi) a lubricant in an amount of about 0.5% (w / w) of the composition.

[0528] In some embodiments, the pharmaceutical composition includes: (i) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.1% to about 60 % (w / w) of the composition; (ii) a silicified microcrystalline cellulose in an amount of from 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) a silica in an amount of about 0.1% to about 1.0% (w / w) of the composition; and (v) a lubricant in an amount of about 0.5 % to about 1.5% (w / w) of the composition.

[0529] In some embodiments, the pharmaceutical composition includes: (i) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 10% to about 20% (w / w) of the composition; (ii) the 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) the silica in an amount of about 0.2% (w / w) of the composition; and (v) magnesium stearate in an amount of about 0.5% of the composition.

[0530] In some embodiments, the pharmaceutical composition includes: (i) an absorption enhancer in an amount of from about 5% to about 65% (w / w) of the composition; (ii) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.1% to about 15% (w / w) of the composition, and (iii) a silicified microcrystalline cellulose in an amount of from about 10% to about 50% (w / w) of the composition.

[0531] In some embodiments, the pharmaceutical composition includes: (i) an absorption enhancer in an amount of from about 30% to about 45% (w / w) of the composition; (ii) a disintegrant in an amount of from about 5% to 10% (w / w) of the composition; and (iii) thecrystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 0.5% to about 15% (w / w) of the composition; (iv) a silicified microcrystalline cellulose in an amount of from about 30% to about 40% (w / w) of the composition; (v) a silica in an amount of about 0.2% to about 1.5% (w / w) of the composition; (vi) a disintegrant in an amount of about 5% to about 10% (w / w) of the composition; (vii) a filler in an amount of about 7.5% to about 15% (w / w) of the composition; and (viii) a lubricant in an amount of about 0.2 % to about 1.5% (w / w) of the composition.

[0532] 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 from about 10% to about 20% (w / w) of the composition; (ii) an absorption enhancer in an amount of from about 30% to about 45% (w / w) of the composition; (iii) a disintegrant in an amount of from about 0.5% to about 1.0% (w / w) of the composition; (iv) crospovidone in an amount of about 5% (w / w) of the composition; (vi) a microcrystalline cellulose in an amount of about 1.3% (w / w) of the composition; (vii) a silicified microcrystalline cellulose in an amount of from 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) a silica in an amount of about 1.0% (w / w) of the composition; and (xi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0533] In some embodiments, the pharmaceutical composition includes: (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) the crystalline form of the pharmaceutically acceptable salt of the compound of Formula (I), or a solvate thereof, in an amount of from about 3.9% (w / w) of the composition; (iv) a 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) a silica in an amount of from 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.

[0534] 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 from about 10% to about 20% (w / w) of the composition; (ii) an absorption enhancer in an amount of from about 30% to about 45% (w / w) of the composition; (iii) a disintegrant in an amount of from about 0.5% to about 1.0% (w / w) of the composition; (iv)crospovidone in an amount of about 5% (w / w) of the composition; (v) a microcrystalline cellulose in an amount of about 1.3% (w / w) of the composition; (vi) a silicified microcrystalline cellulose in an amount of from 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) a silica in an amount of about 1.0% (w / w) of the composition; and (x) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0535] In some aspects, the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 1% (w / w) of the composition; (ii) a 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) a silica in an amount of about 0.5% (w / w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0536] In some aspects, the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 2.5% (w / w) of the composition; (ii) a 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) a silica in an amount of about 0.5% (w / w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition.

[0537] In some aspects, the composition includes: (i) the hydrochloride salt of the compound of Formula (I) or solvate thereof in an amount of about 10% (w / w) of the composition; (ii) a 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) a silica in an amount of about 0.5% (w / w) of the composition; and (vi) magnesium stearate in an amount of about 0.5% (w / w) of the composition. The tablet composition can also include one or more coatings.

[0538] The composition described herein may include a variety of other pharmaceutically acceptable components or excipients, such as, including, but is not limited to, a glidant, a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components or excipients and the like.

[0539] The composition described herein can include at least one disintegrant in any suitable amount in accordance with the present invention. Representative disintegrants for use in the present invention, may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodiumstarch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like. In one aspect, the disintegrant may include croscarmellose sodium. In one aspect, the disintegrant may include crospovidone. In another aspect, suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any fractional amount in between as defined in the present invention. In another aspects of the present invention, disintegrant may be, but is not limited to being present in an amount of about 1 to 10% (w / w) of the composition. In other aspects, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0540] In some aspects, the microcrystalline cellulose can be present in an amount of from 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.

[0541] In some aspects, the composition further may comprise silica. In some aspects, the composition further may comprise silica in an amount of from about 0.1% to about 1.5% (w / w) of the composition. For example, the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w / w) of the composition, including any fraction amount in between as defined herein. In some aspects, the composition further may comprise silica in an amount of from about 0.3% to about 0.7% (w / w) of the composition. In some aspects, the composition further may comprise silica in an amount of from about 0.5% to about 2% (w / w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 0.5% (w / w) of the composition.

[0542] In another aspect, the composition of the present invention may further comprise at least one of: a disintegrant in an amount from about 1% to about 10% (w / w) of the composition, a microcrystalline cellulose in an amount from about 1% to about 10% (w / w) of the composition, a silica in an amount from about 0.1% to about 1.5% (w / w) of the composition, or sorbitol in an amount from about 5% to about 15% (w / w) of the composition.

[0543] In yet another aspect, the composition further may comprise: a disintegrant in an amount from about 1% to about 10% (w / w) of the composition; a microcrystalline cellulose in an amount from about 1% to about 10% (w / w) of the composition; a silica in an amount from about 0.1% to about 1.5% (w / w) of the composition; and sorbitol in an amount from about 5% to about 15% (w / w) of the composition.

[0544] In some aspects, the compositions of the present invention further may comprise at least one of: a microcrystalline cellulose in an amount of about 3.9% (w / w); sorbitol in anamount of about 10.7% (w / w); a disintegrant in an amount of about 5.0% (w / w); and a silica in an amount of about 0.5% (w / w).

[0545] In some aspects, the compositions further may comprise: a microcrystalline cellulose in an amount of about 3.9% (w / w); sorbitol in an amount of about 10.7% (w / w); a disintegrant in an amount of about 5.0% (w / w); and a silica in an amount of about 0.5% (w / w).

[0546] In some aspects, the compositions further may 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).

[0547] The microcrystalline cellulose can include any microcrystalline cellulose known in the art. In some aspects, the microcrystalline cellulose may comprise a silicified microcrystalline cellulose (SMCC).

[0548] In some aspects, for use in the present invention, microcrystalline cellulose may be a silicified microcrystalline cellulose (SMCC) and may have any particle size. In some aspects, the composition includes silicified microcrystalline cellulose in an amount of from about 25% to about 45% (w / w) of the composition. In some aspects, the composition includes silicified microcrystalline cellulose in an amount of about 36.6% (w / w) of the composition.

[0549] The composition can include at least one disintegrant in any suitable amount in accordance with the present invention. Representative disintegrants for use in the present invention, may include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums (like gellan), low-substituted hydroxypropyl cellulose, or mixtures thereof and the like. In one aspect, the disintegrant may include croscarmellose sodium. In one aspect, the disintegrant may include crospovidone. The disintegrant for use in the present invention, may be, but is not limited to being present in an amount of from about 1% to about 99% (w / w) of the composition, or from about 1% to about 50%, or from about 1% to about 25%, or from about 1% to 20%, or from about 1% to about 10%, or from about 2% to about 8%, or from about 4% to about 6% (w / w) of the composition. In another aspect, suitable disintegrant may be, but is not limited to being present in an amount of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any fractional amount in between as defined in the present invention. In another aspects of the present invention, disintegrant may be, but is not limited to being present in an amount of about 1% to about 10% (w / w) of the composition. In other aspects, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0550] In another aspect, the composition may also include silica in any amount in accordance with the present invention. Silica is exemplified by Aerosil 200, having a specific surface area of about 200 m2 / g. Alternatives to silica include, without limitation, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof and the like. Silica (e.g., Aerosil 200) may be present in the compositions in an amount of from about 0.1 to 10% (w / w) of the composition, or from about 0.1 to 5%, or from about 0.1 to 2%, or from about 0.1 to 1.5%, or from about 0.1 to 1%, or from about 0.3 to 0.7% (w / w) of the composition. For example, the Aerosil 200 silica can be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or 1.5% (w / w) of the composition, including any fraction amount in between.

[0551] In some aspects, the composition further may comprise silica (e.g., Aerosil 200). In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in in an amount of from about 0.1% to about 1.5% (w / w) of the composition. For example, the silica can be present in an amount of about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, or about 1.5% (w / w) of the composition, including any fraction amount in between as defined herein. In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.3% to about 0.7% (w / w) of the composition. In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.5% to about 2% (w / w) of the composition. In some aspects, the composition further may comprise silica in an amount of about 0.5% (w / w) of the composition. In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in an amount of about 1% (w / w) of the composition.

[0552] The composition described herein can include a variety of other pharmaceutically excipients or components, which may include, but is not limited to a lubricant, a disintegrant, a binder, a desiccant, a filler, and other components and the like. For use in the present invention, a disintegrant may be present in the compositions in an amount of from about 0.1% to about 10% (w / w) of the composition, or from about 0.1% to about 5%, or from about 0.1% to about 2%, or from about 0.1% to about 1.5%, or from about 0.1% to about 1%, or from about 0.1% to about 0.4% (w / w) of the composition. In some aspects, the composition further may comprise a disintegrant. In some aspects, the composition further may comprise silica (e.g., Aerosil 200) in an amount of from about 0.1% to about 1.5% (w / w) of the composition. In some aspects, the composition further may comprise a disintegrant in an amount of about 0.25% (w / w) of the composition.

[0553] In some aspects, the compositions disclosed herein can further comprise at least one of: a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount from about 1% to about 10% by weight of the composition, or a silica (e.g., Aerosil 200) in an amount from about 0.1% to about 1.5% by weight of the composition.

[0554] In some aspects, the compositions further can include: a lubricant in an amount from about 0.1% to about 0.5% by weight of the composition; a disintegrant in an amount from about 1% to about 10% by weight of the composition; and a silica (e.g., Aerosil 200) in an amount from about 0.1% to about 1.5% by weight of the composition.

[0555] In some aspects the compositions disclosed herein can further comprise at least one of: a disintegrant in an amount of about 5.0% (w / w); a silica (e.g., Aerosil 200) in an amount of about 0.5% (w / w); and a lubricant in an amount of about 0.25% (w / w).

[0556] In some aspects, the compositions comprises: a silicified microcrystalline cellulose in an amount of about 36.6% (w / w); a disintegrant in an amount of about 5.0% (w / w); a silica (e.g., Aerosil 200) in an amount of about 0.5% (w / w); and a lubricant in an amount of about 0.25% (w / w).

[0557] In some aspects, the compositions 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).

[0558] In some aspects, compositions of the present invention may not include or may exclude use of an absorption enhancer depending on the intended delivery or use thereof and / or for treatment of specific indications as defined in the present invention.

[0559] In some embodiments described herein, such as relating to pharmaceutical compositions, tablets, methods, processes, and the like, the absorption enhancer is excluded. In some embodiments described herein, such as relating to compositions, tablets, methods, processes, and the like, the absorption enhancer is included.

[0560] In other aspects, suitable compositions of the present invention may exhibit improved bioavailability when administered in conjunction with an absorption enhancer.

[0561] In some aspects, compositions of the present invention may include an absorption enhancer. When present, the absorption enhancer may be zwitterionic, cationic, anionic or non- ionic. In one aspect, the absorption enhancer is an intestinal permeation enhancer. In some aspects, the absorption enhancer may be selected from, but is not limited to medium-chain saturated fatty acids, such as a caprate, a caprylate, a myristate, a palmitate, or a stearate, including salt forms, such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate) and the like.

[0562] Other absorption enhancers may include, but is not limited to a citric acid or citrate salt, such as sodium citrate, tartaric acid or tartrate salt, a salicylic acid or a derivative thereof, or a salicylate salt, a fatty acid acylated amino acid, an alkylsaccharide, a C8-o- alkylpolysaccharide, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl- beta-D-maltoside, tridecylbeta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose monotetradecanoate, a coco-glucoside, a cyclodextrins, alkanoyl carnitine such as lauroyl carnitine, myristoyl carnitine or palmitoyl carnitine, lauroyl carnitine chloride, myristoyl carnitine chloride or palmitoyl carnitine chloride, fatty acid acylated amino acids, including, without limitation, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L- aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L- histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N- dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl propionate, N-dodecanoyl-L- proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N- dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L- alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N- decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, N-decanoyl-L- glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium capric histidinate, N- decanoyl-L-histidine, sodium capric isoleucinate, N-decanoyl-L-isoleucine, sodium capric leucinate, N-decanoyl-L-leucine, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric propionate, N- decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N- decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophan, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decylleucine, sodium stearoyl glutamate (e.g., Amisoft HS-11 P), sodium myristoyl glutamate (e.g., Amisoft MS-11), sodium lauroyl glutamate (e.g., Amisoft LS-11), sodium cocoyl glutamate (e.g., Amisoft CS-11), sodium cocoyl glycinate (e.g., Am lite GCS-11), sodium N-decyl leucine, sodium cocoyl glycineand pharmaceutically acceptable salts of any of the aforementioned compounds; or an alkanoyl sarcosinate (e.g., a lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or one of the 20 standard proteinogenic alpha-amino acids that is acylated with a C8-C20 alkanoic acid), an alkylsaccharide (e.g., a C1-C20alkylsaccharide, such as, Multitrope™ 1620-LQ-(MV); or, n- octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose monotridecanoate, sucrose mono-tetradecanoate, a coco- glucoside, alkylsaccharides, a cyclodextrin (e.g., alpha-cyclodextrin, beta-cyclodextrin, gamma- cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin), N-[8-(2- hydroxybenzoyl)amino]caprylic acid, a N-[8-(2-hydroxybenzoyl)amino]caprylate, sodium N-[8- (2-hydroxybenzoyl)amino]caprylate, also referred to as "SNAC"), a calcium chelating compound (e.g., ethylenediaminetetraacetic acid (EDTA), cremophor EL (also referred to as "Kolliphor EL"; CAS no.61791-12-6), chitosan, N,N,N-trimethyl chitosan, benzalkonium chloride, bestatin, or alkanols (e.g., ethanol, decanol), caprylocaproyl polyoxylglycerides (such as caprylocaproyl polyoxyl-8 glycerides; available as LABRASOL® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a C8-C20 alkylamine, a C8-C20 alkenylamine (e.g ., oleylamine), phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate (e.g., polysorbate 80), cholic acid (or a cholate salt, e.g., sodium chlolate), a deoxycholate (e.g ., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, or decyldimethyl ammonio propane sulfonate and the like.

[0563] In some aspects, the absorption enhancer may include, but is not limited to sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid (such as LABRASOL®, available from Gattefosse, USA), sucrose laurate, or lauroyl-L-carnitine (LC, such as PEPTELLIGENCE®, available from Enteris BioPharma, NJ, USA) and the like. In some aspects, the absorption enhancer is sodium caprate, sodium caprylate, sodium palmitate, sodium stearate, sodium citrate, sodium salicylate, sodium salcaprozate (SNAC), a polyethylene glycol (PEG)-modified medium chain fatty acid triglyceride of capric and caprylic acid, sucrose laurate, or lauroyl-L-carnitine (LC).The absorption enhancer can be present in a composition in an amount of from about 1% to about 99% (w / w) of the composition, or from about 5% to about 50% (w / w), or from about 10% to about 50% (w / w), or from about 20% to about 50% (w / w), or from about 30% to about 50% (w / w), or from about 30% to about 40% (w / w), or from about 32% to about 38% (w / w), or from about 35% to about 36% (w / w) of the composition. In some aspects, an amount of the absorption enhancer is present in from about 5% to about 50% (w / w). In some aspects, an amount of the absorption enhancer is present in from about 5% to about 40% (w / w). In some aspects, an amount of the absorption enhancer is present in from about 30% to about 40% (w / w). For example, 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 in between. In some aspects, the absorption enhancer is present in an amount of from about 30% to about 40% (w / w). In some aspects, the absorption enhancer can be present in an amount from about 32% to about 38% (w / w). In some aspects, the absorption enhancer can be present in an amount of about 35.7% (w / w).

[0564] In some aspects, the absorption enhancer used in a composition of the present invention may be sodium caprate.

[0565] The sodium caprate can be present in a composition in an amount of from about 1% to about 99% (w / w) of the composition, or from about 5% to about 50% (w / w), or from about 10% to about 50% (w / w), or from about 20% to about 50% (w / w), or from about 30% to about 50% (w / w), or from about 30% to about 40% (w / w), or from about 32% to about 38% (w / w), or from about 35% to about 36% (w / w) of the composition. In some aspects, the sodium caprate is present in an amou...

Claims

CLAIMS What is claimed is:

1. A method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt, or solvate thereof, having rheological properties suitable for manufacturing pharmaceutical compositions, wherein the method comprises the following steps: (a) dissolving the monocyclic peptide compound, or 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d), and removing 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 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture obtained in step (d), and removing residual solvent.

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

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

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

6. The method of any one of claims 1-5, wherein the first solvent comprises methanol and H2O.

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

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

9. The method of any one of claims 1-8, wherein the first solvent comprises methanol and H2O in a ratio of from 3:1 and 3:2 by volume.

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

5.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

30. The method of any one of claims 1-29, further comprising preparing the monocyclic peptide compound by a Solid Phase Peptide Synthesis.

31. The method of any one of claims 1-29, further comprising preparing the monocyclic peptide compound by a Liquid Phase Peptide Synthesis.

32. The method of any one of claims 1-31, when the amount of the monocyclic peptide compound dissolved in step (a) is at least 10 Kg.

33. A method for the preparation of a crystalline form of a monocyclic peptide compound, or a pharmaceutically acceptable salt, or solvate thereof, comprising the following steps:(i) dissolving the monocyclic peptide compound, or 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 salt thereof, from the mixture obtained from step (iii) and removing residual solvent.

34. The method of claim 33, wherein step (i) is carried out at a temperature of from about 25°C to about 55°C 35. The method of any one of claims 33-34, wherein the first solvent comprises an alkyl alcohol.

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

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

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

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

40. The method of any one of claims 33-39, wherein in step (ii) the second solvent is added over a period of time of at least 1 hour 41. The method of any one of claims 33-40, wherein in step (ii) the ratio of the first solvent to second solvent is from 3:1 to 1:3 by volume.

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

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

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

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

46. The method of any one of claims 33-45 wherein after step (iii) the temperature is maintained for a period of time of at least 30 mins.

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

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

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

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

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

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

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

54. The method of claim 53, wherein the crystalline monocyclic peptide compound is dried with 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 gas.

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

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

58. The method of any one of claims 1-32, wherein the seeds of crystalline monocyclic peptide compound are obtained by the method according to any one of claims 33-51.

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

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

62. The method of any one of claims 59-61 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 anti-solvent; (l) isolating the crystalline salt of the monocyclic peptide compound from the mixture obtained from 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 62-63, wherein the antisolvent is selected from the group consisting of tert-butyl methyl ether (TBME), acetonitrile, and isopropanol (IPA).

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

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

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

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

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

70. The method according to any one of claims 1 to 69, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv10 within the range of about 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 by a Dv50 within the range of about 3 µm to 80 µm; about 5 µm to 60 µm; or about 10 µm to 40 µm.

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

73. The method according to 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 1–3.

74. A pharmaceutical tablet comprising a crystalline form of a monocyclic peptide compound prepared by the method of any of the preceding claims, and a pharmaceutical excipient.

75. The method according to 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’) wherein X3 is absent or any amino acid; X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, or Asp; X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha- MeAsn, alpha-MeThr, alpha-MeSer, or Val; X7 is substituted or unsubstituted Trp; X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac),Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp; X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide); X10 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, 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; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha- MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; X13 is any amino acid; X14 is any amino acid; 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 any amino acid; and wherein X4 and X9 form a disulfide bond or a thioether bond.

76. The method according to 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 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, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal;wherein, unless otherwise indicated, X3-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 a Abu-Cys or Abu-Pen thioether bond.

77. The method according to 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 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, carboxy, 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-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 a Abu-Cys or Abu-Pen thioether bond.

78. The method according to 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 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, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal;wherein, unless otherwise indicated, X4-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 a Abu-Cys or Abu-Pen thioether bond.

79. The method according to 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-[Trp]-X8-X9-[Phe]-X11-X12-X13-X14-[Pal]-X16 (IVb), X4- X5-X6-X7-X8- X9-[Phe]-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVc), or X4-X5-X6-[Trp]-X8-X9-X10-[2-Nal]-X12-X13-X14-[Pal]-X16 (IVd) wherein Trp is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein Phe is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal; wherein, unless otherwise indicated, X4-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 a Abu-Cys or Abu-Pen thioether bond.

80. The method according to 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, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; wherein 2-Nal is unsubstituted 2-Nal. wherein Pal is 2Pal, 3Pal, or 4Pal; wherein, unless otherwise indicated, X4-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 a Abu-Cys or Abu-Pen thioether bond.

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

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

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

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

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

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

88. The method according to 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 structure: , or a90. A method for the preparation of a crystalline form of the hydrochloride salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compoundhaving the structure: ,steps: (a) dissolving the monocyclic peptide compound comprising a 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 seeds of 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 a crystalline monocyclic peptide compound in the form of the hydrochloride salt from the mixture, and removing residual solvent.

91. The method of claim 90, further comprising preparing the crude monocyclic peptide compound by a Liquid Phase Peptide Synthesis.

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

93. The method of claim 92, wherein the monocyclic peptide compound has been obtained by a Liquid Phase Peptide Synthesis.

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

95. The method of claim 94, further comprising preparing the crude monocyclic peptide compound by a Liquid Phase Peptide Synthesis.

96. A method for the preparation of a crystalline form of the acetate salt of a monocyclic peptide compound, wherein the monocyclic peptide compound is a compound having the structure:, (a) dissolving the monocyclic peptide compound comprising a hydrochloride salt of the monocyclic peptide compound in a first solvent; (b) percolating the mixture obtained in step (a) through an anion exchange resin of 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 a Liquid Phase Peptide Synthesis.

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

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

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

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

102. The method according to any one of claims 75-101, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv10 within the range of 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 75-102, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv50 within the range of 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 75-103, wherein the crystalline monocyclic peptide compound is a crystalline solid characterized by a Dv90 within the range of about 10 µm to 110 µm; about 20 µm to 100 µm; or about 30 µm to 90 µm.

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

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

107. The method of any 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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