Polymorphs of pentamidine analogs, formulations, and methods thereof.

Abstract

The present invention relates to the crystalline form of 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide (compound A) or a salt or solvate thereof. Methods for preparing compound (A) and its pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising the crystalline form, and methods and / or uses thereof for the treatment of cancer are also provided. JPEG2026513954000041.jpg48162

Description

[Technical Field]

[0001] The present invention relates to pentamidine analogs or salts, their solvates or forms, corresponding pharmaceutical compositions, methods for preparing them, and methods for treating cancer. [Background technology]

[0002] Crystalline forms offer advantageous properties compared to similar amorphous forms, such as ease of isolation, improved purity, and superior physical and chemical stability. These attributes can be particularly important for pharmaceutical formulations requiring large-scale production, reproducibility, and compound purity. The crystalline form of a compound may also be uniquely significant because the corresponding amorphous form is often unsuitable for formulations such as encapsulation or tableting.

[0003] An analogue of pentamidine is described as Compound 1 (hereinafter referred to as "Compound A") in PCT application WO2020 / 132636A1, the contents of which are incorporated herein by reference in their entirety. [Overview of the project] [Problems that the invention aims to solve]

[0004] There remains a need in this field to develop effective pharmaceutical vehicles, such as pharmaceutical compositions, for delivering therapeutic agents to treat and prevent cancer.

[0005] The present invention addresses these needs by providing a pharmaceutical composition of compound A, or a pharmaceutically acceptable salt or solvate of compound A. [Means for solving the problem]

[0006] 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide (compound A) or its salts or solvates are provided herein, as well as methods for preparing compound A, pharmaceutical compositions, methods for treating cancer and / or uses thereof. [ka]

[0007] Generally, the present invention relates to compound A or a salt thereof, or a solvate or form thereof, a corresponding pharmaceutical composition, a method for treating cancer, and / or use thereof.

[0008] In one embodiment, a method for preparing compound A, a salt thereof, or solvates thereof is provided herein.

[0009] In another embodiment, the present invention also provides compound A or pharmaceutically acceptable salts thereof, or crystalline forms of solvates thereof. Pharmacoagulable salts of compound A provided herein include acetates and phosphates.

[0010] The present invention further provides a pharmaceutical composition comprising a crystalline form 1 of compound A's diacetate or its solvate, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1, and a pharmaceutically acceptable additive.

[0011] The present invention further provides a pharmaceutical composition comprising a crystalline form 2 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 14.

[0012] The present invention further provides a pharmaceutical composition comprising a crystalline form 3 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.

[0013] The present invention further provides a pharmaceutical composition comprising a crystalline form 4 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 26.

[0014] The present invention further provides a pharmaceutical composition comprising a crystalline form 5 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 27.

[0015] The present invention further provides a pharmaceutical composition comprising a crystalline form 6 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 32.

[0016] The present invention further provides a pharmaceutical composition comprising a crystalline form 7 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 37.

[0017] The present invention further provides a pharmaceutical composition comprising a crystalline form 8 of compound A's diacetate or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 42.

[0018] The present invention further provides a pharmaceutical composition comprising a crystalline form 9 of compound A's diacetate or its solvate, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 53, and a pharmaceutically acceptable additive.

[0019] The present invention further provides a pharmaceutical composition comprising a crystalline form 11 of compound A's diacetate or its solvate, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 64, and a pharmaceutically acceptable additive.

[0020] The present invention further provides a pharmaceutical composition comprising a crystalline form 12 of a phosphate of compound A or its solvate, and a pharmaceutically acceptable additive, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 65.

[0021] The present invention further provides a pharmaceutical composition comprising a crystalline form 13 of compound A's diacetate or its solvate, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 66, and a pharmaceutically acceptable additive.

[0022] Compositions comprising compound A in an acetate form or solvate thereof in an amount of about 0.1% to about 60% (w / w) of the composition, and one or more pharmaceutically acceptable additives are also provided herein.

[0023] Compositions comprising compound A or a pharmaceutically acceptable salt thereof, or a crystalline form of a solvate thereof, in an amount of about 0.1% to about 60% (w / w) of the composition, and one or more pharmaceutically acceptable additives are further provided herein.

[0024] A method is provided herein that includes forming a mixture comprising silicified microcrystalline cellulose, lactose monohydrate, and colloidal silicon dioxide; adding the acetate form of compound A or its solvate and blending the mixture; adding magnesium stearate and blending the mixture; and filling capsule shells with the blend.

[0025] Capsules formed by the method described herein are further provided.

[0026] The present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of the composition of the present invention to a subject or patient in need, as described herein.

[0027] The present invention provides for the use of the composition of the present invention in the manufacture of pharmaceuticals for treating cancer. [Brief explanation of the drawing]

[0028] [Figure 1] This graph shows the X-ray powder diffraction (XRPD) pattern of crystalline form 1 of the diacetate salt of compound A.

[0029] [Figure 2] This graph shows a thermogravimetric analysis / differential scanning calorimetry (TG / DSC) thermogram of crystalline form 1 of the diacetate salt of compound A.

[0030] [Figure 3] This graph shows the first thermal thermogram of the DSC of crystalline form 1 of the diacetate salt of compound A.

[0031] [Figure 4] This graph shows the cooled thermogram of the DSC of crystalline form 1 of the diacetate salt of compound A.

[0032] [Figure 5] This graph shows the second thermal thermogram of the DSC of crystalline form 1 of the diacetate salt of compound A.

[0033] [Figure 6] This graph shows a linear thermogram of the DSC (Dynamic Stem Cell) of crystalline form 1 of compound A's diacetate from 20°C to 275°C.

[0034] [Figure 7] This graph shows the dynamic vapor sorption (DVS) isotherm curve for crystalline form 1 of the diacetate salt of compound A obtained at 25°C.

[0035] [Figure 8] This graph shows the DVS dynamics plot of crystalline form 1 of the diacetate salt of compound A obtained at 25°C.

[0036] [Figure 9] This figure shows a polarized light microscopy (PLM) image of crystalline form 1 of the diacetate salt of compound A.

[0037] [Figure 10] This graph shows the Fourier transform infrared (FT-IR) spectrum of crystalline form 1 of the diacetate salt of compound A.

[0038] [Figure 11] This graph shows the ¹H nuclear magnetic resonance (¹H NMR) spectrum of crystalline form 1 of the diacetate salt of compound A.

[0039] [Figure 12] This graph shows the diode array detector (DAD) spectrum of the diacetate salt of compound A in crystalline form 1.

[0040] [Figure 13] This graph shows the liquid chromatography-mass spectrometry (LC-MS) spectrum of crystalline form 1 of the diacetate salt of compound A.

[0041] [Figure 14]This graph shows the XRPD pattern of crystalline form 2 of the diacetate salt of compound A.

[0042] [Figure 15] This graph shows the XRPD pattern of crystalline form 3 of the diacetate salt of compound A.

[0043] [Figure 16] This graph shows the 1H NMR spectrum of crystalline form 3 of the diacetate salt of compound A.

[0044] [Figure 17] This graph shows the TG / DSC thermogram of crystalline form 3 of the diacetate salt of compound A.

[0045] [Figure 18] This graph shows the first thermal thermogram of the DSC of crystalline form 3 of the diacetate salt of compound A.

[0046] [Figure 19] This graph shows the cooled thermogram of the DSC of crystalline form 3 of the diacetate salt of compound A.

[0047] [Figure 20] This graph shows the second thermal thermogram of the DSC of crystalline form 3 of the diacetate salt of compound A.

[0048] [Figure 21] This figure shows a PLM image of crystalline form 3 of the diacetate salt of compound A.

[0049] [Figure 22] This graph shows the FT-IR spectrum of crystalline form 3 of the diacetate salt of compound A.

[0050] [Figure 23] This graph shows the DVS isotherm curve for crystalline form 3 of the diacetate salt of compound A obtained at 25°C.

[0051] [Figure 24] This graph shows the DVS dynamics plot of crystalline form 3 of the diacetate salt of compound A obtained at 25°C.

[0052] [Figure 25] This graph shows a linear thermogram of the DSC (Dynamic Stem Cell) of the diacetate salt of compound A in crystalline form 3 from 20°C to 150°C.

[0053] [Figure 26] This graph shows the XRPD pattern of crystalline form 4 of the diacetate salt of compound A.

[0054] [Figure 27] This graph shows the XRPD pattern of crystalline form 5 of the diacetate salt of compound A.

[0055] [Figure 28] This graph shows the 1H NMR spectrum of the crystalline form 5 of the diacetate salt of compound A.

[0056] [Figure 29] This graph shows the TG / DSC thermogram of crystalline form 5 of the diacetate salt of compound A.

[0057] [Figure 30] This figure shows a PLM image of crystalline form 5 of the diacetate salt of compound A.

[0058] [Figure 31] This graph shows the FT-IR spectrum of crystalline form 5 of the diacetate salt of compound A.

[0059] [Figure 32] This graph shows the XRPD pattern of crystalline form 6 of the diacetate salt of compound A.

[0060] [Figure 33] This graph shows the 1H NMR spectrum of the crystalline form 6 of the diacetate salt of compound A.

[0061] [Figure 34] This graph shows the TG / DSC thermogram of crystalline form 6 of the diacetate salt of compound A.

[0062] [Figure 35] This figure shows a PLM image of crystalline form 6 of the diacetate salt of compound A.

[0063] [Figure 36] This graph shows the FT-IR spectrum of crystalline form 6 of the diacetate salt of compound A.

[0064] [Figure 37] This graph shows the XRPD pattern of crystalline form 7 of the diacetate salt of compound A.

[0065] [Figure 38] This graph shows the 1H NMR spectrum of the crystalline form 7 of the diacetate salt of compound A.

[0066] [Figure 39] This graph shows the TG / DSC thermogram of crystalline form 7 of the diacetate salt of compound A.

[0067] [Figure 40] This figure shows a PLM image of crystalline form 7 of the diacetate salt of compound A.

[0068] [Figure 41] This graph shows the FT-IR spectrum of crystalline form 7 of the diacetate salt of compound A.

[0069] [Figure 42] This graph shows the XRPD pattern of crystalline form 8 of the diacetate salt of compound A.

[0070] [Figure 43] This graph shows the 1H NMR spectrum of the crystalline form 8 of the diacetate salt of compound A.

[0071] [Figure 44] This graph shows the TG / DSC thermogram of crystalline form 8 of the diacetate salt of compound A.

[0072] [Figure 45] This graph shows the first thermal thermogram of the DSC of crystalline form 8 of the diacetate salt of compound A.

[0073] [Figure 46] This graph shows the cooled thermogram of the DSC of crystalline form 8 of the diacetate salt of compound A.

[0074] [Figure 47] This graph shows the second thermal thermogram of the DSC of crystalline form 8 of the diacetate salt of compound A.

[0075] [Figure 48] This figure shows a PLM image of crystalline form 8 of the diacetate salt of compound A.

[0076] [Figure 49] This graph shows the FT-IR spectrum of crystalline form 8 of the diacetate salt of compound A.

[0077] [Figure 50] This graph shows the DVS isotherm curve for crystalline form 8 of the diacetate salt of compound A obtained at 25°C.

[0078] [Figure 51] This graph shows the DVS dynamics plot of crystalline form 8 of the diacetate salt of compound A obtained at 25°C.

[0079] [Figure 52] This graph shows a linear thermogram of the DSC (Dynamic Stem Cell) of the crystalline form 8 of compound A's diacetate from 20°C to 150°C.

[0080] [Figure 53]This graph shows the XRPD pattern of crystalline form 9 of the diacetate salt of compound A.

[0081] [Figure 54] This graph shows the 1H NMR spectrum of the crystalline form 9 of the diacetate salt of compound A.

[0082] [Figure 55] This graph shows the TG / DSC thermogram of crystalline form 9 of the diacetate salt of compound A.

[0083] [Figure 56] This graph shows the first thermal thermogram of the DSC of crystalline form 9 of the diacetate salt of compound A.

[0084] [Figure 57] This graph shows the cooled thermogram of the DSC of crystalline form 9 of the diacetate salt of compound A.

[0085] [Figure 58] This graph shows the second thermal thermogram of the DSC of crystalline form 9 of the diacetate salt of compound A.

[0086] [Figure 59] This figure shows a PLM image of crystalline form 9 of the diacetate salt of compound A.

[0087] [Figure 60] This graph shows the FT-IR spectrum of crystalline form 9 of the diacetate salt of compound A.

[0088] [Figure 61] This graph shows the DVS isotherm curve for crystalline form 9 of the diacetate salt of compound A obtained at 25°C.

[0089] [Figure 62] This graph shows the DVS dynamics plot of crystalline form 9 of the diacetate salt of compound A obtained at 25°C.

[0090] [Figure 63] This graph shows a linear thermogram of the DSC of the crystalline form 9 of compound A's diacetate from 20°C to 100°C.

[0091] [Figure 64] This graph shows the XRPD pattern of crystalline form 11 of the diacetate salt of compound A.

[0092] [Figure 65] This graph shows the XRPD patterns of crystalline form 12 of the phosphate of compound A.

[0093] [Figure 66] This graph shows the XRPD pattern of crystalline form 13 of the diacetate salt of compound A.

[0094] [Figure 67] This figure shows a correlation diagram of several forms of the salt of compound A. [Modes for carrying out the invention]

[0095] I. Overview The present invention relates to 5-((5-(4-carbamimidoylphenoxy)pentyl)oxy)picolinimidoamide (compound A), its salt or solvate, or crystalline forms thereof, a method for preparing compound A, its salt or solvate, or any of these crystalline forms, and a pharmaceutical composition containing compound A, its salt or solvate, or any of these crystalline forms. [ka] II. Definition

[0096] "A (a, an, or a(n))" is an indefinite article and, when used herein in reference to a group of substituents or "group of substituents," means at least one.

[0097] When quoting a value, "approximately" includes the stated value ± 10% of the stated value. For example, approximately 50% includes the range of 45% to 55%, and approximately 20 molar equivalents includes the range of 18 to 22 molar equivalents. Therefore, when quoting a range, "approximately" refers to each of the stated values ​​± 10% of the stated value at each end of the range. For example, the ratio approximately 1 to approximately 3 (weight / weight) includes the range of 0.9 to 3.3. In some embodiments, a quote for approximately one value or parameter includes a description of that value or parameter itself. For example, a quote for approximately 20 molar equivalents includes and describes 20 molar equivalents itself.

[0098] "Administering" refers to administering the composition of the present invention to a target.

[0099] As used herein, “composition” or “pharmaceutical composition” is intended to encompass products containing the present invention or specific active product ingredients (APIs), which may include, for example, pharmaceutically acceptable additives, carriers or excipients described herein in specific amounts as defined throughout the entire disclosure initially filed, and which result from specific combinations of components, for example, specific components in specific amounts described herein.

[0100] A "granulated mixture" refers to a mixture of two or more pharmaceuticals prepared by mixing two or more pharmaceuticals and granulating them together into a specific form. Such a mixture provides a specific substance consisting of two or more pharmaceuticals. For example, in the present invention, a composition may, but is not limited to, a granulated mixture of compound A in acetate form or its solvate and an absorption or penetration enhancer, such as sodium caprate. Such a granulated mixture is formed into particle form or tablet form containing compound A in acetate form or its solvate and sodium caprate. In some embodiments, the composition may include a granulated mixture containing sodium caprate.

[0101] A "disintegrant" refers to a pharmaceutical additive incorporated into a composition to promote disintegration upon contact with a liquid. For example, a disintegrant is a pharmaceutically acceptable agent used in the preparation of tablets that decomposes and releases the pharmaceutical substance when the tablet comes into contact with moisture. Examples of disintegrants include, but are not limited to, cross-linked polymers containing cross-linked polyvinylpyrrolidone (crospovidone) and cross-linked sodium carboxymethylcellulose (croscarmellose sodium), as well as modified starch, sodium starch glycolate, etc. Typical disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium croscarmellose, crospovidone, potassium polaritrin, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as Guerlain), low-substituted hydroxypropylcellulose, or mixtures thereof. In some embodiments, the disintegrant for use in the present invention may include, but is not limited to, sodium croscarmellose. Further 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, and combinations thereof. Representative disintegrants for use in the present invention may include, but are not limited to, starch, clay, cellulose, alginates and gums and cross-linked starch, cellulose and polymers, and combinations thereof.

[0102] "To cover" refers to placing one phase or coating agent on top of another phase or coating agent. Such arrangements can be adapted to the shape of the underlying phase or coating agent so that the layering of the phases and coating agents does not leave any substantial gaps between them.

[0103] "Enteric coating" refers to any of the commonly applied polymer coatings used for the delayed release of active ingredients. As conventionally understood in the art, enteric coatings are generally polymer barriers applied to oral medications to prevent their dissolution or breakdown in the gastric environment. This helps either protect the drug from stomach acid, protect the stomach from the drug's harmful effects, or release the drug after the stomach (usually in the upper intestinal tract). Some drugs are unstable at the pH of stomach acid and need protection from degradation. Enteric coatings are also an effective way to achieve drug targeting (e.g., gastric resistance). Such delayed release is typically pH-dependent, allowing for further release of the active ingredient in the intestinal tract where the pH differs from that of the stomach. Generally, suitable materials used in enteric coatings may include, but are not limited to, fatty acids, waxes, shellac, plastics, and plant fibers. Such enteric materials may include, but are not limited to, cellulose phthalate acetate, polyvinyl alcohol phthalate, shellac, zein, hydroxypropyl methylcellulose phthalate, cellulose acetate trimalate, and film resins. Additional examples of enteric coatings for use herein include, but are not limited to, those based on esters such as aleurtic acid, cellulose acetate phthalate (CAP), poly(methacrylate-co-methacrylate), poly(vinyl acetate phthalate: PVAP), cellulose acetate trimellitate (CAT), and hydroxypropyl methylcellulose phthalate (HPMCP).Other suitable materials used in enteric coating agents may also include poly(methacrylic acid ethyl acrylate) (L100D-55), as well as combinations of methyl acrylate, methyl methacrylate, hydroxypropyl methylcellulose (HPMC), methacrylic acid (FS30D), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and L-type HPMC-AS, but are not limited thereto. In some embodiments, the enteric coating agent covers the subcoating agent.

[0104] "Flow promoter" refers to a substance added to a powder to improve its fluidity and / or lubricity. Examples of flow promoters include, but are not limited to, magnesium stearate, fumed silica, starch, talc, etc.

[0105] "Silica" refers to a pharmaceutical additive that can be used as a fluidizing agent (anti-caking agent), adsorbent, and desiccant in the form of a solid product. It can also be used to increase the mechanical stability and disintegration rate of the composition. Silica can be fumed, i.e., it refers to its product through a pyrolysis method that generates fine particles of silica. The particles of fumed silica can have various sizes, such as 5 nm to 100 nm, or 5 to 50 nm. The particles are non-porous and can have a surface area of 50 to 1,000 m 2 / g or 50 to 600 m 2 / g. An example of silica is Aerosil 200, which has a specific surface area of about 200 m 2 / g. Silica can be hydrophilic. Examples of suitable silica materials include, but are not limited to, SiO2, colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, fumed silicon dioxide, colloidal anhydrous silica, colloidal silicon dioxide, etc.

[0106] "Lubricant" refers to a substance added to a formulation to reduce friction. Compounds that function as lubricants can also have properties as flow promoters. Examples of lubricants include, but are not limited to, talc, silica, and fats such as vegetable stearin, magnesium stearate or stearic acid.

[0107] "Microcrystalline cellulose" or "MCC" refers to a pharmaceutical grade cellulose manufactured from purified wood pulp. MCC can be unmodified, such as silicified microcrystalline cellulose (SMCC), or can be chemically modified. MCC can function as a bulking agent and adjuvant in tablet formation due to its desirable compressibility.

[0108] "Patient" or "subject" refers to a living body and includes, but is not limited to, human subjects who have or are prone to suffer from a disease or condition that can be treated by administration of the pharmaceutical composition provided herein. Further non-limiting examples include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, female cows, deer, horses, and other mammalian animals. In some embodiments, the patient is human.

[0109] "Pharmaceutically acceptable" means that a carrier, excipient or additive should be compatible with other components or ingredients of the composition of the present invention, i.e., acceptable for pharmaceutical use, useful, safe and non-toxic. According to the present invention, pharmaceutically acceptable means approved or approvable as listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0110] "Free base" refers to 5-((5-(4-carbamimidoylphenoxy)pentyl)oxy)picolylimidamide (Compound A) having the following structure:

Chemical formula

[0111] The "crystalline salt" refers to the crystalline form of a pharmaceutically acceptable salt of Compound A, and may include, but is not limited to, the crystalline acetate salt of Compound A and the crystalline phosphate salt of Compound A.

[0112] The composition or pharmaceutical composition of the present invention can be in different pharmaceutically acceptable forms, and may include, but is not limited to, liquid compositions, tablet or matrix compositions, capsule compositions, etc. When the composition is a tablet composition, the tablet may include different layers, but is not limited thereto. The tablet composition can also include one or more coating agents, but is not limited thereto.

[0113] "Silicified microcrystalline cellulose" or "SMCC" refers to an aggregate of particles of microcrystalline cellulose and silicon dioxide processed simultaneously. SMCC is suitable for use in the present invention and may contain from about 0.1% to about 20% of silicon dioxide, based on the weight of microcrystalline cellulose, but is not limited thereto. Silicon dioxide can have a particle size of from about 1 nanometer (nm) to about 100 micrometers (μm) based on the major average particle size. For example, 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. Further, silicon dioxide can have a particle size of from about 5 nm to about 40 μm, or from about 5 nm to about 50 μm. Silicon dioxide is from about 10 m 2 / g to about 500 m 2 / g, or from about 50 m 2 / g to about 500 m 2 / g, or from about 175 m 2 / g to about 350 m 2It may have a surface area of ​​ / g. Silicified microcrystalline cellulose is commercially available from several suppliers known to those skilled in the art, including Penwest Pharmaceuticals, Inc. (as the trademark PROSOLV®). PROSOLV® is available in several grades, including, for example, PROSOLV® SMCC 50, PROSOLV® SMCC 90, and PROSOLV® HD. Other products include, but are not limited to, SMCC 50LD, SMCC HD90, and SMCC 90LM, etc.

[0114] As used herein, “solvate” means a physical bond of compound A or a salt thereof of the present invention with one or more solvent molecules. This physical bond includes various degrees of bonding, including hydrogen bonds. In certain examples, the solvate is isolated. The term “solvate” is intended to encompass both the solution phase and the isolateable solvate. Hydrates are a non-limiting example of a preferred solvate.

[0115] "Sorbitol" refers to the sugar alcohol D-glucitol, which can function as a binder to promote the adhesion of ingredients in a tablet composition.

[0116] As used herein, "sugar alcohol" refers to a sugar-derived compound containing one or more hydroxyl groups. Sugar alcohols may contain multiple -OH groups and may be classified as polyols. Examples of sugar alcohols include, but are not limited to, sorbitol, mannitol, and xylitol.

[0117] "Sub-coating agent" refers to any number of film layers covering a core tablet that may provide one or more advantages, such as providing a smooth tablet surface that facilitates swallowing of the composition, conforming to coloring that aids in identifying the pills, providing a moisture barrier, and providing a high-tensile outer layer for the tablet. Such sub-coating agents may, but are not limited to, graft copolymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG). Commercial products providing sub-coating agents include product lines under trademark names such as OPADRY® and OPAGLOS®. Sub-coating agents may be further coated with one or more additional coating agents.

[0118] In some embodiments, the sub-coating agent refers to any number of film layers covering the core tablet. Examples of materials suitable for cosmetic sub-coating agents include polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymer (e.g., OPADRY® QX). Other coating agents include, but are not limited to, HPMC, HPC, PVA, and Eudragit E-based coating agents.

[0119] In some embodiments, the subcoating agent may be further coated with one or more additional coating agents, such as enteric coating agents or functional coating agents. In certain embodiments, the subcoating agent includes one or more plasticizers, anti-tackifiers, colorants, HPMC, HPC, PVA, and Eudragit E-based coating agents. In some embodiments, the subcoating agent is coated with one or more additional coating agents. In certain embodiments, one or more additional coating agents on the subcoating agent are enteric coating agents. In other embodiments, one or more additional coating agents on the subcoating agent are functional coating agents.

[0120] In some embodiments, the sub-coating agent is not coated with one or more further coating agents and is referred to as a cosmetic sub-coating agent. For example, in certain embodiments, the core tablet is coated with a cosmetic coating agent, and the cosmetic coating agent is not further coated with an enteric coating agent or a functional coating agent. In some embodiments, the cosmetic coating agent can function as a smooth surface to aid in swallowing the tablet. In some embodiments, the cosmetic coating agent can provide a vehicle for coloring to identify the tablet and function as a smooth surface to aid in swallowing the tablet.

[0121] The term "core tablet" refers to a mixture of the constituent elements of the core tablet. In some embodiments, the constituent elements are one or more crystalline forms of compound A, a pharmaceutically acceptable salt thereof, or solvates thereof, and preferred additives. In some embodiments, preferred additives are one or more of the following fillers, disintegrants, flow enhancers, lubricants, and absorption enhancers, but are not limited to these. Sub-coatings, cosmetic coatings, enteric coatings, or any combination thereof may cover the core tablet.

[0122] The “therapeutic dose” refers to the amount of a compound (i.e., compound A) or pharmaceutical composition that is useful in treating or alleviating a specific disease or condition, or in exhibiting a detectable therapeutic or inhibitory effect. The “therapeutic dose” further implies a non-toxic but sufficient amount of the specific drug cited to produce the desired therapeutic effect. The exact amount required varies from subject to subject depending on factors such as the patient's overall health and age. The exact amount depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0123] "To treat," "to treat," and "treatment" mean any sign of success in treating or improving an injury, pathology, or condition, including any objective or subjective parameters such as relief, remission, reduction, or greater tolerance to the injury, pathology, or condition, slowing the rate of degeneration or debilitation, reducing the final point of degeneration to milder debilitation, or improving the patient's physical or mental well-being. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0124] The abbreviation “(V / V)” refers to the phrase “volume to volume”, that is, the ratio of a specific substance in a mixture measured by the volume or volume amount of the components of the composition disclosed herein to the total volume amount of the composition. Therefore, the component amount has no unit and represents the percentage amount of the volume of the component relative to the total volume of the composition. For example, a 2% (V / V) solvent mixture can indicate that 2 mL of one solvent is present in 100 mL of the solvent mixture.

[0125] The abbreviation “(w / w)” refers to the phrase “weight to weight”, that is, the ratio of a specific substance in a mixture measured by the weight or mass or weight amount of the components of the composition disclosed herein to the total weight amount of the composition. Therefore, the component amount has no unit and represents the percentage amount of the weight of the component relative to the total weight of the composition. For example, a 2% (w / w) solution can indicate that 2 grams of solute are dissolved in 100 grams of the solution.

[0126] The systemic administration route conventionally understood in the medical or pharmaceutical field refers to or is defined as the administration route of a drug, pharmaceutical composition or formulation, or other substance into the circulatory system such that various body tissues and organs are exposed to the drug, formulation or other substance. As conventionally understood in the art, administration can be by oral (ingesting a drug or oral preparation through the mouth and absorbing it through the digestive tract), enteral administration (drug absorption also occurs through the digestive tract), or parenteral administration (generally by injection, infusion, or implantation, etc.).

[0127] Bioavailability refers to the degree and rate at which the active moiety (drug or metabolite) enters the systemic circulation and approaches the site of action. The bioavailability of a drug is affected by the characteristics of the dosage form and depends in part on its design and manufacture.

[0128] III. Crystal Forms The crystalline forms of carbamimidoylphenoxy)pentyl)oxy)picolinimidoamide (compound A) or its salts, or solvates thereof, are provided herein. The crystalline forms of salts of compound A and solvates of salts of compound A were unexpectedly obtained and isolated. The crystalline forms of pharmaceutically acceptable salts of compound A were prepared, isolated, and found to be suitable for use in pharmaceutical formulations. Therefore, the crystalline form of a compound may be uniquely significant, as the corresponding amorphous form is often unsuitable for formulations such as capsules.

[0129] In one embodiment, the present invention relates to compound A: [ka] This relates to pharmaceutical compositions of pharmaceutically acceptable salts thereof, or crystalline salts of these solvates.

[0130] In one embodiment, the present invention relates to a pharmaceutical composition of the acetate salt of compound A. In some modifications, the acetate salt of compound A is a diacetate.

[0131] In another embodiment, the present invention relates to a pharmaceutical composition of a phosphate of compound A.

[0132] In another embodiment, the present invention relates to a pharmaceutical composition of a solvate of the acetate salt of compound A. In some variations, the solvate is the solvate of the diacetate of compound A. In some variations, the solvate is a hydrate. In some variations, the solvate is a monohydrate. In some variations, the solvate is a tetrahydrate. In some variations, the solvate is a tetrahydrofuran (THF) solvate. In some variations, the solvate is an N,N-dimethylacetamide (DMA) solvate. In some variations, the solvate is an N-methylpyrrolidone (NMP) solvate. In some variations, the solvate is an ethanol solvate.

[0133] In another embodiment, the present invention relates to a pharmaceutical composition in the crystalline form of the acetate salt of compound A. In some modifications, the crystalline form is the crystalline form of the diacetate salt of compound A.

[0134] In another aspect, the present invention relates to a pharmaceutical composition in the crystalline form of a phosphate of compound A.

[0135] In another embodiment, the present invention relates to a pharmaceutical composition in crystalline form of a solvate of the acetate salt of compound A. In some variations, the solvate is a solvate of the diacetate of compound A. In some variations, the solvate is a hydrate. In some variations, the solvate is a monohydrate. In some variations, the solvate is a tetrahydrate. In some variations, the solvate is a tetrahydrofuran (THF) solvate. In some variations, the solvate is an N,N-dimethylacetamide (DMA) solvate. In some variations, the solvate is an N-methylpyrrolidone (NMP) solvate. In some variations, the solvate is an ethanol solvate.

[0136] In another embodiment, the present invention relates to a pharmaceutical composition of a pharmaceutically acceptable crystalline form of a salt of compound A. The pharmaceutically acceptable crystalline form of a salt of compound A may be a crystalline acetate or crystalline phosphate of compound A.

[0137] In other embodiments, the crystalline acetate form of compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some embodiments, the crystalline acetate form or its solvate is a diacetate. In some embodiments, the crystalline acetate form of compound A is characterized by an XRPD pattern substantially as shown in Figures 1, 14, 15, 26, 27, 32, 37, 42, 53, 64, or substantially as shown in Figure 66.

[0138] In other embodiments, the crystalline phosphate form of compound A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 65.

[0139] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline salt or its solvate as described herein and a pharmaceutically acceptable additive. In some modifications, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline acetate or its solvate as described herein and a pharmaceutically acceptable additive. In some modifications, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a crystalline phosphate or its solvate as described herein and a pharmaceutically acceptable additive.

[0140] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of compound A or a salt thereof as described herein, or a mixture of two or more crystalline forms of these solvates, and a pharmaceutically acceptable additive. Salt form

[0141] In some embodiments, the pharmaceutically acceptable salt of compound A is an acetate. In some embodiments, the acetate of compound A is crystalline. In some embodiments, the acetate of compound A is in solvate form. In certain embodiments, the solvate of the acetate of compound A is a hydrate. In some other embodiments, the acetate of compound A is crystalline and in solvate form.

[0142] In other embodiments, the pharmaceutically acceptable salt of compound A is a phosphate. In some embodiments, the phosphate of compound A is crystalline. In some embodiments, the phosphate of compound A is in solvate form. In certain embodiments, the solvate of the phosphate of compound A is a hydrate. In some other embodiments, the phosphate of compound A is crystalline and in solvate form. Salt ratio

[0143] In some embodiments, compound A is in the form of a pharmaceutically acceptable salt. In certain embodiments, the pharmaceutically acceptable salt of compound A is crystalline. In some embodiments, the crystalline pharmaceutically acceptable salt of compound A comprises the cationic form of compound A and the pharmaceutically acceptable anion. For example, the crystalline diacetate of compound A comprises compound A in its cationic form and in the form of two acetate anions. The salt compositions described herein comprise salts of compound A, the salts being pharmaceutically acceptable salts selected from acetates and phosphates.

[0144] In some embodiments, the pharmaceutically acceptable salt of compound A is an acetate, and the anion is an acetate ion. In some embodiments, the acetate is a diacetate. In some embodiments, the pharmaceutically acceptable salt of compound A is a phosphate, and the anion is a phosphate ion.

[0145] In some embodiments, the molar equivalent of the anion of the crystalline salt of compound A per mole of compound A is about 0.2 to about 2.5. In some embodiments, the molar equivalent of the anion of the salt of compound A per mole of compound A 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, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5, including any amount in between and fractions thereof.

[0146] In some embodiments, the molar equivalent of acetate anions of crystalline acetate of compound A per mole of compound A is about 0.2 to about 2.5. In some embodiments, the molar equivalent of acetate anions of crystalline acetate of compound A per mole of compound A is about 1.5 to about 2.5. Form 1 of compound A diacetate

[0147] In some embodiments, the crystalline form of compound A diacetate is crystalline form 1 of compound A diacetate (hereinafter referred to as "form 1"). In some embodiments, form 1 is the anhydrous crystalline form of compound A diacetate. In some embodiments, form 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two theta angles selected from 17.86, 24.21, 24.29, and 25.87 ± 0.2° 2-theta. In some embodiments, form 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two theta angles selected from 17.86, 24.21, 24.29, and 25.87 ± 0.3° 2-theta. In some embodiments, form 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two theta angles selected from 17.86, 24.21, 24.29, and 25.87 ± 0.4° 2-theta.

[0148] In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two theta angles selected from 3.19, 8.92, 12.62, 16.54, 17.20, 17.86, 19.54, 24.21, 24.29, 24.94, 25.87, 30.29, 32.04, and 33.45 ± 0.2°2 theta. In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two theta angles selected from 3.19, 8.92, 12.62, 16.54, 17.20, 17.86, 19.54, 24.21, 24.29, 24.94, 25.87, 30.29, 32.04, and 33.45 ± 0.3°2 theta. In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at two-theta angles selected from 3.19, 8.92, 12.62, 16.54, 17.20, 17.86, 19.54, 24.21, 24.29, 24.94, 25.87, 30.29, 32.04, and 33.45 ± 0.4°2-theta.

[0149] In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 3.19, 5.19, 6.35, 7.18, 8.92, 12.62, 14.55, 15.43, 16.54, 17.20, 17.86, 18.66, 19.54, 21.26, 21.82, 23.05, 24.21, 24.29, 24.94, 25.87, 28.62, 30.29, 31.02, 32.04, and 33.45 ± 0.2° 2-theta. In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 3.19, 5.19, 6.35, 7.18, 8.92, 12.62, 14.55, 15.43, 16.54, 17.20, 17.86, 18.66, 19.54, 21.26, 21.82, 23.05, 24.21, 24.29, 24.94, 25.87, 28.62, 30.29, 31.02, 32.04, and 33.45 ± 0.3° 2-theta. In some embodiments, Embodiment 1 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 3.19, 5.19, 6.35, 7.18, 8.92, 12.62, 14.55, 15.43, 16.54, 17.20, 17.86, 18.66, 19.54, 21.26, 21.82, 23.05, 24.21, 24.29, 24.94, 25.87, 28.62, 30.29, 31.02, 32.04, and 33.45 ± 0.4° 2-theta.

[0150] In some embodiments, Embodiment 1 is characterized by an XRPD pattern substantially as shown in Figure 1.

[0151] In some embodiments, Embodiment 1 is characterized by having an exothermic peak at approximately 133.1°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, Embodiment 1 is characterized by having a DSC thermogram substantially as shown in Figure 2. In certain embodiments, Embodiment 1 is characterized by having a first thermal thermogram of DSC substantially as shown in Figure 3. In certain embodiments, Embodiment 1 is characterized by having a cooling thermogram of DSC substantially as shown in Figure 4. In certain embodiments, Embodiment 1 is characterized by having a second thermal thermogram of DSC substantially as shown in Figure 5. In certain embodiments, Embodiment 1 is characterized by having a DSC thermogram substantially as shown in Figure 6.

[0152] In some embodiments, Embodiment 1 is characterized by having a weight loss of approximately 31.9% at approximately 193.1°C, as determined by thermogravimetric analysis (TGA). In certain embodiments, Embodiment 1 is characterized by having a TGA graph substantially as shown in Figure 2.

[0153] In some embodiments, Embodiment 1 is characterized by having DVS isotherm curves substantially as shown in Figure 7. In some embodiments, Embodiment 1 is characterized by having DVS dynamics plots substantially as shown in Figure 8.

[0154] In some embodiments, Form 1 is 431.07 cm -1 460.29cm -1 498.29cm -1 525.01cm -1 613.02cm -1 635.80cm -1 646.52cm -1 665.50cm -1 738.69cm -1 837.69cm -1874.51cm -1 921.40cm -1 , 1001.68cm -1 , 1045.70cm -1 , 1108.19cm -1 1157.97cm -1 , 1195.04cm -1 , 1250.47cm -1 , 1271.17cm -1 1312.28cm -1 1397.95cm -1 1463.97cm -1 1494.69cm -1 , 1535.17cm -1 , 1571.14cm -1 , 1609.62cm -1 , 1689.24cm -1 , 2869.02cm -1 , and 3248.30cm -1 It is characterized by having an FT-IR spectrum with a peak selected from . In some embodiments, form 1 is 460.29 cm⁻¹ -1 1397.95cm -1 , and 1689.24cm -1 It is characterized by having an FT-IR spectrum with a peak selected from. In some embodiments, Embodiment 1 is characterized by having an FT-IR spectrum substantially as shown in Figure 10.

[0155] In some embodiments, Embodiment 1 is substantially as shown in Figure 11. 1 It is characterized by having a 1H NMR spectrum.

[0156] In some embodiments, Embodiment 1 is characterized by having a DAD substantially as shown in Figure 12.

[0157] In some embodiments, Embodiment 1 is characterized by having an LC-MS spectrum substantially as shown in Figure 13.

[0158] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 1 and a pharmaceutically acceptable additive. Form 2 of compound A diacetate

[0159] In some embodiments, the crystalline form of compound A diacetate is crystalline form 2 of compound A diacetate (hereinafter referred to as "form 2"). In some embodiments, form 2 is the crystalline form of the hydrate of compound A diacetate. In some embodiments, form 2 is the crystalline form of the tetrahydrate of compound A diacetate.

[0160] In some embodiments, Embodiment 2 is characterized by an XRPD pattern substantially as shown in Figure 14.

[0161] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 2 and a pharmaceutically acceptable additive. Form 3 of compound A diacetate

[0162] In some embodiments, the crystalline form of compound A diacetate is crystalline form 3 of compound A diacetate (hereinafter referred to as "form 3"). In some embodiments, form 3 is the crystalline form of the THF solvate of compound A diacetate. In some embodiments, Embodiment 3 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6.5564, 7.8144, 9.9506, 10.134, 10.9291, 13.0904, 14.2252, 16.57, 17.8797, 19.2866, 20.0202, 20.7913, 21.8401, 22.4817, 23.7331, 25.3538, 26.9498, 28.3475, 29.1425, 30.1636, 32.3995, and 33.3307 ± 0.2° 2-theta. In some embodiments, Embodiment 3 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6.5564, 7.8144, 9.9506, 10.134, 10.9291, 13.0904, 14.2252, 16.57, 17.8797, 19.2866, 20.0202, 20.7913, 21.8401, 22.4817, 23.7331, 25.3538, 26.9498, 28.3475, 29.1425, 30.1636, 32.3995, and 33.3307 ± 0.3° 2-theta. In some embodiments, form 3 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6.5564, 7.8144, 9.9506, 10.134, 10.9291, 13.0904, 14.2252, 16.57, 17.8797, 19.2866, 20.0202, 20.7913, 21.8401, 22.4817, 23.7331, 25.3538, 26.9498, 28.3475, 29.1425, 30.1636, 32.3995, and 33.3307 ± 0.4° 2-theta.

[0163] In some embodiments, Embodiment 3 is characterized by an XRPD pattern substantially as shown in Figure 15.

[0164] In some embodiments, Embodiment 3 is characterized by having an endothermic peak at approximately 125.6°C and / or approximately 197.8°C, as determined by differential scanning calorimetry (DSC). In some embodiments, Embodiment 3 is characterized by having an endothermic peak at approximately 134.24°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, Embodiment 3 is characterized by having a DSC thermogram substantially as shown in Figure 17. In certain embodiments, Embodiment 3 is characterized by having a first thermal thermogram of the DSC substantially as shown in Figure 18. In certain embodiments, Embodiment 3 is characterized by having a cooling thermogram of the DSC substantially as shown in Figure 19. In certain embodiments, Embodiment 3 is characterized by having a second thermal thermogram of the DSC substantially as shown in Figure 20. In certain embodiments, Embodiment 3 is characterized by having a DSC thermogram substantially as shown in Figure 25.

[0165] In some embodiments, form 3 is characterized by having a weight loss of approximately 14.9% from approximately 74.0°C to approximately 125.6°C and a weight loss of approximately 27.9% from approximately 183.7°C to 197.8°C, as determined by thermogravimetric analysis (TGA). In some embodiments, form 3 is characterized by having a weight loss of approximately 29.4% at approximately 134.24°C. In a particular embodiment, form 3 is characterized by having a TGA graph substantially as shown in Figure 17.

[0166] In some embodiments, Embodiment 3 is characterized by having DVS isotherm curves substantially as shown in Figure 23. In some embodiments, Embodiment 3 is characterized by having DVS dynamics plots substantially as shown in Figure 24.

[0167] In some embodiments, form 3 is 403.8274 cm -1 , 410.9281cm -1 , 417.8627cm -1 , 427.3548cm -1 , 455.8276cm -1 , 497.1622cm -1 527.8366cm -1 613.4535cm -1 647.0587cm -1 667.471cm -1 735.8367cm -1 748.4115cm -1 773.6263cm -1 784.4192cm -1 792.6738cm -1 838.9931cm -1 917.0699cm -1 948.7131cm -1 , 1008.2646cm -1 , 1045.1361cm -1 , 1113.3962cm -1 , 1173.4743cm -1 , 1204.3088cm -1 , 1254.3655cm -1 , 1275.8158cm -1 , 1314.4654cm -1 , 1405.5281cm -1 , 1466.0255cm -1 , 1496.6866cm -1 , 1563.3625cm -1 , 1611.6379cm -1 , 1688.4984cm -1 , 2780.6369cm -1 , 2877.7248cm -1 , 2912.3429cm -1 , 2962.7601cm -1 , 2997.3795cm -1 , 3257.3184cm -1It is characterized by having an FT-IR spectrum with a peak selected from. In some embodiments, form 3 is characterized by having an FT-IR spectrum substantially as shown in Figure 25.

[0168] In some embodiments, Embodiment 3 is substantially as shown in Figure 16. 1 It is characterized by having a 1H NMR spectrum.

[0169] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 3 and a pharmaceutically acceptable additive. Form 4 of compound A diacetate

[0170] In some embodiments, the crystalline form of compound A diacetate is crystalline form 4 of compound A diacetate (hereinafter referred to as "form 4"). In some embodiments, form 4 is the crystalline form of the DMA solvate of compound A diacetate.

[0171] In some embodiments, form 4 is characterized by an XRPD pattern substantially as shown in Figure 26.

[0172] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 4 and a pharmaceutically acceptable additive. Form 5 of compound A diacetate

[0173] In some embodiments, the crystalline form of compound A diacetate is crystalline form 5 of compound A diacetate (hereinafter referred to as "form 5"). In some embodiments, form 5 is the crystalline form of the NMP solvate of compound A diacetate. In some embodiments, form 5 is 3.0955, 7.3039, 8.7822, 9.0458, 9.616, 10.0584, 10.3195, 10.6414, 10.7975, 11.5462, 11.995, 13.8128, 14.9066, 16.0215, 16.8793, 17.3302, 17.6481, 18.1419, 18.6845, 19.5967, 19.8517, 21.4041, Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 22.4378, 22.8546, 23.906, 24.8112, 25.2272, 26.4792, 27.8054, 28.3711, 28.6915, 29.0081, 30.4056, 30.8846, 33.1832, 34.3317, and 34.5123 ± 0.2° 2-theta. In some embodiments, form 5 is 3.0955, 7.3039, 8.7822, 9.0458, 9.616, 10.0584, 10.3195, 10.6414, 10.7975, 11.5462, 11.995, 13.8128, 14.9066, 16.0215, 16.8793, 17.3302, 17.6481, 18.1419, 18.6845, 19.5967, 19.8517, 21.4041, Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 22.4378, 22.8546, 23.906, 24.8112, 25.2272, 26.4792, 27.8054, 28.3711, 28.6915, 29.0081, 30.4056, 30.8846, 33.1832, 34.3317, and 34.5123 ± 0.3° 2-theta.In some embodiments, form 5 is 3.0955, 7.3039, 8.7822, 9.0458, 9.616, 10.0584, 10.3195, 10.6414, 10.7975, 11.5462, 11.995, 13.8128, 14.9066, 16.0215, 16.8793, 17.3302, 17.6481, 18.1419, 18.6845, 19.5967, 19.8517, 21.4041, Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 22.4378, 22.8546, 23.906, 24.8112, 25.2272, 26.4792, 27.8054, 28.3711, 28.6915, 29.0081, 30.4056, 30.8846, 33.1832, 34.3317, and 34.5123 ± 0.4° 2-theta.

[0174] In some embodiments, form 5 is characterized by an XRPD pattern substantially as shown in Figure 27.

[0175] In some embodiments, Embodiment 5 is characterized by having endothermic peaks at approximately 161.0°C and / or approximately 204.1°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, Embodiment 5 is characterized by having a DSC thermogram substantially as shown in Figure 29.

[0176] In some embodiments, form 5 is characterized by having a weight loss of approximately 18.2% from approximately 145.4°C to approximately 161.0°C and a weight loss of approximately 24.4% from approximately 190.2°C to approximately 204.1°C, as determined by thermogravimetric analysis (TGA). In a particular embodiment, form 5 is characterized by having a TGA graph substantially as shown in Figure 29.

[0177] In some embodiments, form 5 is 454.9594 cm -1 , 469.0604cm -1, 611.6827 cm -1 , 637.6883 cm -1 , 650.0553 cm -1 , 672.3002 cm -1 , 740.3731 cm -1 , 750.7427 cm -1 , 777.2387 cm -1 , 840.4285 cm -1 , 917.5764 cm -1 , 1008.4717 cm -1 , 1109.8542 cm -1 , 1139.6816 cm -1 , 1167.3318 cm -1 , 1200.3449 cm -1 , 1256.0996 cm -1 , 1275.2878 cm -1 , 1314.5075 cm -1 , 1401.2548 cm -1 , 1463.7291 cm -1 , 1494.7887 cm -1 , 1566.8599 cm -1 , 1610.4636 cm -1 , 1686.825 cm -1 , 2868.4556 cm -1 , and 2943.5756 cm -1 characterized by having an FT-IR spectrum having peaks selected from. In some embodiments, Form 5 is characterized by having an FT-IR spectrum substantially as shown in FIG. 31.

[0178] In some embodiments, Form 5 is substantially as shown in FIG. 28 1 characterized by having an H NMR spectrum.

[0179] In some aspects, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 5 and a pharmaceutically acceptable additive. Form 6 of Compound A Diacetate

[0180] In some embodiments, the crystalline form of compound A diacetate is crystalline form 6 of compound A diacetate (hereinafter referred to as "form 6"). In some embodiments, form 6 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5.6904, 7.4999, 9.0887, 9.5349, 11.4096, 12.5161, 17.054, 17.5331, 18.2714, 18.4887, 20.1801, 21.8337, 22.4764, 24.7984, 26.0531, 26.5658, 31.3369, and 32.5215 ± 0.2° 2-theta. In some embodiments, form 6 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5.6904, 7.4999, 9.0887, 9.5349, 11.4096, 12.5161, 17.054, 17.5331, 18.2714, 18.4887, 20.1801, 21.8337, 22.4764, 24.7984, 26.0531, 26.5658, 31.3369, and 32.5215 ± 0.3° 2-theta. In some embodiments, form 6 is characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5.6904, 7.4999, 9.0887, 9.5349, 11.4096, 12.5161, 17.054, 17.5331, 18.2714, 18.4887, 20.1801, 21.8337, 22.4764, 24.7984, 26.0531, 26.5658, 31.3369, and 32.5215 ± 0.4° 2-theta.

[0181] In some embodiments, form 6 is characterized by an XRPD pattern substantially as shown in Figure 32.

[0182] In some embodiments, Embodiment 6 is characterized by having endothermic peaks at approximately 113.6°C and / or approximately 203.9°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, Embodiment 6 is characterized by having a DSC thermogram substantially as shown in Figure 34.

[0183] In some embodiments, form 6 is characterized by having a weight loss of approximately 13.6% from approximately 58.2°C to approximately 113.6°C and a weight loss of approximately 21.2% from approximately 190.6°C to approximately 203.9°C, as determined by thermogravimetric analysis (TGA). In a particular embodiment, form 6 is characterized by having a TGA graph substantially as shown in Figure 34.

[0184] In some embodiments, form 6 is 415.3786 cm -1 , 449.3573cm -1 , 465.4179cm -1 , 495.8008cm -1 , 521.5347cm -1 , 612.5942cm -1 , 647.363cm -1 670.4807cm -1 , 695.6592cm -1 731.8654cm -1 745.9633cm -1 774.2919cm -1 839.3638cm -1 922.9869cm -1 942.7633cm -1 986.3551cm -1 , 1008.8106cm -1 , 1034.18cm -1 , 1058.8405cm -1 , 1121.3221cm -1 ,cm -1 , 1156.6177cm -1 , 1197.1751cm -1, 1262.8981cm -1 , 1274.7356cm -1 , 1306.6066cm -1 , 1334.7588cm -1 , 1404.0304cm -1 , 1465.1639cm -1 , 1488.4329cm -1 , 1509.518cm -1 , 1567.7745cm -1 , 1587.841cm -1 , 1610.2619cm -1 , 1655.8039cm -1 , 2868.3153cm -1 , and 2939.6823cm -1 It is characterized by having an FT-IR spectrum with a peak selected from. In some embodiments, form 6 is characterized by having an FT-IR spectrum substantially as shown in Figure 36.

[0185] In some embodiments, form 6 is substantially as shown in Figure 33. 1 It is characterized by having a 1H NMR spectrum.

[0186] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 6 and a pharmaceutically acceptable additive. Form 7 of compound A diacetate

[0187] In some embodiments, the crystalline form of compound A diacetate is crystalline form 7 of compound A diacetate (hereinafter referred to as "form 7"). In some embodiments, form 7 is the crystalline form of the hydrate of compound A diacetate. In some embodiments, form 7 is the crystalline form of the monohydrate of compound A diacetate. In some embodiments, form 7 is 5.1087, 5.6134, 10.1362, 10.4265, 10.6607, 11.3637, 11.5103, 11.6747, 12.7372, 13.0192, 14.3972, 14.8513, 15.3999, 16.4208, 16.6467, 16.7178, 17.7524, 17.9449, 18.4299, 18.5083, 18.7792, 20.3597, 20.5204, 21.0321, 21.8055, 22.0923, 22.4226, 22 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 0.7017, 22.8773, 23.4679, 23.7026, 24.1586, 24.7744, 25.2874, 26.2699, 27.2182, 27.4644, 27.9591, 28.2391, 29.1359, 29.5639, 30.1954, 31.1076, 31.4344, 31.7841, 33.1681, 33.9234, and 34.7491 ± 0.2° 2-theta.In some embodiments, form 7 is 5.1087, 5.6134, 10.1362, 10.4265, 10.6607, 11.3637, 11.5103, 11.6747, 12.7372, 13.0192, 14.3972, 14.8513, 15.3999, 16.4208, 16.6467, 16.7178, 17.7524, 17.9449, 18.4299, 18.5083, 18.7792, 20.3597, 20.5204, 21.0321, 21.8055, 22.0923, 22.4226, 22 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 0.7017, 22.8773, 23.4679, 23.7026, 24.1586, 24.7744, 25.2874, 26.2699, 27.2182, 27.4644, 27.9591, 28.2391, 29.1359, 29.5639, 30.1954, 31.1076, 31.4344, 31.7841, 33.1681, 33.9234, and 34.7491 ± 0.3° 2-theta. In some embodiments, form 7 is 5.1087, 5.6134, 10.1362, 10.4265, 10.6607, 11.3637, 11.5103, 11.6747, 12.7372, 13.0192, 14.3972, 14.8513, 15.3999, 16.4208, 16.6467, 16.7178, 17.7524, 17.9449, 18.4299, 18.5083, 18.7792, 20.3597, 20.5204, 21.0321, 21.8055, 22.0923, 22.4226, 22 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 0.7017, 22.8773, 23.4679, 23.7026, 24.1586, 24.7744, 25.2874, 26.2699, 27.2182, 27.4644, 27.9591, 28.2391, 29.1359, 29.5639, 30.1954, 31.1076, 31.4344, 31.7841, 33.1681, 33.9234, and 34.7491 ± 0.4° 2-theta.

[0188] In some embodiments, form 7 is characterized by an XRPD pattern substantially as shown in Figure 37.

[0189] In some embodiments, Embodiment 7 is characterized by having endothermic peaks at approximately 147.9°C and / or approximately 213.0°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, Embodiment 7 is characterized by having a DSC thermogram substantially as shown in Figure 39.

[0190] In some embodiments, form 7 is characterized by having a moderate 7.5% mass loss before a sharp 4.6% mass loss from about 147.7°C to about 147.9°C, and a mass loss of about 26.2% from about 195.1°C to about 213.0°C, as determined by thermogravimetric analysis (TGA). In some embodiments, form 7 is characterized by having a 4.6% mass loss from about 147.7°C to about 147.9°C, as measured by TGA. In a particular embodiment, form 7 is characterized by having a TGA graph substantially as shown in Figure 39.

[0191] In some embodiments, form 7 is 411.1117 cm -1 429.951cm -1 457.3076cm -1 501.991cm -1 , 512.5004cm -1 529.0548cm -1 , 550.4058cm -1 , 561.6064cm -1 591.7189cm -1 , 611.2152cm -1 647.1254cm -1 665.4149cm -1 740.8762cm -1 771.4092cm -1 785.1443cm -1 834.2445cm-1 , 917.4091cm -1 , 1008.155cm -1 , 1038.2526cm -1 , 1112.6934cm -1 , 1170.4312cm -1 , 1200.3311cm -1 , 1253.1489cm -1 , 1272.6386cm -1 , 1313.3134cm -1 , 1335.9096cm -1 , 1402.5501cm -1 , 1468.5722cm -1 , 1495.6468cm -1 , 1537.5083cm -1 , 1563.8372cm -1 , 1610.9948cm -1 , 1631.9449cm -1 , 1692.5437cm -1 , 2874.9139cm -1 , 2949.921cm -1 , and 3263.8881cm -1 It is characterized by having an FT-IR spectrum with a peak selected from. In some embodiments, form 7 is characterized by having an FT-IR spectrum substantially as shown in Figure 41.

[0192] In some embodiments, form 7 is substantially as shown in Figure 38. 1 It is characterized by having a 1H NMR spectrum.

[0193] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of form 7 and a pharmaceutically acceptable additive. Form 8 of compound A diacetate

[0194] In some embodiments, the crystalline form of compound A diacetate is crystalline form 8 of compound A diacetate (hereinafter referred to as "form 8"). In some embodiments, form 8 is the crystalline form of the ethanol solvate of compound A diacetate. In some embodiments, form 8 is 5.5331, 9.2347, 10.4522, 11.0878, 12.1465, 13.9753, 14.9568, 16.7343, 17.8535, 18.4906, 19.0176, 20.2017, 21.5889, 21.9169, 22.5325, 23.4194, 24.04, 24.62 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5, 24.8346, 25.5526, 25.9083, 26.4698, 27.6197, 28.6765, 28.7907, 30.0882, 30.8638, 31.6522, and 33.6849 ± 0.2°2-theta. In some embodiments, form 8 is 5.5331, 9.2347, 10.4522, 11.0878, 12.1465, 13.9753, 14.9568, 16.7343, 17.8535, 18.4906, 19.0176, 20.2017, 21.5889, 21.9169, 22.5325, 23.4194, 24.04, 24.62 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5, 24.8346, 25.5526, 25.9083, 26.4698, 27.6197, 28.6765, 28.7907, 30.0882, 30.8638, 31.6522, and 33.6849 ± 0.3°2-theta.In some embodiments, form 8 is 5.5331, 9.2347, 10.4522, 11.0878, 12.1465, 13.9753, 14.9568, 16.7343, 17.8535, 18.4906, 19.0176, 20.2017, 21.5889, 21.9169, 22.5325, 23.4194, 24.04, 24.62 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 5, 24.8346, 25.5526, 25.9083, 26.4698, 27.6197, 28.6765, 28.7907, 30.0882, 30.8638, 31.6522, and 33.6849 ± 0.4°2-theta.

[0195] In some embodiments, form 8 is characterized by an XRPD pattern substantially as shown in Figure 42.

[0196] In some embodiments, form 8 is characterized by having an endothermic peak at approximately 203.7°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, form 8 is characterized by having a DSC thermogram substantially as shown in Figure 44. In certain embodiments, form 8 is characterized by having a first thermal thermogram of DSC substantially as shown in Figure 45. In certain embodiments, form 8 is characterized by having a cooling thermogram of DSC substantially as shown in Figure 46. In certain embodiments, form 8 is characterized by having a second thermal thermogram of DSC substantially as shown in Figure 47. In certain embodiments, form 8 is characterized by having a DSC thermogram substantially as shown in Figure 52.

[0197] In some embodiments, form 8 is characterized by having a weight loss of approximately 28.6% from approximately 186.0°C to approximately 203.7°C, as determined by thermogravimetric analysis (TGA). In certain embodiments, form 8 is characterized by having a TGA graph substantially as shown in Figure 44.

[0198] In some embodiments, Embodiment 8 is characterized by having DVS isotherm curves substantially as shown in Figure 50. In some embodiments, Embodiment 8 is characterized by having DVS dynamics plots substantially as shown in Figure 51.

[0199] In some embodiments, form 8 is 610.2657 cm -1 , 633.8131cm -1 , 650.1075cm -1 , 664.611cm -1 745.5844cm -1 769.0208cm -1 835.8804cm -1 , 1013.4095cm -1 , 1034.2339cm -1 , 1049.5794cm -1 , 1157.2206cm -1 , 1197.3449cm -1 , 1248.3703cm -1 , 1267.7224cm -1 , 1312.6521cm -1 , 1402.7999cm -1 , 1463.1612cm -1 , 1490.611cm -1 , 1570.1416cm -1 , 1611.382cm -1 , 1677.1372cm -1 , 1686.6121cm -1 , 2867.0613cm -1 , 2944.0111cm -1 , and 2960.2257cm -1It is characterized by having an FT-IR spectrum having a peak selected from. In some embodiments, form 8 is characterized by having an FT-IR spectrum substantially as shown in Figure 49.

[0200] In some embodiments, form 8 is substantially as shown in Figure 43. 1 It is characterized by having a 1H NMR spectrum.

[0201] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 8 and a pharmaceutically acceptable additive. Form 9 of compound A diacetate

[0202] In some embodiments, the crystalline form of compound A diacetate is crystalline form 9 of compound A diacetate (hereinafter referred to as "form 9"). In some embodiments, form 9 is the crystalline form of the hydrate of compound A diacetate. In some embodiments, form 9 is 3.9466, 4.9134, 6.3449, 7.0644, 10.3976, 11.4501, 12.5469, 12.7439, 13.6904, 14.0455, 14.1993, 14.8142, 15.0272, 16.0564, 17.0908, 17.4764, 17.9115, 18.6031, 19.1762, 19.3881, 19.8051, 20.0332, 20.8087, 21.3351, 21.4789, 23.036 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6, 23.2768, 23.6282, 24.1482, 24.602, 25.0239, 25.2132, 26.0594, 26.5702, 27.4322, 27.6305, 28.1236, 28.5678, 29.0804, 29.6687, 30.1387, 30.9207, 31.4008, 32.3553, and 34.516±0.2°2-theta. In some embodiments, form 9 is 3.9466, 4.9134, 6.3449, 7.0644, 10.3976, 11.4501, 12.5469, 12.7439, 13.6904, 14.0455, 14.1993, 14.8142, 15.0272, 16.0564, 17.0908, 17.4764, 17.9115, 18.6031, 19.1762, 19.3881, 19.8051, 20.0332, 20.8087, 21.3351, 21.4789, 23.036 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6, 23.2768, 23.6282, 24.1482, 24.602, 25.0239, 25.2132, 26.0594, 26.5702, 27.4322, 27.6305, 28.1236, 28.5678, 29.0804, 29.6687, 30.1387, 30.9207, 31.4008, 32.3553, and 34.516±0.3°2-theta.In some embodiments, form 9 is 3.9466, 4.9134, 6.3449, 7.0644, 10.3976, 11.4501, 12.5469, 12.7439, 13.6904, 14.0455, 14.1993, 14.8142, 15.0272, 16.0564, 17.0908, 17.4764, 17.9115, 18.6031, 19.1762, 19.3881, 19.8051, 20.0332, 20.8087, 21.3351, 21.4789, 23.036 Characterized by having an XRPD pattern with two or more diffraction peaks at a 2-theta angle selected from 6, 23.2768, 23.6282, 24.1482, 24.602, 25.0239, 25.2132, 26.0594, 26.5702, 27.4322, 27.6305, 28.1236, 28.5678, 29.0804, 29.6687, 30.1387, 30.9207, 31.4008, 32.3553, and 34.516±0.4°2-theta.

[0203] In some embodiments, form 9 is characterized by an XRPD pattern substantially as shown in Figure 53.

[0204] In some embodiments, form 9 is characterized by having endothermic peaks at approximately 74.25°C and / or approximately 206.7°C, as determined by differential scanning calorimetry (DSC). In certain embodiments, form 9 is characterized by having a DSC thermogram substantially as shown in Figure 55. In certain embodiments, form 9 is characterized by having a first thermal thermogram of DSC substantially as shown in Figure 56. In certain embodiments, form 9 is characterized by having a cooling thermogram of DSC substantially as shown in Figure 57. In certain embodiments, form 9 is characterized by having a second thermal thermogram of DSC substantially as shown in Figure 58. In certain embodiments, form 9 is characterized by having a DSC thermogram substantially as shown in Figure 63.

[0205] In some embodiments, form 9 is characterized by having a weight loss of approximately 6.7% at approximately 50°C and a weight loss of approximately 30.9% from approximately 191.6°C to approximately 206.7°C, as determined by thermogravimetric analysis (TGA). In a particular embodiment, form 9 is characterized by having a TGA graph substantially as shown in Figure 55.

[0206] In some embodiments, form 9 is characterized by having DVS isotherm curves substantially as shown in Figure 61. In some embodiments, form 9 is characterized by having DVS dynamics plots substantially as shown in Figure 62.

[0207] In some embodiments, form 9 is 414.6559 cm -1 448.747cm -1 , 486.815cm -1 546.2329cm -1 , 633.7561cm -1 648.299cm -1 672.9115cm -1 740.6708cm -1 771.3666cm -1 838.3607cm -1 919.3036cm -1 , 1006.5771cm -1 , 1039.8083cm -1 , 1112.0083cm -1 1158.8791cm -1 , 1179.2694cm -1 , 1256.6641cm -1 , 1310.0412cm -1 , 1338.2741cm -1 , 1394.2529cm -1 , 1461.6026cm -1 , 1486.7422cm -1 , 1557.2577cm -1 , 1608.2499cm -1 , 1682.2509cm-1 , 2873.5453cm -1 , and 2950.3382cm -1 It is characterized by having an FT-IR spectrum having a peak selected from. In some embodiments, form 9 is characterized by having an FT-IR spectrum substantially as shown in Figure 60.

[0208] In some embodiments, form 9 is substantially as shown in Figure 54. 1 It is characterized by having a 1H NMR spectrum.

[0209] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of form 9 and a pharmaceutically acceptable additive. Form 10 of compound A diacetate

[0210] In some embodiments, the crystalline form of compound A diacetate is crystalline form 10 of compound A diacetate (hereinafter referred to as "form 10").

[0211] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 10 and a pharmaceutically acceptable additive. Form 11 of compound A diacetate

[0212] In some embodiments, the crystalline form of compound A diacetate is crystalline form 11 of compound A diacetate (hereinafter referred to as "form 11").

[0213] In some embodiments, form 11 is characterized by an XRPD pattern substantially as shown in Figure 64.

[0214] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 11 and a pharmaceutically acceptable additive. Form 12 of compound A phosphate

[0215] In some embodiments, the crystalline form of compound A phosphate is crystalline form 12 of compound A phosphate (hereinafter referred to as "form 12").

[0216] In some embodiments, form 12 is characterized by an XRPD pattern substantially as shown in Figure 65.

[0217] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 12 and a pharmaceutically acceptable additive. Form 13 of compound A diacetate

[0218] In some embodiments, the crystalline form of compound A diacetate is crystalline form 13 of compound A diacetate (hereinafter referred to as "form 13").

[0219] In some embodiments, form 13 is characterized by an XRPD pattern substantially as shown in Figure 66.

[0220] In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of Form 13 and a pharmaceutically acceptable additive. purity

[0221] In some embodiments, the crystalline salt of compound A or its solvate produced by the method described herein has a purity level of at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least 98%, or at least about 99%, as determined by ultra-performance liquid chromatography (UPLC), high-performance liquid chromatography (HPLC), or other suitable method. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of about 90% to 100%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least about 95.0%, about 96.0%, about 97.0%, about 98.0%, about 99.0%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9%, including any amount in between and fractions thereof. In other embodiments, the crystalline salt of compound A or its solvate has a purity level of about 95.0% to 99.9%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 95%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 96%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 97%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 98%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 99%. In some embodiments, the crystalline salt of compound A or its solvate has a purity level of at least 99.5%.

[0222] In some embodiments, form 1 of compound A 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, form 1 has a purity level of about 96.0% to 98%. In a particular embodiment, form 1 has a purity level of at least 96.0%.

[0223] In some embodiments, any one of Forms 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of compound A may have 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. IV. Synthesis method

[0224] Generally, the present invention relates to a method for preparing compound A or a salt thereof, or solvates thereof. In one modification, a method for preparing the diacetate salt of compound A is provided. In another modification, a method for preparing form 1 of the diacetate salt of compound A is provided.

[0225] In one embodiment, a method for preparing compound A diacetate is provided herein, comprising reacting compound A with an acetate in the presence of a solvent. In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol. In some embodiments, the acetate is ammonium acetate. In some embodiments, the diacetate of compound A is form 1 of compound A diacetate. In some embodiments, the method comprises mixing compound A, the acetate, and the solvent, heating the mixture to about 30°C for about 12 hours, and then heating the mixture to about 35°C for about 2 hours. In some embodiments, the method further comprises filtering the reaction mixture. In some embodiments, the filtering is performed under vacuum at about 40°C. In some embodiments, the method further comprises slurring the reaction mixture with acetone at about 30°C. In some embodiments, the method further comprises slurring the reaction mixture with n-heptane at about 60°C to 65°C. In some embodiments, the method further comprises drying the product under vacuum at about 60°C to 70°C. In some embodiments, the method further includes preparing compound A by any of the methods described herein.

[0226] In some embodiments, a method is provided for preparing compound A, comprising (i) reacting 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinimidoamide acetate (INT-3) with an acid in the presence of ethanol to provide ethyl 4-((5-((6-carbamimidoylpyridine-3-yl)oxy)pentyl)oxy)benzimidate (INT-4), and (ii) reacting ethyl 4-((5-((6-carbamimidoylpyridine-3-yl)oxy)pentyl)oxy)benzimidate (INT-4) with an ammonium source and a base in the presence of a solvent to provide compound A. [ka] In some embodiments, the acid is hydrochloric acid. In some embodiments, the reaction of (INT-3), the acid, and ethanol is carried out at about 15°C to 20°C. In some embodiments, the method further includes heating the reaction mixture to about 30°C. In some embodiments, the method further includes holding the reaction mixture at about 30°C for about 12 hours. In some embodiments, the reaction of (INT-4), the ammonium source, and the base is carried out in the presence of methanol as the solvent. In some embodiments, both the ammonium source and the base are ammonium carbonate. In some embodiments, the reaction of (INT-4), the ammonium source, and the base takes place at 25°C. In some embodiments, the reaction mixture is held at 25°C for about 10 hours. In some embodiments, the method further includes preparing INT-3 by any of the methods described herein.

[0227] In some embodiments, a method is provided for preparing 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinimidoamide acetate (INT-3), comprising reacting 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinonitrile (INT-2) with (i) an alkali metal methoxide and (ii) ammonium acetate in the presence of a solvent. [ka] In some embodiments, the alkali metal methoxide is sodium methoxide. In some embodiments, the solvent is a polar solvent. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol. In some embodiments, the method involves misciblering INT-2 with the alkali metal methoxide at about 10°C and heating the reaction mixture to about 50°C. In some embodiments, the reaction mixture is held at about 50°C for about 6 hours. In some embodiments, ammonium acetate is added to the reaction mixture at about 30°C. In some embodiments, the reaction mixture is held at 30°C for about 16 hours following the addition of ammonium acetate. In some embodiments, the method further includes preparing INT-2 by any of the methods described herein.

[0228] In some embodiments, a method is provided for preparing 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinonitrile (INT-2), comprising reacting 4-((5-bromopentyl)oxy)benzonitrile (INT-1) with 5-hydroxypicolinonitrile (SM-3) and a base in the presence of a solvent. [ka] In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the solvent is N,N-dimethylformamide (DMF). In some embodiments, the method includes heating the reaction mixture to about 75°C. In some embodiments, the method includes heating the reaction mixture to about 75°C for about 1 hour. In some embodiments, the method further includes cooling the reaction mixture to about 30°C. In some embodiments, the method further includes quenching the reaction with water. In some embodiments, the method further includes preparing INT-1 by any of the methods described herein.

[0229] In some embodiments, a method is provided for preparing 4-((5-bromopentyl)oxy)benzonitrile (INT-1), comprising reacting 4-hydroxybenzonitrile (SM-1) with 1,5-dibromopentane (SM-2) and a base in the presence of a solvent. [ka] In some embodiments, the solvent is N,N-dimethylformamide (DMF). In some embodiments, the base is a carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the method involves mixing SM-2, the base, and a solution of SM-1 and the solvent. In some embodiments, the addition occurs over approximately 1 hour. In some embodiments, the reaction mixture is held at approximately 40°C during the addition. In some embodiments, the method further includes holding the reaction mixture at approximately 40°C for approximately 4 hours following the addition. In some embodiments, the method further includes cooling the reaction mixture to 30°C. In some embodiments, the method further includes quenching the reaction mixture with water. V. Pharmaceutical Compositions

[0230] Generally, the present invention relates to compound A or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable forms and compositions of these solvates, corresponding pharmaceutically acceptable compositions, methods for the treatment of cancer as defined herein, and / or uses thereof.

[0231] In one embodiment, the present invention relates to the acetate salt of compound A: [ka] This relates to pharmaceutical compositions of the corresponding solvates.

[0232] In another embodiment, the acetate of compound A or the corresponding solvate thereof may exist in any form, such as a hydrate or other solvate.

[0233] In some embodiments, the acetate of compound A or its solvate may be formed in crystalline, amorphous, or semicrystalline form. In some embodiments, the acetate of compound A or its solvate is in crystalline form. In some embodiments, the acetate of compound A or its solvate is in amorphous form. In some embodiments, the acetate of compound A or its solvate is in semicrystalline form. In one embodiment, the composition of the acetate of compound A or its solvate is a diacetate. In some embodiments, the diacetate has about 1.5 to about 2.5 molar equivalents of acetate compared to compound A. In some embodiments, the hemiacetate has about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or about 2.5 molar equivalents of acetate compared to compound A. In some embodiments, the diacetate has about 2.0 molar equivalents of acetate compared to compound A.

[0234] In some embodiments, the acetate form of compound A or its solvate is a hydrate. In some embodiments, the hydrate of compound A acetate contains about 0.2 to about 10 molar equivalents of water compared to compound A. In some embodiments, the hydrate of compound A acetate contains about 1 or about 4 molar equivalents of water compared to compound A.

[0235] The acetate composition of the present invention can be administered to a subject or patient by any means in accordance with therapeutic administration to achieve the intended purpose or pharmaceutical efficacy. Examples include oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. In some embodiments, administration of the acetate composition of the present invention is suitable for oral administration.

[0236] In another embodiment, the present invention provides a composition comprising an acetate of compound A or its solvate in an amount of about 0.1% to about 60% (w / w) of the composition and one or more pharmaceutically acceptable additives.

[0237] In another embodiment, the present invention provides a composition comprising an acetate of compound A or a solvate thereof, and a phosphate-buffered aqueous solution with a pH of about 50 mM.

[0238] In another embodiment, the present invention provides a composition comprising an acetate of compound A or a solvate thereof, one or more fillers, a flow promoter, and a lubricant. In yet another embodiment, the present invention provides a composition comprising an acetate of compound A or a solvate thereof in an amount of about 0.1% to about 60% (w / w) of the composition, one or more fillers in an amount of about 10% to about 90% (w / w) of the composition, a flow promoter in an amount of about 0.1% to about 5% (w / w) of the composition, and a lubricant in an amount of about 0.1% to about 5% (w / w) of the composition.

[0239] In another aspect, the present invention provides a composition comprising the acetate of compound A or its solvate, silicified microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. In another aspect, the present invention provides a composition comprising the acetate of compound A or its solvate in an amount of about 0.1% to about 60% (w / w) of the composition, silicified microcrystalline cellulose in an amount of about 10% to about 70% (w / w) of the composition, lactose monohydrate in an amount of about 5% to about 30% (w / w) of the composition, colloidal silicon dioxide in an amount of about 0.1% to about 5% (w / w) of the composition, and magnesium stearate in an amount of about 0.1% to about 5% (w / w) of the composition.

[0240] In another embodiment, the acetate of compound A or its solvate may be present in any amount from about 0.1% to about 60% (w / w) of the composition. For example, the acetate of compound A or its solvate may be present in amounts from about 15% to about 35% (w / w), or from about 40% to about 60%. In some modifications, the acetate of compound A may be present in amounts from about 25%. In some modifications, the acetate of compound A may be present in amounts from about 50%.

[0241] In some variations, compositions are provided that contain form 1, form 2, form 3, form 4, form 5, form 6, form 7, form 8, form 9, form 10, form 11, or form 13 of compound A acetate in an amount of about 0.1% to about 60% (w / w) of the composition. In some embodiments, the composition contains form 12 of compound A phosphate in an amount of about 0.1% to about 60% (w / w) of the composition.

[0242] In some embodiments, the composition contains Form 1 of the acetate salt of compound A in an amount of about 0.1% to about 60% (w / w) of the composition. In some modifications, Form 1 may be present in an amount of about 25%. In some modifications, Form 1 may be present in an amount of about 50%.

[0243] In another embodiment, the acetate of compound A or its solvate may be present in any amount, such as about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 1 mg to about 1000 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 5 mg to about 300 mg. In another embodiment, the amount of the acetate of compound A or its solvate is about 25 mg to about 150 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 25 mg to about 100 mg. In another embodiment, the acetate of compound A or its solvate may be present in an amount of about 1 mg to about 100 mg. In another embodiment, the acetate of compound A or its solvate may be present in an amount of about 20 mg to about 40 mg. In another embodiment, the acetate salt of compound A or its solvate may be present in an amount of about 20 mg to about 30 mg.

[0244] In another embodiment, the acetate of compound A or its solvate may be present in amounts of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg, or about 150 mg, including any amount in between and fractions thereof. In another embodiment, the amount of the acetate of compound A or its solvate may be about 5 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 10 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 20 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 30 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 40 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 50 mg. In another embodiment, the amount of the acetate of compound A or its solvate may be about 75 mg. In another embodiment, the amount of compound A acetate or its solvate may be about 100 mg. In another embodiment, the amount of compound A acetate or its solvate may be about 120 mg. In another embodiment, the amount of compound A acetate or its solvate may be about 150 mg.

[0245] In another embodiment, the amount of pharmaceutically acceptable salt of compound A or its solvate in crystalline form may be in amounts of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 120 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.

[0246] In general, the pharmaceutical compositions of the present invention may be formed into different dosage forms prepared using conventional materials and techniques known in the fields of pharmacy and prescriptions, including, but not limited to, techniques such as mixing, blending, and techniques described throughout this disclosure. Furthermore, the pharmaceutical compositions used to form the dosage forms may also include, but not limited to, suitable auxiliaries, carriers, additives, or stabilizers, and may be in solid or liquid form, including, but not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions. In accordance with the present invention, the solid unit dosage form may be any other conventional type known in the art.

[0247] Preferred compositions of the present invention include, but are not limited to, liquids, tablets, capsules, and other forms. In some embodiments, the composition may be a tablet composition or a capsule composition.

[0248] Furthermore, suitable solutions for use in the present invention may include, but are not limited to, water, physiological saline, dextrose aqueous solutions, and related sugar solutions. Glycols such as propylene glycol or polyethylene glycol, buffer solutions, etc., are preferred liquid carriers, particularly for injection solutions. Under normal storage and use conditions, these preparations contain preservatives that prevent microbial growth.

[0249] The compositions described herein include, but are not limited to, flow promoters, lubricants, disintegrants, binders, drying agents, fillers, and other components or additives, and may include a variety of other pharmaceutically acceptable components or additives. These components are described herein.

[0250] In accordance with the present invention, the compositions described herein may comprise at least one filler. In some embodiments, the compositions of the present invention may comprise one or more fillers, including but not limited to, alphacellulose, betacellulose, gammacellulose, silicified microcrystalline cellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate. In some embodiments, the compositions of the present invention may comprise mannitol. In other embodiments, the compositions of the present invention may comprise sorbitol.

[0251] Typical fillers for use in the compositions of the present invention may include, but are not limited to, starch, lactitol, lactose, inorganic calcium salts, microcrystalline cellulose, silicified microcrystalline cellulose sucrose, and combinations thereof. Further fillers or excipients for use in the compositions of the present invention may include, but are not limited to, fillers or excipients conventionally known in the art, i.e., those typically used in the formulation of pharmaceutical compounds. Examples of such fillers or excipients for use in accordance with the present invention include, but are not limited to, sugars such as lactose, dextrose, glucose, sucrose, cellulose, starch and carbohydrate derivatives, polysaccharides (including dextrose and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrin, calcium carbonate, magnesium carbonate, microcrystalline cellulose, and combinations thereof. In some embodiments, such fillers or excipients suitable for use in the present invention may include, but are not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0252] Furthermore, in another embodiment, the filler for use in the present invention may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 60%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 3% to about 5% (w / w) of the composition as defined herein. Furthermore, such 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 amount in between as defined.

[0253] In some embodiments, the filler is present in an amount of about 10% to about 60% (w / w) of the composition as defined herein. In some embodiments, the filler is present in an amount of about 40% to about 60% (w / w) of the composition as defined herein.

[0254] In some embodiments, the composition may further contain microcrystalline cellulose. Several types of microcrystalline cellulose may be suitable for use in the compositions described herein, and may be selected from, for example, MICROCEL® or AVISEL® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, etc., and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. In one embodiment, the composition for use in the present invention may contain microcrystalline cellulose (AVICEL PH102). In another embodiment, the composition suitable for use in the present invention may contain microcrystalline cellulose (AVICEL PH101).

[0255] In other embodiments, microcrystalline cellulose may be present in amounts of about 1% to about 99% (w / w) of the composition, or about 1% to about 60%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 3% to about 5% (w / w) of the composition as defined herein. In some embodiments, microcrystalline cellulose may also be present in amounts of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, which may include any amount in between as defined. In some embodiments, microcrystalline cellulose may also be present in amounts of about 3% to about 5% (w / w) of the composition.

[0256] In some embodiments, the composition may further contain silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose may be, but is not limited to, SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. In some embodiments, the silicified microcrystalline cellulose may be SMCC 50, SMCC 50LD, SMCC 90, SMCC HD90, or SMCC 90LM. While not bound by theory, it is understood that the silicified microcrystalline cellulose, due to the presence of sodium caprate in the composition, protects the enteric coating from immature erosion. The silicified microcrystalline cellulose may be present in any amount suitable for use in the present invention. For example, SMCC may be present in amounts of approximately 1% to approximately 99% (w / w) of the composition, or approximately 10% to approximately 60%, or approximately 20% to approximately 50%, or approximately 25% to approximately 45%, or approximately 30% to approximately 40%, or approximately 35% to approximately 37% (w / w). In some embodiments, the amount of silicified microcrystalline cellulose is approximately 30% to approximately 70% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is approximately 65% ​​to approximately 85% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is approximately 66.5% to approximately 81.3% (w / w) of the composition. In some embodiments, the amount of silicified microcrystalline cellulose is about 31.3%, about 36.6%, about 37.7%, about 50.9%, about 52%, about 65.2%, about 71.5%, about 79%, or about 80.5% of the composition. SMCC can be present in amounts 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.

[0257] In some embodiments, SMCC is present in an amount of about 20% to about 90% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 25% to about 85% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 25% to about 45% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 30% to about 40% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 65% to about 90% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 70% to about 85% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 70% to about 75% (w / w), including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 80% to about 85% (w / w), including but not limited to any 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%, including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 50%, including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 60%, including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 70%, including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 80%, including but not limited to any amount in between. In some embodiments, SMCC is present in an amount of about 90%, including but not limited to any amount in between.

[0258] In some embodiments, SMCC is a mixture of microcrystalline cellulose and colloidal silicon dioxide.

[0259] In some embodiments, the composition may further comprise one or more of alphacellulose, betacellulose, gammacellulose, starch, modified starch, sorbitol, mannitol, lactose, dextrose, sucrose, dibasic calcium phosphate, tribasic calcium phosphate, or calcium carbonate. In some embodiments, the composition may further comprise mannitol.

[0260] In some embodiments, the composition of the present invention may contain lactose. In some embodiments, lactose is lactose monohydrate. For example, for use in the present invention, lactose may be present in an amount of about 1% to about 99% (w / w) of the composition, or about 1% to about 50%, or about 1% to about 25%, or about 5% to about 25%, or about 5% to about 20%, or about 5% to about 15%, or about 8% to about 12% (w / w). In another embodiment, lactose may be present in an amount of about 15% (w / w) of the composition. In yet another embodiment, lactose may be present in an amount of about 25% (w / w) of the composition.

[0261] The compositions of the present invention may, but are not limited to, contain at least one disintegrant in a therapeutically effective amount for use determined in accordance with the present invention. Typical disintegrants for use in the present invention include, but are not limited to, starch, clay, cellulose, alginates and gums and cross-linked starch, cellulose and polymers, and combinations thereof. Further typical disintegrants for use in the present invention may, 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, and combinations thereof.

[0262] In another embodiment, the composition of the present invention may also contain, but is not limited to, any amount of silica that is the object of the present invention. In particular, silica is about 200 m 2 Aerosil 200, which has a specific surface area of ​​1 / g, is an example. Substitutes for silica include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof.

[0263] In some embodiments, the composition of the present invention may further contain silica. In one embodiment, silica may be present in the composition of the present invention in an amount of about 0.1% to about 10% (w / w), or about 0.1% to about 5%, or about 0.1% to about 2%, or about 0.1% to about 1.5%, or about 0.1% to about 1%, or about 0.3% to about 0.7% (w / w). For example, the silica 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%, or about 1.5% (w / w), including any amount in between as defined. In another embodiment, the composition of the present invention may further contain silica in an amount of about 0.1% to about 1.5% (w / w). In another embodiment, the composition of the present invention may further contain silica in an amount of about 0.5% to about 2% (w / w) of the composition. In yet another embodiment, the composition of the present invention may further contain silica in an amount of about 0.3% to about 0.7% (w / w) of the composition. In yet another embodiment, the composition of the present invention may further contain silica in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition may further contain silica in an amount of about 1% (w / w) of the composition. Examples of suitable silica materials include, but are not limited to, colloidal silicon dioxide, aerosol, colloidal silica, fumed silica, fumed silicon dioxide, colloidal anhydrous silica, and colloidal silicon dioxide. In some embodiments, the silica is colloidal silica.

[0264] The compositions may also contain binders. 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 hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and sodium carboxymethylcellulose), glycols, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginate, and starch), corn starch, pre-gelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, and combinations thereof.

[0265] In the present invention, the composition may contain a lubricant in any amount suitable for use as described herein. Examples of lubricants suitable for use in the present invention include, but are not limited to, magnesium carbonate, magnesium lauryl sulfate, calcium silicate, talc, fumed silicon dioxide, and combinations thereof. Other useful and suitable lubricants may include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, and combinations thereof.

[0266] In some embodiments, the lubricant may include, but is not limited to, magnesium stearate. In one embodiment, the amount of lubricant may be about 1% to about 10% (w / w) of the composition, or about 0.1% to about 5%, or about 0.1% to about 1%, or about 0.1% to about 0.5% (w / w). In some embodiments, the amount of lubricant may be about 0.1% to about 0.5% (w / w) of the composition. In some embodiments, the amount of lubricant is about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the amount of lubricant is about 0.5% (w / w) of the composition. The lubricant may also be present in amounts of about 0.10% (w / w) of the composition, or in amounts of 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. In some embodiments, the lubricant may be present in amounts of about 0.25% (w / w).

[0267] In some embodiments, the composition comprises (i) an acetate of compound A or its solvate in an amount of about 27% (w / w) of the composition; (ii) silicified microcrystalline cellulose in an amount of about 47.25% (w / w) of the composition; (iii) lactose monohydrate in an amount of about 23.6% (w / w) of the composition; (iv) silica in an amount of about 1.6% (w / w) of the composition; and (v) magnesium stearate in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition is encapsulated in a capsule. In some embodiments, the capsule is an HPMC capsule.

[0268] In some embodiments, the composition comprises (i) an acetate or solvate of compound A in an amount of about 50.8% (w / w) of the composition; (ii) silicified microcrystalline cellulose in an amount of about 31.4% (w / w) of the composition; (iii) lactose monohydrate in an amount of about 15.7% (w / w) of the composition; (iv) silica in an amount of about 1.6% (w / w) of the composition; and (v) magnesium stearate in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition is encapsulated in a capsule. In some embodiments, the capsule is an HPMC capsule.

[0269] The compositions described herein include, but are not limited to, flow promoters, lubricants, disintegrants, binders, desiccants, fillers, and other components or additives, and may include a variety of other pharmaceutically acceptable components or additives.

[0270] The compositions described herein may contain at least one disintegrant in any suitable amount according to the present invention. Typical disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as Guerlain), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one embodiment, the disintegrant may include croscarmellose sodium. In one embodiment, the disintegrant may include crospovidone. In another embodiment, a suitable disintegrant may be present in amounts of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any amount between those amounts as defined in the present invention, but are not limited to these. In another aspect of the present invention, the disintegrant may be present in an amount of about 1 to 10% (w / w) of the composition, but is not limited thereto. In yet another aspect, the disintegrant may be present in an amount of about 5.0% (w / w) of the composition.

[0271] In some embodiments, the composition may further contain silica. In some embodiments, the composition may further contain silica in an amount of about 0.1% to about 2% (w / w) of the composition. For example, 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%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or about 2% (w / w) of the composition, including any amount in between as defined. In some embodiments, the composition may further contain silica in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition may further contain silica in an amount of about 0.5% to about 1.6% (w / w) of the composition. In some embodiments, the composition may further contain silica in an amount of about 0.5% (w / w) of the composition.

[0272] Microcrystalline cellulose may include any microcrystalline cellulose known in the art. In some embodiments, microcrystalline cellulose may include silicified microcrystalline cellulose (SMCC).

[0273] In some embodiments, for use herein, the microcrystalline cellulose may be silicified microcrystalline cellulose (SMCC) and may have any particle size.

[0274] The composition may contain at least one disintegrant in any suitable amount according to the present invention. Typical disintegrants for use in the present invention may include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polaritrin, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algins, other celluloses, gums (such as Guerlain), low-substituted hydroxypropyl cellulose, or mixtures thereof. In one embodiment, the disintegrant may include croscarmellose sodium. In one embodiment, the disintegrant may include crospovidone. The disintegrant for use in the present invention may be present in amounts of about 1% to about 99% (w / w) of the composition, or about 1% to about 50%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 10%, or about 2% to about 8%, or about 4% to about 6% (w / w) of the composition, but is not limited thereto. In another embodiment, the suitable disintegrant may be present in amounts of about 1% (w / w), 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10% (w / w) of the composition, including any amount in between as defined in the present invention, but is not limited thereto. In yet another embodiment, the disintegrant may be present in amounts of about 1% to about 10% (w / w) of the composition, but is not limited thereto. In yet another embodiment, the disintegrant may be present in amounts of about 5.0% (w / w) of the composition.

[0275] In another embodiment, the composition may also contain silica in any amount according to the present invention. The silica is approximately 200 m 2Aerosil 200, which has a specific surface area of ​​1 / g, is an example. Substitutes for silica include, but are not limited to, talc, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, precipitated silica, sodium aluminosilicate, and combinations thereof. Silica (e.g., Aerosil 200) may be present in the composition in amounts of about 0.1 to 10% (w / w), or about 0.1 to 5%, or about 0.1 to 2%, or about 0.1 to 1.5%, or about 0.1 to 1%, or about 0.3 to 0.7% (w / w). For example, Aerosil 200 silica can be present in amounts of approximately 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 amount in between.

[0276] In some embodiments, the composition may further contain silica (e.g., Aerosil 200). In some embodiments, the composition may further contain silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% (w / w) of the composition. For example, 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 amount in between as defined. In some embodiments, the composition may further contain silica (e.g., Aerosil 200) in an amount of about 0.3% to about 0.7% (w / w) of the composition. In some embodiments, the composition may further contain silica (e.g., Aerosil 200) in an amount of about 0.5% to about 2% (w / w) of the composition. In some embodiments, the composition may further contain silica in an amount of about 0.5% (w / w) of the composition. In some embodiments, the composition may further contain silica (e.g., Aerosil 200) in an amount of about 1% (w / w) of the composition.

[0277] The compositions described herein may include, but are not limited to, lubricants, disintegrants, binders, drying agents, fillers, and other components, and may also include a variety of other pharmaceutical additives or components. For use in the present invention, disintegrants may be present in the composition in amounts of about 0.1% to about 10% (w / w), or about 0.1% to about 5%, or about 0.1% to about 2%, or about 0.1% to about 1.5%, or about 0.1% to about 1%, or about 0.1% to about 0.4% (w / w). In some embodiments, the composition may further contain disintegrants. In some embodiments, the composition may further contain silica (e.g., Aerosil 200) in amounts of about 0.1% to about 1.5% (w / w). In some embodiments, the composition may further contain disintegrants in amounts of about 0.25% (w / w).

[0278] In some embodiments, the compositions disclosed herein may further comprise at least one of a lubricant in an amount of about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount of about 1% to about 10% by weight of the composition, or silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% by weight of the composition.

[0279] In some embodiments, the composition may further comprise a lubricant in an amount of about 0.1% to about 0.5% by weight of the composition, a disintegrant in an amount of about 1% to about 10% by weight of the composition, and silica (e.g., Aerosil 200) in an amount of about 0.1% to about 1.5% by weight of the composition.

[0280] In some embodiments, the composition of the present invention may be in the form of a tablet or a capsule, but is not limited to these dosage forms. In some embodiments, the composition may be in the form of a tablet or a capsule. In some embodiments, the composition may be a tablet composition. In some embodiments, the composition may be a capsule composition. In some embodiments, the composition may contain a unit dose size of about 20 mg to about 2000 mg, about 500 mg to about 2000 mg, but is not limited to these amounts. The composition of the present invention may contain 20, 30, 40, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, The compositions of the present invention may be, but are not limited to, any preferred size according to the present invention, such as tablets or capsules in doses or amounts such as 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 milligrams (mg). In one embodiment, the compositions of the present invention may be tablets of 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg or 1400 mg, which may be administered once or twice daily, or as determined by medical necessity, but are not limited to these. In some embodiments, the composition may have a unit dose size of approximately 500 mg to approximately 2000 mg. In some embodiments, the composition may have a unit dose size of approximately 1400 mg. In some embodiments, the composition may have a unit dose size of approximately 1000 mg.

[0281] In some embodiments, the composition may contain unit dose sizes ranging from 500 mg to approximately 2000 mg. The tablet composition may be, but is not limited to, any preferred size according to the present invention, such as tablets of 20, 30, 40, 50, 75, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, or 2000 mg. In some embodiments, the composition is a 1400 mg tablet.

[0282] Tablets or capsules formed from the compositions of the present invention may be administered as a single or multiple dose, depending on the dosage and frequency required and tolerated by the patient, and such tablets or capsules may contain an amount or quantity of the activator sufficient to effectively treat a specific disease condition. Thus, in one embodiment, the present invention relates to an oral administration composition of the acetate of compound A or its solvate, which may be taken in a daily dose of about 0.05 to about 30 mg per kg of body weight per day. In some embodiments, the dose may be about 0.1 mg to about 20 mg per kg of body weight per day. In another embodiment, the dose may be about 0.1 mg to about 5 mg per kg of body weight per day. In yet another embodiment, the dose may be about 0.1 mg to about 1 mg per kg of body weight per day.

[0283] In any of the embodiments described above, the acetate form of compound A or its solvate may be form 1. Coating agent Cosmetic sub-coating agent

[0284] In some embodiments, the composition may further contain a sub-coating agent. In some embodiments, the sub-coating agent is a cosmetic sub-coating agent. In some embodiments, the cosmetic sub-coating agent may also function as a physical barrier. The cosmetic coating agent may include polyethylene glycol-polyvinyl alcohol (PEG-PVA) graft copolymer, polyvinyl alcohol (PVA), hypromellose (hydroxypropyl methylcellulose: HPMC), and hydroxypropyl cellulose (HPC). In some embodiments, the weight of the cosmetic sub-coating agent is compared by weight / weight to the weight of the composition before coating. In some embodiments, the cosmetic sub-coating agent may be present in an amount of about 1% to about 10% (w / w). In some embodiments, the cosmetic sub-coating agent may be present in an amount of about 1% to about 5% (w / w). For example, the cosmetic sub-coating agent can be present in amounts of about 1%, 1.5%, 2.0%, 2.5%, and about 3%, including any amount in between and in the range of about 2.0% to 3.0%. In some embodiments, the cosmetic sub-coating agent is present in an amount of about 3% (w / w). In some embodiments, the weight of the cosmetic sub-coating agent is compared by weight / weight to the weight of the composition before coating or the weight of the core tablet.

[0285] In other embodiments, the cosmetic sub-coating level is expressed as the weight (mg) of cosmetic sub-coating per unit surface area of ​​the core tablet. In some embodiments, the surface area is the surface area of ​​the outermost layer of coating covering the core tablet. For example, in some embodiments, the surface area for calculating the cosmetic sub-coating level is the surface area of ​​the core tablet. In other embodiments, the surface area is the surface area of ​​the cosmetic sub-coating, sub-coating, or enteric coating covering the core tablet. For example, in some embodiments, two or more coatings cover the core tablet, and the surface area refers to the surface area of ​​the outermost coating.

[0286] In some embodiments, the cosmetic sub-coating agent level is approximately 6 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the level of the cosmetic sub-coating agent is approximately 9 mg / cm³. 2 ~about 30mg / cm 2 In other embodiments, the cosmetic sub-coating agent level is approximately 12 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the cosmetic sub-coating agent level is approximately 17 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the cosmetic sub-coating agent level is approximately 20 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the cosmetic sub-coating agent level is approximately 25 mg / cm³. 2 ~about 30mg / cm 2 For example, the level of a cosmetic sub-coating agent is approximately 6 mg / cm³. 2 , 7 mg / cm³ 2 , 8 mg / cm³ 2 , 9 mg / cm³ 2 , 10 mg / cm³ 2 , 6 mg / cm³ 2 , 11 mg / cm³ 2 , 12 mg / cm³ 2 , 13 mg / cm³ 2 , 14 mg / cm³2 , 15 mg / cm³ 2 , 16 mg / cm³ 2 , 17 mg / cm³ 2 , 18 mg / cm³ 2 , 19 mg / cm³ 2 , 21 mg / cm³ 2 , 22 mg / cm³ 2 , 23 mg / cm³ 2 , 24 mg / cm³ 2 , 25 mg / cm³ 2 , 26 mg / cm³ 2 , 27 mg / cm³ 2 , 28 mg / cm³ 2 , 29 mg / cm³ 2 , or 30 mg / cm³ 2 In some embodiments, the cosmetic sub-coating agent level is approximately 6 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 7 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 8 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 9 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 10 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 11 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 6 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 12 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 13 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 14 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 15 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 16 mg / cm³. 2 In some embodiments, the cosmetic sub-coating agent level is approximately 17 mg / cm³. 2In some embodiments, the cosmetic sub-coating agent level is approximately 18 mg / cm³. 2 That is the case. Sub-coating agent

[0287] In some embodiments, the composition may further include a PVA-PEG graft copolymer subcoating agent covering the composition. In some embodiments, the composition may include a PVA-PEG graft copolymer subcoating agent covering the core tablet. This coating agent may function as a smooth surface to aid in swallowing the tablet. It may also form a scaffold for a further layer which may include an enteric coating agent covering the subcoating agent. In some embodiments, the subcoating agent may also provide a vehicle for coloring to identify the tablet. Other coating agents include, but are not limited to, HPMC, HPC, PVA, Eudragit E-based coating agents, etc. In some embodiments, the composition may further include a subcoating agent. This coating agent may function as a barrier between the components of the core tablet and the enteric coating agent or functional coating agent. The subcoating agent may include OPADRY® class products and may be present in any desired amount. In some embodiments, the weight of the subcoating agent is compared by weight / weight to the weight of the composition before coating. In some embodiments, the subcoating agent may be present in an amount of about 1% to about 10% (w / w). In some embodiments, the sub-coating agent is present in an amount of approximately 1% to approximately 5% (w / w). In some embodiments, the sub-coating agent can be present in an amount of approximately 1% to approximately 3% (w / w) compared to the core tablet before coating. For example, the sub-coating agent can be present in amounts of approximately 1%, 1.5%, 2.0%, 2.5%, and approximately 3%, including any amount in between. In some embodiments, the sub-coating agent is present in an amount of approximately 3% (w / w). In some embodiments, the weight of the sub-coating agent is compared by weight / weight to the weight of the composition before coating or the weight of the core tablet.

[0288] In other embodiments, the sub-coating agent level is the weight increase of the coating agent (mg / cm³). 2 ) is measured. In some embodiments, the sub-coating agent level is approximately 6 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments (emobidments), the sub-coating agent level is approximately 9 mg / cm³. 2 ~about 30mg / cm 2 In other embodiments, the sub-coating agent level is approximately 12 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the sub-coating agent level is approximately 17 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the sub-coating agent level is approximately 20 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the sub-coating agent level is approximately 25 mg / cm³. 2 ~about 30mg / cm 2 For example, the sub-coating agent level is approximately 6 mg / cm³. 2 , 7 mg / cm³ 2 , 8 mg / cm³ 2 , 9 mg / cm³ 2 , 10 mg / cm³ 2 , 6 mg / cm³ 2 , 11 mg / cm³ 2 , 12 mg / cm³ 2 , 13 mg / cm³ 2 , 14 mg / cm³ 2 , 15 mg / cm³ 2 , 16 mg / cm³ 2 , 17 mg / cm³ 2 , 18 mg / cm³ 2 , 19 mg / cm³ 2 , 21 mg / cm³ 2 , 22 mg / cm³ 2 , 23 mg / cm³ 2 , 24 mg / cm³ 2 , 25 mg / cm³ 2 , 26 mg / cm³ 2 , 27 mg / cm³ 2 , 28 mg / cm³2 , 29 mg / cm³ 2 , or 30 mg / cm³ 2 In some embodiments, the sub-coating agent level is approximately 6 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 7 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 8 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 9 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 10 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 11 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 6 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 12 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 13 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 14 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 15 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 16 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 17 mg / cm³. 2 In some embodiments, the sub-coating agent level is approximately 18 mg / cm³. 2 That is the case. Enteric coating agent

[0289] In some embodiments, the composition includes an enteric coating covering a subcoating agent. In some embodiments, the enteric coating is selected to allow for the release of the tablet's contents in a pH range of about 5 to about 8. In some embodiments, the enteric coating is a pH 5.5 enteric coating. The enteric coating may include, but is not limited to, those based on cellulose acetate phthalate (CAP), poly(methacrylate-co-methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate): PVAP, or hydroxypropyl methylcellulose phthalate (HPMCP). In some embodiments, the enteric coating may be a methacrylate copolymer.

[0290] In some embodiments, the enteric coating agent may include, but is not limited to, poly(ethyl acrylate methacrylate) (L100D-55), methyl acrylate, a combination of methyl methacrylate and methacrylic acid (FS30D), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), L-type HPMC-AS, or copolymers of ethyl acrylate methacrylate (e.g., Acryl-eze®).

[0291] In some embodiments, the weight of the enteric coating is compared to the weight of the composition before coating by weight / weight. In some embodiments, the enteric coating may be present in an amount of about 1% to about 15% (w / w). In some embodiments, the enteric coating may be present in an amount of about 2% to about 15% (w / w). In some embodiments, the enteric coating may constitute about 5% to about 15% (w / w) of the core tablet of the composition. For example, the amount of enteric coating may be about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or about 15% (w / w), including fractions thereof. In some embodiments, the enteric coating may be present in an amount of about 6% (w / w). In some embodiments, the enteric coating may be present in an amount of about 7% (w / w). In some embodiments, the enteric coating may be present in an amount of about 8% (w / w). In some embodiments, the weight of the enteric coating is compared to the weight of the core tablet before coating by weight / weight.

[0292] In other embodiments, the enteric coating level is the weight increase of the coating (mg / cm³). 2 It is measured at ). In some embodiments, the enteric coating level is approximately 6 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is approximately 9 mg / cm³. 2 ~about 30mg / cm 2 In other embodiments, the enteric coating level is approximately 12 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is approximately 17 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is approximately 20 mg / cm³. 2 ~about 30mg / cm 2 In some embodiments, the enteric coating level is approximately 25 mg / cm³. 2 ~about 30mg / cm 2 For example, the enteric coating level is approximately 6 mg / cm³.2 , 7 mg / cm³ 2 , 8 mg / cm³ 2 , 9 mg / cm³ 2 , 10 mg / cm³ 2 , 6 mg / cm³ 2 , 11 mg / cm³ 2 , 12 mg / cm³ 2 , 13 mg / cm³ 2 , 14 mg / cm³ 2 , 15 mg / cm³ 2 , 16 mg / cm³ 2 , 17 mg / cm³ 2 , 18 mg / cm³ 2 , 19 mg / cm³ 2 , 21 mg / cm³ 2 , 22 mg / cm³ 2 , 23 mg / cm³ 2 , 24 mg / cm³ 2 , 25 mg / cm³ 2 , 26 mg / cm³ 2 , 27 mg / cm³ 2 , 28 mg / cm³ 2 , 29 mg / cm³ 2 , or 30 mg / cm³ 2 In some embodiments, the enteric coating level is approximately 6 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 7 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 8 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 9 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 10 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 11 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 6 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 12 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 13 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 14 mg / cm³. 2In some embodiments, the enteric coating level is approximately 15 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 16 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 17 mg / cm³. 2 In some embodiments, the enteric coating level is approximately 18 mg / cm³. 2 That is the case.

[0293] In some embodiments, the tablet composition of the present invention may have a sub-coating agent of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating agent of Acryl-eze® Yellow in an amount of about 6% (w / w).

[0294] In some embodiments, the tablet composition of the present invention may have a sub-coating agent of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating agent of Acryl-eze® Yellow in an amount of about 7% (w / w).

[0295] In some embodiments, the tablet composition of the present invention may have a sub-coating agent of OPADRY® QX Yellow in an amount of about 3% (w / w) and an enteric coating agent of Acryl-eze® Yellow in an amount of about 8% (w / w). Order of coating agents

[0296] In some embodiments, the core tablet is coated with one or more cosmetic coatings, subcoatings, enteric coatings, or any combination thereof. When two or more cosmetic coatings, subcoatings, and / or enteric coatings coat the core tablet, such coatings can be applied in any order to directly apply any of the cosmetic coatings, subcoatings, and / or enteric coatings to the surface of the core tablet. In such examples, any further cosmetic coatings, subcoatings, and / or enteric coatings may be subsequently applied in any order.

[0297] In some embodiments, the core tablet is coated with a cosmetic sub-coating agent. In some embodiments, the core tablet is coated with a cosmetic sub-coating agent and then with an enteric coating agent. In some embodiments, the core tablet is coated with a cosmetic sub-coating agent and then with a sub-coating agent, and in certain embodiments, the core tablet is coated with a cosmetic sub-coating agent followed by a sub-coating agent, and then with an enteric coating agent. In certain embodiments, the core tablet is coated with a cosmetic sub-coating agent followed by an enteric coating agent, and then with a sub-coating agent.

[0298] In other embodiments, the core tablet is coated with a sub-coating agent. In some embodiments, the core tablet is coated with a sub-coating agent and then with an enteric coating agent. In some embodiments, the core tablet is coated with a sub-coating agent and then with a cosmetic sub-coating agent. In certain embodiments, the core tablet is coated with a sub-coating agent followed by an enteric coating agent and then with a cosmetic sub-coating agent. In certain embodiments, the core tablet is coated with a sub-coating agent followed by a cosmetic sub-coating agent and then with an enteric coating agent.

[0299] In other embodiments, the core tablet is coated with an enteric coating agent. In other embodiments, the core tablet is coated with an enteric coating agent and then with a sub-coating agent. In a particular embodiment, the core tablet is coated with an enteric coating agent and then with a cosmetic sub-coating agent. In other embodiments, the core tablet is coated with an enteric coating agent followed by a sub-coating agent and then with a cosmetic sub-coating agent. In a particular embodiment, the core tablet is coated with an enteric coating agent followed by a cosmetic sub-coating agent and then with a sub-coating agent.

[0300] In some embodiments, the tablet composition of the present invention may have a bioavailability of about 1% to about 10% (w / w). In some embodiments, the tablet composition of the present invention may have a bioavailability of about 10% to about 50%. For example, the bioavailability may be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. Bioavailability can be measured using the area under curve (AUC) for oral administration versus the AUC for intravenous administration.

[0301] A single dose of one of the compositions described herein may be administered by the methods and / or uses of the present invention. In some embodiments, a single dose of one of the compositions of the present invention may be administered once daily, twice daily, or three times daily. In some embodiments, a single dose of one of the compositions of the present invention may be administered once daily. In some embodiments, a single dose of one of the compositions of the present invention may be administered twice daily. In some embodiments, a single dose of one of the compositions of the present invention may be administered three times daily.

[0302] For example, in some embodiments described herein relating to pharmaceutical compositions, tablets, methods, processes, etc., the acetate of compound A is excluded. For example, in some embodiments described herein relating to compositions, tablets, methods, processes, etc., the acetate of compound A is included. VI. Method or process for preparing dosage forms

[0303] In accordance with the present invention, a pharmaceutical composition comprises, as defined throughout this disclosure, an active main component (i.e., the acetate of compound A or its solvate), and at least one or more further pharmaceutically acceptable components (i.e., may, but is not limited to, absorption enhancers), and adjuvants, carriers, additives, or stabilizers.

[0304] In some embodiments, the active ingredient is a crystalline salt of compound A as described herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof. In some embodiments, the active ingredient is Embodiment 1 as described herein.

[0305] The percentage or amount of the active principal ingredient (API) in the compositions of the present invention naturally varies as the amount of the active compound in such therapeutically useful compositions, but a suitable dosage for administration to the subject or patient can be obtained. It will be understood that the actually preferred dosage of the API used in the compositions of the present invention will vary depending on the particular composition being formulated, the mode of administration, the specific site of administration, and the host being treated. The selection of the most appropriate initial dose for a particular patient is determined by the practitioner using well-known medical principles, including but not limited to body weight.

[0306] Furthermore, the oral tablet dosage form of the present invention may, but is not limited to, an enteric coating on its surface layer, and may be an enteric coating agent as defined in the Definitions section herein. For example, the oral tablet dosage form may be formulated to have a core component, separate continuous layers, or a combination thereof, and the components of the tablet, such as the core and other layers, may have different release-modified component properties based on the gastrointestinal environment, pH, or time. Thus, the oral tablet dosage form of the present invention may also be coated with a pH-sensitive polymer.

[0307] Tablets containing the composition of the present invention can be prepared using conventional tablet forming equipment known in the art, which may utilize compression, rollers, etc. VII. Method of treatment and / or use

[0308] In one embodiment, the present invention relates to a method and / or use for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of compound A or a salt thereof, or a crystalline form of a solvate thereof. In some modifications, the present invention relates to a method and / or use for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline acetate or solvate of compound A disclosed herein, or a composition thereof.

[0309] Methods for treating cancer are provided herein, comprising administering compositions described herein to a subject requiring such treatment. In some embodiments, the method comprises treating a solid tumor. In some embodiments, the method comprises treating a cancer selected from the group consisting of liver cancer, cholangiocarcinoma, colon cancer, hepatobiliary carcinoma, breast cancer, pancreatic cancer, lung cancer, and kidney cancer. In some embodiments, liver cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is extrahepatic (e.g., colon, pancreas, breast, kidney, esophagus, stomach, melanoma, and lung) that has metastasized to and grows in the liver. In some embodiments, the subject is human.

[0310] The compositions described herein can be administered to subjects requiring treatment for proliferative disorders, such as cancer, particularly liver cancer, cholangiocarcinoma, osteosarcoma, melanoma, breast cancer, kidney cancer, prostate cancer, gastric cancer, colorectal cancer, thyroid cancer, head and neck cancer, ovarian cancer, pancreatic cancer, neuronal cancer, lung cancer, uterine cancer, leukemia, or lymphoma. Subjects are typically diagnosed mammals, often humans, who require treatment for one or more of these proliferative disorders. The method comprises administering an effective amount of at least one of the compositions of the present invention, and optionally, the composition may be administered in combination with one or more further therapeutic agents, in particular therapeutic agents known to be effective in treating cancer or proliferative disorders affecting a particular subject. Those skilled in the art will understand that colorectal cancer and colon cancer are interchangeable, and kidney cancer and renal cancer are interchangeable.

[0311] The compositions of this disclosure are administered as a whole in a therapeutically effective dose. The term “therapeutic dose” can mean the amount (or dosage) of a compound or other therapy that is necessary and sufficient to prevent, reduce, alleviate, treat or eliminate a condition or its risk when administered to a subject requiring the compound or other therapy. The amount of composition administered to a subject may be determined by a physician or caregiver taking into account relevant circumstances, including the condition being treated, the chosen route of administration, the composition administered and its relative activity, the individual patient’s age, weight, response, and the severity of the patient’s symptoms. Thus, therapeutically effective doses can vary, for example, depending on the subject’s condition, weight and age, severity of the disease condition, mode of administration, etc.

[0312] The compositions of this disclosure may be administered by any of the permitted modes of administration for drugs having similar uses, for example, by oral, cutaneous, topical, intradermal, intrashelter, intravenous, subcutaneous, intramuscular, intra-articular, intrathecal, or spinal, nasal, epidural, rectal, vaginal, or percutaneous / transmucosal routes. The preferred route depends on the nature and severity of the condition being treated. Oral administration may be the primary route of administration for the compounds of this disclosure, as it generally results in increased oral bioavailability and improved organ targeting, combined with reduced in vivo toxicity. However, intravenous (IV) administration may be a route of administration for the compounds of this disclosure. Intramuscular (IM) administration may also be a route of administration for the compounds of this disclosure. Subcutaneous, sublingual, or percutaneous administration may also be considered as routes of administration for the compounds of this disclosure. Sublingual administration may be performed with appropriate formulations for the compounds. Inhalation administration may also be used as a route of administration for appropriate formulations for the compounds and the types of cancer that can benefit from this route (e.g., lung cancer).

[0313] In certain examples, the pharmaceutical compositions provided herein can be orally administered to human patients at doses ranging from approximately 0.1 mg per kg to approximately 300 mg per kg, or even at doses of 500 mg per kg. In another embodiment, the pharmaceutical compositions provided herein can be orally administered to human patients at doses ranging from approximately 1 mg per kg to approximately 300 mg per kg per day. In yet another specific example, the pharmaceutical compositions provided herein can be orally administered to human patients at doses ranging from approximately 1 mg per kg to approximately 100 mg per kg.

[0314] The subject may be susceptible to cancer. The subject may be a mammal. The subject may be a human patient suffering from cancer. Examples of cancer include, but are not limited to, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, blood cancer, bone cancer, brain tumor, breast cancer, cardiovascular cancer, cervical cancer, colon cancer, digestive system cancer, endocrine system cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, digestive tumors, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, cholangiocarcinoma, lymphoma, mesothelioma, muscular system cancer, myelodysplastic syndrome, myeloma, nasal cavity cancer, nasopharyngeal cancer, nervous system cancer, lymphatic system cancer, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, reproductive system cancer, respiratory system cancer, sarcoma, salivary gland cancer, skeletal system cancer, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymic cancer, thyroid cancer, bladder cancer, or vaginal cancer. In one embodiment, the subject has liver cancer. In another embodiment, the subject has cholangiocarcinoma. In another embodiment, the subject has hepatobiliary cell carcinoma. In yet another embodiment, the subject has kidney cancer. In yet another embodiment, the subject has colon cancer. In yet another embodiment, the subject has lung cancer (e.g., small cell lung cancer or non-small cell lung cancer). In yet another embodiment, the subject has breast cancer. In yet another embodiment, the subject has ovarian cancer. In some embodiments, the cancer is of extrahepatic origin (e.g., colon, pancreas, breast, kidney, esophagus, stomach, melanoma, and lung) that has metastasized to and grown in the liver.

[0315] Examples of cancer include cancers that produce solid tumors and cancers that do not produce solid tumors. Furthermore, any cancer described herein may be a primary cancer (for example, a cancer named after the part of the body where it first began to grow) or a secondary or metastatic cancer (for example, a cancer originating from another part of the body).

[0316] In some embodiments, a method for inhibiting cancer cell proliferation in an individual is provided herein, comprising administering a compound provided herein to the individual. In some embodiments, at least about 10% of cell proliferation is inhibited (including, for example, at least one of about 20%, about 30%, about 40%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the proliferation of solid tumors is inhibited. In some embodiments, the proliferation of liver cancer cells is inhibited. In some embodiments, the proliferation of colon cancer cells is inhibited. In some embodiments, the proliferation of kidney cancer cells is inhibited. In some embodiments, the proliferation of cholangiocarcinoma cells is inhibited.

[0317] Methods for inhibiting tumor metastasis in an individual, comprising administering compounds provided herein to the individual, are also provided herein. In some embodiments, at least about 10% of metastases (including, for example, at least one of about 20%, about 30%, about 40%, about 60%, about 70%, about 80%, about 90%, or about 100%) are inhibited. In some embodiments, metastases of liver cancer are inhibited. In some embodiments, metastases of colon cancer are inhibited. In some embodiments, metastases of kidney cancer are inhibited. In some embodiments, metastases of cholangiocarcinoma are inhibited. In any of the above embodiments, metastases of lymph nodes, lungs, bones, or brain are inhibited. In any of the above embodiments, tumor metastases may be inhibited for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks following treatment.

[0318] In some embodiments, the method includes reducing tumor size and / or tumor load in an individual. In some embodiments, the tumor size is reduced by at least about 10% (including at least one of, e.g., about 20%, about 30%, about 40%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the tumor is liver cancer. In some embodiments, the tumor is kidney cancer. In some embodiments, the tumor is colon cancer. In some embodiments, the tumor is cholangiocarcinoma.

[0319] In some embodiments, the method includes extending the progression-free survival period in an individual. In some embodiments, the method extends the time of disease progression by at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, the individual has a solid tumor. In some embodiments, the individual has liver cancer. In some embodiments, the individual has kidney cancer. In some embodiments, the individual has colon cancer. In some embodiments, the individual has cholangiocarcinoma.

[0320] In some embodiments, the method includes alleviating one or more symptoms in an individual having cancer. In some embodiments, the individual has a solid tumor. In some embodiments, the individual has liver cancer. In some embodiments, the individual has kidney cancer. In some embodiments, the individual has colon cancer. In some embodiments, the individual has cholangiocarcinoma.

[0321] In some embodiments, the method includes improving the quality of life of an individual having cancer. In some embodiments, the individual has a solid tumor. In some embodiments, the individual has liver cancer. In some embodiments, the individual has kidney cancer. In some embodiments, the individual has colon cancer. In some embodiments, the individual has cholangiocarcinoma.

[0322] In some embodiments, the method yields an objective response (e.g., partial or complete response) from a patient with cancer. In some embodiments, the individual has a solid tumor. In some embodiments, the individual has liver cancer. In some embodiments, the individual has kidney cancer. In some embodiments, the individual has colon cancer. In some embodiments, the individual has cholangiocarcinoma.

[0323] In some embodiments, the compositions of the present invention are not metabolized by cytochrome P-450, resulting in reduced toxicity, particularly hepatotoxicity, compared to existing treatments. Accordingly, in some embodiments, a method for treating cancer in an individual, wherein the individual has impaired liver function, is provided herein. In some embodiments, the individual has a Child-Pugh score of class B or class C.

[0324] In some embodiments, the method results in a reduction of one or more markers of liver injury or tumor burden in individuals with liver cancer. In some embodiments, the method results in a reduction of one or more levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphate (ALP). In some embodiments, the levels of markers of liver injury are reduced by at least about 5% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%).

[0325] In any of the methods of treatment and / or embodiments of use detailed herein, such methods and uses may include any of the crystalline forms and pharmaceutical compositions of Compound A described herein, as any combination is specifically and individually enumerated. For example, in some embodiments, any method of treatment and / or use may involve administering to a subject a therapeutically effective amount of Compound A, a pharmaceutically acceptable salt thereof, or a crystalline form of such solvate. In some embodiments, the crystalline form is selected from the acetate and phosphate of Compound A. In some embodiments, the crystalline form is selected from Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, Form 12, and Form 13. In some embodiments, the crystalline form is Form 1.

[0326] In some embodiments, the methods and / or uses of the present invention may include administering a crystalline acetate or solvate of compound A or a composition thereof of the present invention to a subject requiring it. In some embodiments, the subject requiring it has been diagnosed with cancer or is determined to be at risk of developing cancer. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0327] In some embodiments, the present invention provides a method or use of a crystalline acetate or solvate of compound A, or a composition thereof, in the manufacture of a pharmaceutical for treating cancer.

[0328] In some embodiments, the method and / or use involves orally administering a crystalline acetate or solvate of compound A or a composition thereof of the present invention.

[0329] In some embodiments, the methods and / or uses of the present invention involve orally administering a crystalline acetate or solvate of compound A in tablet form, or a composition thereof of the present invention, by patient treatment. In some embodiments, the tablets are administered once, twice, or three times a day.

[0330] In some embodiments, the methods and / or uses of the present invention involve administering a single dose of the crystalline acetate or solvate of compound A or a composition thereof. In some embodiments, the acetate or solvate of compound A may be present in any dose range, such as about 1 mg to about 1000 mg, or about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 50 mg, about 20 mg to about 40 mg, or about 20 mg to about 30 mg. In other embodiments, the dose range of the acetate or solvate of compound A may be about 1 mg to about 1000 mg. In other embodiments, the dose range of the acetate or solvate of compound A may be about 5 mg to about 300 mg. In other embodiments, the dose range of the acetate or solvate of compound A is about 25 mg to about 150 mg. In other embodiments, the dose range of the acetate or solvate of compound A may be about 25 mg to about 100 mg. In another embodiment, the acetate of compound A or its solvate may be present in a dose range of about 1 mg to about 100 mg. In another embodiment, the acetate of compound A or its solvate may be present in a dose range of about 20 mg to about 40 mg. In another embodiment, the acetate of compound A or its solvate may be present in a dose range of about 20 mg to about 30 mg.

[0331] In another embodiment, the method and / or use of the present invention involves administering a dose of crystalline acetate or solvate or a composition of compound A in doses of about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg, or about 150 mg, including any amount in between and fractions thereof. In another embodiment, the dose of acetate or solvate of compound A may be about 5 mg. In another embodiment, the dose of acetate or solvate of compound A may be about 10 mg. In another embodiment, the dose of acetate or solvate of compound A may be about 20 mg. In another embodiment, the dose of acetate or solvate of compound A may be about 30 mg. In another embodiment, the dose of acetate or solvate of compound A may be about 40 mg. In another embodiment, the dose of acetate or solvate of compound A may be about 50 mg. In another embodiment, the dose of compound A acetate or its solvate may be approximately 75 mg. In another embodiment, the dose of compound A acetate or its solvate may be approximately 100 mg. In another embodiment, the dose of compound A acetate or its solvate may be approximately 120 mg. In another embodiment, the dose of compound A acetate or its solvate may be approximately 150 mg.

[0332] In some embodiments, the method and / or use of the present invention involves administering a dose of about 10 mg, about 30 mg, or about 120 mg of crystalline acetate or solvate or a composition of compound A once or twice daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 10 mg of crystalline acetate or solvate or a composition of compound A twice daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 30 mg of crystalline acetate or solvate or a composition of compound A twice daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 120 mg of crystalline acetate or solvate or a composition of compound A twice daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 10 mg of crystalline acetate or solvate or a composition of compound A once daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 30 mg of crystalline acetate or solvate of compound A or a composition thereof once daily. In some embodiments, the method and / or use of the present invention involves administering a dose of about 120 mg of crystalline acetate or solvate of compound A or a composition thereof once daily.

[0333] For example, in some embodiments described herein relating to compositions, tablets, capsules, methods, processes, etc., the acetate of compound A is excluded. For example, in some embodiments described herein relating to compositions, tablets, methods, processes, etc., the acetate of compound A is included.

[0334] For example, in some embodiments described herein relating to compositions, tablets, capsules, methods, processes, etc., the acetate of compound A is excluded. For example, in some embodiments described herein relating to compositions, tablets, methods, processes, etc., the acetate of compound A is included.

[0335] Each aspect of the Invention as defined in this section or any other section may incorporate definitions and limitations as those set out throughout the original filing disclosure, specification and claims. VIII. Examples

[0336] In describing the present invention, the abbreviations and symbols used herein follow the usual use of such abbreviations and symbols by those skilled in the art of chemistry and biology. Methods of characterization X-ray Powder Diffraction (XRPD)

[0337] XRPD analysis was performed using PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample at 3–35°²θ. The material was gently pulverized to release any aggregates, and the sample was supported by loading it into a multiwell plate with Kapton or Mylar polymer film. The multiwell plate was then placed in a diffractometer and analyzed using CuK radiation (α1λ=1.54060A; α2=1.5444A; β=1.39225A; α1:α2 ratio=0.5) operating in transmission mode (step size 0.0130°²θ, step time 18.87s) with a 40kV / 40mA generator setting. The data were visualized, and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017). Polarized Light Microscopy (PLM)

[0338] The presence of crystalline (birefringent) material was determined using an Olympus BX50 microscope equipped with cross-polarizing lenses and a Motic camera. Images were acquired using Motic Images Plus 3.0. All images were recorded using a 20x objective lens unless otherwise specified. Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC)

[0339] Approximately 5-10 mg of the substance was placed in a pre-weighed open-top aluminum dish and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, which was kept at room temperature. The sample was then heated from 30°C to 400°C at a rate of 10°C / min, during which the change in sample weight was recorded along the heat flow response (DSC). Nitrogen was supplied at 200 cm³. 3 It was used as a purge gas for the sample at a flow rate of [number] minutes. Differential Scanning Calorimetry (DSC)

[0340] Approximately 1–5 mg of the substance was weighed into an aluminum DSC dish and sealed with an aluminum lid without airtight sealing. The sample dish was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with an RC90 condenser. The sample and reference were heated to 170°C at a scan rate of 10°C / min, and the resulting heat flow response was monitored. After the sample was recooled to 20°C, everything was reheated to 275°C at 10°C / min. Nitrogen was supplied in a 50 cm³ chamber. 3 It was used as a purge gas at a flow rate of [per minute]. Infrared Spectroscopy (IR)

[0341] Infrared spectroscopy was performed using a Bruker ALPHA P spectrometer. A sufficient amount of material was placed in the center of the spectrometer plate, and the spectrum was obtained using the following parameters: Resolution: 4cm -1 Background scan time: 16 scans Sample scan time: 16 scans Data acquisition: 4000~400cm -1 Resulting spectrum: transmittance Software: OPUS version 6 Nuclear Magnetic Resonance (NMR)

[0342] 1¹H NMR tests were performed using a Bruker AVIIIHD spectrometer equipped with a DCH frozen probe operating at 500.12 MHz relative to protons. The tests were conducted with deuterated dimethyl sulfoxide (d6-DMSO), and each sample was prepared to a concentration of approximately 5–25 mM. Dynamic vapor sorption (DVS)

[0343] Approximately 10–20 mg of sample was placed in a mesh vapor adsorption pan and loaded onto a DVS Intrinsic dynamic vapor sorbent balance using Surface Measurement Systems. The sample was subjected to a ramping profile at 40–90% relative humidity (RH) in 10% increments, with the sample maintained at each step until a stable weight was achieved at 25°C (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min). After the adsorption cycle was complete, the sample was dried to 0% RH using the same procedure, and then returned to 40% RH for a second adsorption cycle. Two cycles were performed. The weight change between adsorption / desorption cycles was plotted to allow determination of the hygroscopicity of the sample. XRPD analysis was then performed on any remaining solid. High-performance liquid chromatography-ultraviolet detection (HPLC-UV)

[0344] The following parameters were used: Equipment: Dionex Ultimate 3000 Column: X-Bridge C18 150×4.6mm 3.5μm Column temperature: 30℃ Autosampler temperature: 5℃ UV wavelength: 260nm Injection volume: 5.00 μL Flow rate: 0.7mL / min Mobile phase A: 0.1% TFA in H2O Mobile phase B: Acetonitrile Excipients: Water: Methanol v / v 50:50

[0345] The following gradient program was used: [Table 1]

[0346] LC-MS was performed at the University of Edinburgh. Samples were prepared to a concentration of approximately 20 μg / mL in 0.1% FA of 1:1 water / acetonitrile. Analysis was performed using electrospray on a SolariXR FT-ICR MS equipped with a 12T superconducting magnet (Bruker Daltonics). Variable Humidity X-ray Powder Diffraction (VH-XRPD)

[0347] XRPD analysis was performed using a Philips X'Pert Pro Multipurpose diffractometer equipped with a humidity chamber. Samples were scanned from 4 to 36°²θ using CuK radiation (α1λ=1.54060A; α2=1.54443A; β=1.39225A; α1:α2 ratio=0.5) operating in Bragg-Brentano geometry (step size 0.008°²θ) with a 40kV / 40mA generator setting. Measurements were performed at 30°C during the humidity profiles described below: Initial scan at 40% RH Humidity increased to 90% RH in 105 minutes (scans at 5 and 105 minutes). Humidity decreased to 40% RH in 10 minutes (scan after 5 minutes). Humidity decreased to 5% RH in 60 minutes (scan performed after 60 minutes). Humidity dropped to 0% RH in 17 hours (scan performed after 17 hours). Humidity increased to 40% RH in 60 minutes (scans performed at 30 and 60 minutes). Humidity increased to 60% RH in 105 minutes (scans performed at 5 and 105 minutes). Humidity increased to 80% RH in 60 minutes (scans performed at 5 and 55 minutes). [Example 1] Synthesis of Form 1 of compound A diacetate

[0348] Form 1 of 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate (compound A diacetate) was prepared in 6 steps from the starting materials 4-hydroxybenzonitrile (SM-1), 1,5-dibromopentane (SM-2), and 5-hydroxypicolinonitrile (SM-3). The synthetic route is shown in Scheme 1 below. [ka]

[0349] In the first step, SM-1 was alkylated with SM-2 in the presence of potassium carbonate in N,N-dimethylformamide (DMF) to obtain INT-1. Next, SM-3 was alkylated with INT-1 in the presence of potassium carbonate in DMF to obtain INT-2. Then, the nitrile at the 2-position of the pyridine ring was converted to amidine by sequential treatment with sodium methoxide and ammonium acetate in methanol to obtain INT-3. Treatment of INT-3 with ethanolic HCl yielded an iminoester INT-4, which could not be isolated but could be converted to the corresponding amidine by treatment with ammonium carbonate in methanol, and compound A was obtained by conversion to a diacetate by treatment with ammonium acetate in methanol. Step 1: Preparation of 4-((5-bromopentyl)oxy)benzonitrile (INT-1)

[0350] A mixture of SM-2 (22.19 kg, 5.0 equivalents) and potassium carbonate (3.19 kg, 1.2 equivalents) in DMF (6.9 L), heated to 40 ± 5 °C, was to be mixed with a solution of SM-1 (2.30 kg, 1.0 equivalent) in DMF (11.5 L) for approximately 1 hour. The reaction mixture was stirred at 40 ± 5 °C for approximately 4 hours, at which point intra-process analysis (IPC-1) indicated that the reaction was complete. The reaction mixture was cooled to approximately 30 °C and quenched with water. The two-phase mixture was separated, and the aqueous layer was extracted with n-heptane. The combined organic layers were washed with water and then cooled to 25 ± 5 °C. The resulting solid was collected by filtration and washed with n-heptane. The filtrate was cooled to -25 ± 5 °C for approximately 3 hours, and the resulting solid was collected by filtration and washed with n-heptane. The combined solids were dried under vacuum at 30±5℃ to obtain the crude product.

[0351] The crude product and n-heptane were combined and heated at 65±5°C for approximately 1 hour. The solution was then cooled to 37.5±2.5°C and filtered. The filtrate containing the product was concentrated to approximately 5 volumes by distillation and cooled to 30°±5°C, during which time the product crystallized. The product was collected by filtration, washed with n-heptane, and dried under vacuum at 30±5°C to obtain INT-1 (1.444 kg, yield 26%, HPLC purity 97.8%).

[0352] The second batch was prepared using the same process with 0.875 kg of SM-1 and 22.19 kg of SM-2, yielding 0.776 kg of INT-1 (39% yield, 98.5% HPLC purity). Step 2: Preparation of 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinonitrile (INT-2)

[0353] Potassium carbonate (3.00 kg, 2.0 equivalents) was added in three separate additions to a solution of SM-3 (2.83 kg, 1.17 equivalents) in DMF (7.20 L) heated to 30 ± 5 °C. The resulting mixture was heated to 75 ± 5 °C, and then a solution of INT-1 (2.40 kg, 1.0 equivalent) in DMF (12 L) was added. The reaction mixture was stirred for approximately 1 hour, at which point intra-process analysis (IPC-1) indicated that the reaction was complete. The reaction mixture was cooled to 30 ± 5 °C, quenched with purified water, and stirred for approximately 2 hours. The solid was collected by filtration, washed with purified water, and dried under vacuum at 50-55 °C to obtain INT-2 (2.46 kg, yield 89%, HPLC purity 97.3%). Step 3: Preparation of 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinimido acetate (INT-3)

[0354] A mixture of INT-2 (2.43 kg, 1.0 equivalent) in methanol (24 L), cooled to 10±5°C, was gradually increased by adding a sodium methoxide solution (0.318 kg, 30% solution in methanol, 0.2 equivalents) while maintaining a batch temperature of 10±5°C. Upon completion of the addition, the reaction mixture was heated to approximately 50°C for about 6 hours. The reaction mixture was cooled to 30±5°C and sampled for in-process analysis (IPC-1). Next, ammonium acetate (1.82 kg, 3.0 equivalents) was added, and the resulting mixture was stirred for approximately 16 hours, at which point the in-process analysis indicated that the reaction was complete (IPC-2). The reaction mixture was then quenched with purified water and stirred for approximately 2 hours. The solid was collected by filtration and washed with purified water. The wet solid was slurryed with acetone, heated to 50±5°C for approximately 2 hours, cooled to 30±5°C, filtered, and washed with acetone. This slurrying process was repeated two more times. The wet solid was dried under vacuum at 55±5°C to obtain INT-3 (2.50 kg, yield 82.5%, HPLC purity 97.5%). Steps 4 and 5: Preparation of 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide (Compound A)

[0355] A mixture of INT-3 (2.44 kg) and ethanolic HCl (48.8 L, 5.0 M in ethanol) was cooled to 15-20°C. HCl gas was passed through the reaction mixture until the HCl content reached 32.0% or higher (IPC-1). The reaction mixture was heated to 30±5°C and stirred for approximately 12 hours, at which point in-process analysis indicated that the reaction was complete (IPC-2). Methyl tert-butyl ether (MTBE) was added to the reaction mixture, and the solid (INT-4) was collected by filtration and washed with MTBE. The wet solid was slurryed with MTBE, filtered, and washed with MTBE to obtain INT-4. A mixture of INT-4 and ammonium carbonate (3.17 kg) in methanol (24.5 L) was stirred for approximately 10 hours at 25±5°C, at which point in-process analysis indicated that the reaction was complete (IPC-3). The solvent was removed by distillation until approximately 6 volumes remained. The batch temperature was adjusted to 30±5°C, and acetone was added to the slurry. After 1 hour, the solid was collected by filtration, washed with acetone, and dried under vacuum at approximately 50-55°C to obtain crude compound A (2.12 kg).

[0356] To a solution of crude compound A (2.12 kg) in N,N-dimethyl sulfoxide (DMSO, 21.2 L), dichloromethane (DCM, 53.1 L) was added, and the resulting mixture was stirred at 30±5°C for approximately 5 hours. The solid was collected by filtration, washed with DCM, and dried under vacuum at 50-55°C to obtain 1.91 kg of compound A. Based on the results from in-process elemental impurity testing (IPC-4), the batch was further purified in two batches as described below.

[0357] Activated carbon (Norit® CGP Super, 0.283 kg) was added to a solution of compound A (0.945 kg) in methanol (47.25 L). The resulting mixture was stirred for 24 hours at 30 ± 5 °C. The mixture was filtered through a Celite® bed. The filter bed was washed twice with methanol. The combined filtrate was concentrated by distillation until approximately 18 L remained. Acetone was added, and the mixture was stirred for approximately 4 hours at 30 ± 5 °C. The solid was collected by filtration and washed with acetone.

[0358] The wet cakes from two batches were combined and slurryed with an aqueous sodium bicarbonate solution. The solid was collected by filtration and washed with purified water. The wet solid was slurryed with acetone, filtered, washed with acetone, and dried under vacuum at approximately 30-35°C to obtain purified compound A (1.10 kg, yield 58%, HPLC purity 99.0%). Step 6: Preparation of 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate (form 1 of compound A diacetate)

[0359] A mixture of compound A (1.09 kg) and ammonium acetate (0.49 equivalents) in methanol (10.9 L) was stirred at 30 ± 5°C for approximately 12 hours. Then, methanol (54.5 L) was added, and the batch was heated to 35 ± 5°C and stirred for approximately 2 hours. The reaction mixture was filtered, and the filtrate was washed with methanol. The combined filtrate was distilled under vacuum at approximately 40°C until approximately 20 L remained. Then, acetone was added, and the resulting slurry was stirred at 30 ± 5°C for approximately 45 minutes. The product was collected by filtration and washed with acetone. The solvent-moistened product was slurryed with n-heptane at 60–65°C for approximately 2 hours. The slurry was cooled to approximately 30°C. The product was collected by filtration, washed with n-heptane, and dried under vacuum at approximately 60–70°C to obtain form 1 of compound A diacetate (0.903 kg, yield 61%, HPLC purity 99.0%). [Example 2] Characterization of Form 1 of Compound A

[0360] Form 1 of compound A diacetate ("Form 1") was crystalline according to XRPD, as shown in Figure 1. A summary of the main peaks identified in the XRPD spectrum of Form 1 is shown in Table 1 below. [Table 2]

[0361] TG analysis identified a 31.9% mass loss (1.81 equivalents of acetic acid) associated with an endothermic event with an initiation at 193.1°C and a peak at 217.7°C, likely corresponding to melting in form 1. The sample was found to decompose above 250°C (Figure 2).

[0362] During the first heating phase with DSC to 170°C, a small exothermic event was identified, with an initiation at 133.1°C and a peak at 135.2°C (Figure 3). No significant thermal events were observed during the cooling phase with DSC (Figure 4). During the second heating phase with DSC, a large endothermic event corresponding to sample melting was found, with an initiation at 220.4°C and a peak at 228.6°C (Figure 5).

[0363] A second DSC test was performed, in which the material was heated from 20°C to 275°C, and an endothermic event corresponding to sample melting was identified, with an initiation at 221.0°C and a peak at 228.7°C. Subsequently, a sharp exothermic event corresponding to recrystallization of the free form of the API followed closely, with an initiation at 228.9°C and a peak at 229.9°C (Figure 6).

[0364] In morphology 1, slight hygroscopicity was observed by DVS analysis, accompanied by 1.8% mass uptake (0.5 equivalents of water) at 90% RH (Figure 7). No signs of any morphological change were observed in the dynamical plot in Figure 8. The solid recovered after DVS analysis was maintained as pattern 1, as accepted by XRPD.

[0365] Small, poorly birefringent crystals were observed in PLM, but no clear morphology was detected. Aggregation was also visualized (Figure 9).

[0366] The FT-IR spectrum shown in Figure 10 was consistent with the expected structure of compound A. 1 The 1H NMR spectrum is shown in Figure 11, which is consistent with the expected structure of compound A and confirms the diacetate.

[0367] HPLC analysis yielded a relative area purity value of 96.7%.

[0368] The DAD spectrum can be found in Figure 12 (λmax 264.0 mAU).

[0369] LC-MS confirmed that the molecular weight of the API of compound A was 342.2[M+H]+1 with an error margin of 80 ppb (Figure 13).

[0370] In a one-week stability assessment of morphology 1, no morphological changes were observed by XRPD at 2 and 7 days at 40°C / 75% RH, 80°C, or ambient temperature and humidity.

[0371] The results of the characterization tests described above are summarized in Table 2 below. [Table 3] [Example 3] Screening of solvent solubility for compound A diacetate

[0372] Approximately 380 mg of Form 1 was dissolved in 35 mL of methanol and subjected to a rotary evaporator. The resulting solid was analyzed by XRPD and found to be a mixture of the novel patterns shown in Forms 1 and 2. Subsamples were further characterized (TG / DSC, 1 The material was collected by 1H NMR and PLM. After rotational evaporation, the isolated crystalline substance was redissolved in 27 mL of water. Since the solution remained slightly turbid, it was filtered with a syringe to obtain a clear solution, which was equally divided into 18 vials, yielding approximately 20 mg of the substance per vial. The samples were then frozen at -50°C and freeze-dried for approximately 72 hours. The resulting solid was subjected to XRPD and1 Analysis by 1H NMR revealed poor crystallinity. This substance was used as an input for the solvent solubility screening described below.

[0373] The solubility of compound A diacetate was tested in 18 different solvent systems. A suitable solvent was added to approximately 20 mg of lyophilized compound A diacetate in 100 μL aliquots. Between each addition, the mixture was checked for dissolution. If dissolution was not observed, the mixture was heated to approximately 40°C and checked again. This procedure was continued until dissolution was observed or until 100 volumes of solvent had been added.

[0374] If the solid did not dissolve after adding 2 mL of solvent, the slurry was circulated between room temperature and 40°C for 48 hours. The solid was then isolated by centrifugal filtration and analyzed by XRPD. If the sample dissolved completely upon addition of solvent (methanol and water only), it was left uncapped and allowed to evaporate at room temperature. Any solid recovered after evaporation was then analyzed by XRPD.

[0375] The results of the preliminary solvent solubility screening are summarized in Table 3 below. The substance was found to have low solubility (<5 mg / mL) in all solvents investigated except methanol (20 mg / mL) and water (50 mg / mL). XRPD analysis of the recovered solid revealed six novel diffractogram patterns. [Table 4] [Example 4] Primary polymorph screening

[0376] The amorphous form of compound A diacetate was prepared via lyophilization. Approximately 750 mg of form 1 of compound A diacetate was dissolved in 78 mL of water. Gentle heating and ultrasonic treatment were used to aid dissolution, but the solution remained slightly cloudy, so it was filtered in a syringe to obtain a clear solution. This solution was then equally divided into 14 vials, yielding approximately 50 mg per vial. The samples were then frozen at -50°C and lyophilized for approximately 48 hours. Subsamples were then taken from one sample and analyzed by XRPD. The material was successfully made amorphous.

[0377] Next, the amorphous form was added to one of 13 solvents and subjected to the following methods: thermal circulation, evaporation, crash cooling, addition of a poor solvent, or solvent drop grinding. heat circulation

[0378] A slurry was formed by adding a suitable solvent to a lyophilized compound A diacetate in 100 μL aliquots. The sample was then sealed and placed in an incubator shaker, with temperature circulation between room temperature and 40°C for approximately 72 hours. After temperature circulation, the slurry was centrifuged and filtered to isolate the solid, which was analyzed by XRPD. The saturated mother liquor solution was divided equally into four vials for crystallization testing. The XRPD plates were dried at 40°C, and all samples were re-analyzed by XRPD to check for morphological changes. The remaining isolated solid was gently dried under vacuum at room temperature, and if a new morphology was identified, the solid was analyzed again by XRPD. 1 1H NMR, TG / DSC, PLM, and FT-IR analyses were performed.

[0379] The results of the thermal circulation tests are summarized in Table 4. The entire solid recovered after thermal circulation was crystalline according to XRPD analysis. Form 2 was recovered from THF and water, but when the THF solid was dried under vacuum, it was observed to be converted to Form 3, and when dried at 40°C, a mixture of Forms 1 and 2 was obtained. When the solid of Form 2 recovered from water was dried, a new form, Form 9, was obtained, which could only be isolated from water, suggesting the possibility of a hydrate. The solid of Form 3 was recovered from thermal circulation in 1,4-dioxane, IPA, acetone, and DCM, but when the solid slurryed in DCM was dried at 40°C for 72 hours, a morphological change to Form 11 was observed. Form 4 was isolated only from DMA, and Form 5 was obtained from NMP, indicating a solvate of DMA and NMP. Both forms appeared to be stable when dried at 40°C, but when Form 4 was dried under vacuum, it was observed to be converted to a mixture of Forms 4 and 5. Solvent contamination occurs when samples are dried under vacuum, resulting in novel forms of contamination. 1 ¹H NMR analysis revealed that Form 4 is a solvate of DMA and may have been contaminated with NMP in the vacuum oven used to obtain the mixture of Form 5. Form 6 was isolated from a thermal cycle in toluene but showed poor crystallinity according to XRPD and remained unchanged when dried at 40°C. Form 7 was recovered from acetonitrile and methanol and showed no change in morphology upon drying. Form 8 was recovered from ethanol and ethyl acetate and showed no change in morphology upon drying, although a significant decrease in crystallinity was observed when the ethanol solid was dried under vacuum. evaporation

[0380] A saturated mother liquor solution was prepared as described in the "Thermal Circulation" section above, but without capping, it was left to stand and evaporated at room temperature. Observations were recorded after evaporation, and any recovered solid was analyzed by XRPD.

[0381] The results of the evaporation tests are summarized in Table 4. The solid was not recovered from the evaporation of most saturated mother liquor solutions, which is likely due to the low solubility of compound A diacetate in these solvent systems. The white solid was recovered from the evaporation of an aqueous solution of compound A diacetate, which was identified as morphology 9 by XRPD, with several additional peaks present. Crash Cooling

[0382] A saturated mother liquor solution was prepared as described in the "Thermal Circulation" section above and stored at approximately 4°C for 5 days. Observations were recorded, and where possible, solids were recovered and analyzed by XRPD. If no precipitation occurred, or if there were not enough solids for XRPD analysis, the sample was placed in a storage chamber at approximately -18°C for 6 days. Further observations were then recorded, and any solids were analyzed by XRPD.

[0383] The results of the crush cooling test are summarized in Table 4. Except for the water sample which returned to a turbid solution, no precipitate was observed when the saturated mother liquor solution was cooled to 4°C. XRPD analysis of the solid recovered after filtration of this solution yielded morphology 2. Further cooling of the mother liquor to -18°C yielded a small amount of precipitate in the methanol sample, but not enough material was recovered for XRPD analysis. Addition of poor solvent

[0384] The poor solvent was added to a suitable saturated mother liquor solution in 100 μL aliquots until precipitation occurred or 1 mL was added. If precipitation was observed, the sample was centrifuged and the recovered solid was analyzed by XRPD. If no precipitation occurred, the sample was cooled in a refrigerator at 4°C.

[0385] Heptane was used as a poor solvent for 1,4-dioxane, 2-propanol, acetone, ethanol, ethyl acetate, N-methylpyrrolidone, tetrahydrofuran, toluene, and DCM. Acetone was used as a poor solvent for acetonitrile, N,N-dimethylacetamide, and water.

[0386] The results of the poor solvent addition test are summarized in Table 4. Except for water, which reverted to an amorphous state, no precipitate was observed when the poor solvent was added to the saturated mother liquor solution. Solvent droplet pulverization

[0387] Form 1 of compound A diacetate was made amorphous via lyophilization for use in a solvent droplet pulverization test. Approximately 260 mg of form 1 of compound A diacetate was weighed and dissolved in 26 mL of water. Gentle heating and ultrasonic treatment were used to aid dissolution. The slightly turbid solution was then filtered through a syringe to obtain a clear solution, which was divided equally into 13 vials. The samples were frozen at -50°C for approximately 3 hours, followed by lyophilization for approximately 16 hours. Since lyophilization was incomplete at this point, an additional 2 mL of water was added to each sample to redissolve the substance. The samples were frozen again at -50°C, followed by lyophilization for approximately 72 hours. Subsample No. 13 was analyzed by XRPD to confirm successful lyophilization. Four 2.8 mm stainless steel beads were placed in each vial containing the lyophilized compound A diacetate substance. One to two drops of a suitable saturated mother liquor solution obtained after thermal circulation were added to each sample vial. Next, the sample was ground using the following method: speed: 5000 RPM, cycle time: 60 seconds, number of cycles: 5, time between cycles: 10 seconds.

[0388] The results of the solvent droplet pulverization test are summarized in Table 4. Very poorly crystalline / amorphous substances were recovered from IPA, acetone, acetonitrile, ethanol, NMP, and water. Solids of form 3 were obtained from 1,4-dioxane and THF, while solids of form 4 were obtained from DMA. Novel diffractograms shown in form 10 were obtained from ethyl acetate, toluene, and DCM. Further preparation of polymorphic forms

[0389] Since Form 2 was converted to Forms 3 and 1 when dried at room temperature under vacuum, and Form 4 was converted to a mixture of Forms 4 and 5, attempts were made to re-prepare these forms for further characterization. In addition, the solid of Form 8 from ethanol lost a significant amount of crystallinity when dried, so these solids were also reprocessed in attempts to restore the crystallinity of the material.

[0390] For Form 2, 2 mL of THF was added to the solid of Form 3, which was obtained by drying the THF solid under vacuum, to form a slurry.

[0391] For Form 4, 2 mL of DMA was added to the solid of Form 4 / Form 5, which was obtained by drying the DMA solid under vacuum, to form a slurry.

[0392] For Form 8, 2 mL of ethanol was added to the poorly crystalline Form 8 substance isolated by drying under vacuum to form a slurry.

[0393] Next, these slurries were shaken at 50°C for approximately 5 hours, then centrifuged and filtered, and the solids were analyzed by XRPD. While the crystallinity of the substance in form 8 was successfully restored, no change in morphology was observed in the THF or DMA slurries. Therefore, an additional 1 mL of DMA was added to the mixture of form 4 / form 5, and an additional 2 mL of THF was added to the solid in form 3. These slurries were then subjected to temperature cycling between room temperature and 40°C in 4-hour cycles with stirring for approximately 72 hours. The samples were then centrifuged and filtered, and the solids were again analyzed by XRPD. Again, no change in morphology was observed; the DMA solid remained in the mixture of form 4 / form 5, and the THF solid remained in form 3.

[0394] The results of the primary polymorph screening are summarized in Table 4 below. Eleven polymorphic forms of compound A diacetate were identified during the primary polymorph screening, demonstrating that the diacetate possesses complex polymorphic properties. The characterization of the novel forms is summarized in Table 5, and a diagram illustrating the relationships between the forms is shown in Figure 67.

[0395] In form 2, it was found that it could not be reproduced from THF, but this is not surprising as it is now known to be a tetrahydrate. Form 3 is TG / DSC and 1 Solvation was observed by 1H NMR, with both identifying 1.0 and 1.2 equivalents of THF in the sample, respectively. However, it was advised to scale up this solvated form to further investigation from several process-related solvents (1,4-dioxane, 2-propanol, acetone, and THF). Form 4 was obtained only from DMA and is therefore likely to be a DMA solvate, and similarly, Form 5 was found to be an NMP solvate, with TG / DSC confirming 0.8 equivalents of NMP present in the sample. Form 6 was obtained from toluene and yielded a poorly crystallinity diffractogram and a moderate 13.6% mass loss (0.7 equivalents of toluene) from the start of heating by TG / DSC.

[0396] Form 7 was obtained from methanol and acetonitrile. 1 ¹H NMR did not detect methanol in the analyzed solid, and TG / DSC analysis identified a sharp 4.5% mass loss corresponding to 1.2 equivalents of water, which hydrated Form 7. Form 8 was obtained from ethanol and ethyl acetate and was initially thought to be an anhydrous form because there was no mass loss when the substance was heated in TG / DSC. Salt disproportionation / sample melting was observed at a lower temperature of 186.1°C than for Form 1, which meant that Form 8 was initially thought to be a metastable anhydrous form of compound A diacetate. It was later concluded during secondary screening that Form 8 was another solvated form.

[0397] Form 9 was obtained from water, and for this reason, it was scaled up during secondary screening. TG / DSC analysis revealed 1.7 equivalents of water in the sample, and the large, highly birefringent lath-like morphology was present due to PLM. Form 10 was observed only from solvent droplet pulverization tests, while Form 11 was observed only when Form 3 was dried from DCM. [Table 5] [Table 6] Characterization of novel polymorphs Form 2

[0398] The XRPD diffractogram for morphology 2 is shown in Figure 14. Form 3

[0399] Form 3 was recovered from thermally circulating amorphous compound A diacetate in 1,4-dioxane, IPA, acetone, and DCM. Form 3 was also recovered after drying the Form 2 substance from THF under vacuum, and after solvent droplet pulverization using a saturated THF solution. The XRPD diffractogram is shown in Figure 15, along with a list of peaks shown in Table 6. The Form 3 substance obtained after drying the Form 2 substance from THF was used for further characterization. 1 ¹H NMR identified 1.2 equivalents of THF with a 4.89H peak at 3.60 ppm. The substance was consistent with the structure of compound A diacetate, which corresponds to CH3 in acetic acid and has a 6.00H peak at 1.74 ppm (Figure 16). [Table 7]

[0400] TG / DSC analysis of Form 3 identified a 14.9% mass loss (0.95 equivalents of THF) associated with a broad endothermic event with an initiation at 74.0°C and a peak at 125.6°C, likely due to desolvation of the substance. Subsequently, a broad endothermic event similar to Form 1 occurred, associated with sample melting, with an initiation at 183.7°C and a peak at 197.8°C, including a 27.9% associated weight loss (1.6 equivalents of acetic acid). This suggests the possibility of desolvation in Form 1 (Figures 17-20, 25). PLM analysis did not reveal clear particle morphology, but the presence of birefringence was observed. Aggregation was also visualized (Figure 21). The FT-IR spectrum is shown in Figure 22. The presence of water was detected at 3255.68 cm⁻¹. -1The peaks observed were those at the specified point (list of peaks shown in Table 7). [Table 8] Form 4

[0401] The XRPD diffractogram for form 4 is shown in Figure 26. Form 5

[0402] Form 5 was recovered from amorphous compound A diacetate in thermally circulating NMP. The XRPD diffractogram is shown in Figure 27, along with a list of peaks shown in Table 8. 1 In 1H NMR, 2.6 equivalents of NMP were found at 2.70 ppm with a 7.72H CH3 peak. Less than 0.1 equivalents of 1,4-dioxane and THF, 0.1 equivalents of DMA, and 0.2 equivalents of hexane were also present in the NMR spectrum due to solvent cross-contamination during drying the solid in a vacuum oven. The substance was consistent with the structure of compound A diacetate, which corresponds to the CH3 of acetic acid and has a 6.00H peak at 1.74 ppm (Figure 28). [Table 9]

[0403] TG / DSC analysis identified an 18.2% mass loss (0.84 equivalents of NMP) associated with a small endothermic event with an initiation at 145.4°C and a peak at 161.0°C. Subsequently, a large endothermic event corresponding to sample melting occurred, with an initiation at 190.2°C and a peak at 204.1°C, including an associated 24.4% mass loss (1.4 equivalents of acetic acid). This indicates desolvation of form 1 (Figure 29). PLM analysis did not reveal any clear morphology, but birefringent particles and aggregates were present (Figure 30). FT-IR showed: 1 The structure of compound A diacetate was consistent with the expected structure based on 1H NMR data (Figure 31). form 6

[0404] Form 6 was the amorphous compound A diacetate after thermal cycling and isolation in toluene. The XRPD diffractogram is shown in Figure 32, along with a list of peaks shown in Table 9. 1 ¹H NMR revealed 2.2 equivalents of toluene present in the sample, with a 6.5H peak at 2.30 ppm. Less than 0.1 equivalents of dioxane and IPA, as well as 0.1 equivalents of DMA, NMP, and hexane, were also present in the NMR spectrum (Figure 33). The substance was consistent with the structure of compound A diacetate, with a 6.00H peak at 1.74 ppm. [Table 10]

[0405] TG / DSC analysis identified a mild 13.6% mass loss (0.7 equivalents of toluene) associated with a broad endothermic event with a peak at 113.6°C and an initiation at 58.2°C, likely corresponding to desolvation. Subsequently, sample melting occurred, with a peak at 203.9°C and an initiation at 190.6°C, including a related 21.2% mass loss (1.2 equivalents of acetic acid). This indicates desolvation to Form 1 due to a similar melting at 193.1°C (Figure 34). PLM images are shown in Figure 35. Although no distinct morphology was observed, birefringent particles and aggregates were present. The FT-IR spectrum was consistent with the expected diacetate structure (Figure 36). Form 7

[0406] Form 7 was obtained from a substance of amorphous compound A diacetate circulating temperature in acetonitrile and methanol. The XRPD diffractogram is shown in Figure 37, along with a list of peaks shown in Table 10. 1 ¹H NMR analysis revealed no methanol remaining in the sample after drying under vacuum, but 0.1 equivalents of DCM and dioxane, 0.8 equivalents of DMA, 0.2 equivalents of NMP and ethyl acetate, and less than 0.1 equivalents of IPA, toluene, and acetone were all present in the spectrum. The substances were also found to be consistent with the diacetate structure, confirming that no salt disproportionation had occurred (Figure 38). [Table 11]

[0407] TG analysis identified a moderate mass loss of 7.5% preceded by a sharp mass loss of 4.6% (1.2 equivalents of water) associated with a small endothermic event, with an initiation at 147.7°C and a peak at 147.9°C. The sample then melted, with an initiation at 195.1°C and a peak at 213.0°C, including a 26.2% mass loss (1.5 equivalents of acetic acid) corresponding to salt disproportionation (Figure 39). The PLM image is shown in Figure 40 and contains small, highly birefringent visible particles. No distinct crystalline morphology was identified. FT-IR analysis yielded 3263.89 cm⁻¹. -1 This was consistent with the expected diacetate structure, which was accompanied by a clear water peak (Figure 41). A list of FT-IR peaks is shown in Table 11. [Table 12] Form 8

[0408] Form 8 was obtained from amorphous compound A diacetate, which underwent temperature cycling in ethanol and ethyl acetate. The XRPD diffractogram is shown in Figure 42, along with a list of peaks shown in Table 12. 1 The 1H NMR spectrum is shown in Figure 43, confirming the diacetate structure. The large amount of ethanol visualized as a substance was not dried for pre-NMR analysis due to the loss of crystallinity observed upon drying. [Table 13]

[0409] Compound A appears anhydrous by TG / DSC, with no weight loss identified up to a 28.6% mass loss (1.6 equivalents of acetic acid) associated with sample melting, with an initiation at 186.0°C and a peak at 203.7°C (Figures 44-47, 52). PLM images are shown in Figure 48, visualizing small, poorly birefringent particles. The FT-IR spectrum is consistent with the expected diacetate structure and is shown in Figure 49, along with a list of peaks shown in Table 13. [Table 14] Form 9

[0410] Form 9 was recovered after drying Form 2 from water and then evaporating the saturated aqueous solution, indicating the possibility of hydration. The XRPD diffractogram is shown in Figure 53, along with a list of peaks shown in Table 14. 1 ¹H NMR was consistent with the diacetate structure containing less than 0.1 equivalents of dioxane and IPA, as well as 0.1 equivalents of DMA, NMP, and hexane (Figure 54). TG / DSC analysis identified sample melting / salt disproprtion, involving a 30.9% mass loss (1.8 equivalents of acetate) associated with an endothermic event, with an initial 6.7% mass loss (1.7 equivalents of water) at approximately 50°C, likely corresponding to dehydration (Figures 55-58, 63). This indicates that form 9 is immediately dehydrated to form 1. [Table 15]

[0411] PLM analysis identified large, highly birefringent lath-like morphologies with visible aggregation (Figure 59). The FT-IR spectrum was 3232.61 cm⁻¹. -1 Figure 60 shows the expected diacetate structure with water peaks visualized, which is consistent with the FT-IR peaks. A list of FT-IR peaks is shown in Table 15. [Table 16] Form 11

[0412] The XRPD diffractogram for morphology 11 is shown in Figure 64. [Example 5] Secondary polymorph screening

[0413] Crystal forms 3, 8, and 9 were scaled up for further characterization.

[0414] Approximately 1.2 g of compound A diacetate form 1 was weighed and dissolved in 126 mL of water. The solution was gently heated and sonicated to aid dissolution, then filtered in a syringe and equally divided into three Duran vials, yielding approximately 400 mg of the substance per vial. The samples were then frozen at -50°C and lyophilized for 4 days. Subsamples were analyzed by XRPD after lyophilization to confirm successful amorphization. Preparation and Characterization of Form 3

[0415] 25.6 mL of 2-propanol was added to lyophilized compound A diacetate to form a slurry. The slurry was then subjected to temperature cycling between room temperature and 40°C in 4-hour cycles with stirring for approximately 24 hours. The slurry was then filtered, and the isolated solid was collected in a scintillation vial. Subsamples were analyzed by XRPD, and the vial was left uncapped to allow the solid to dry at room temperature for approximately 24 hours. The material was then re-analyzed by XRPD after drying and fully characterized using the following techniques: DVS, PLM, FT-IR, including TG / DSC, DSC, and XRPD analysis after DVS. 1Purity by 1H NMR and HPLC, TG / DSC including TG / DSC followed by XRPD analysis, and 7-day stability assessment (approximately 10 mg of the substance was stored for 1 week at 40°C / 75% RH, 80°C, and ambient light and humidity. The solid was then analyzed by HPLC for XRPD and purity). Thermodynamic solubility in water and pH 7.4 phosphate buffer (approximately 20 mg of the substance was added to 100 μL aliquots of the appropriate medium to form a slurry. The sample was then sealed and stirred at room temperature for approximately 24 hours, followed by centrifugation filtration. The isolated solid was analyzed by XRPD, and the concentration of the mother liquor was determined by HPLC).

[0416] Since it was confirmed by XRPD, the scale-up of Form 3 was successful, and the morphology and crystallinity were maintained when dried at room temperature for approximately 24 hours. TG / DSC analysis confirmed the removal of the solvent from the surface and identified a 11.7% two-step mass loss (0.9 equivalents of IPA) associated with a small endothermic event with an initiation at 129.1°C and a peak at 126.6°C, likely corresponding to desolvation / dehydration. A large mass loss of 29.4% (1.7 equivalents of acetic acid) occurred with a large endothermic event with an initiation at 192.2°C and a peak at 209.8°C, related to salt disproportionation / melting of Form 1 (Figure 17). The large endothermic event was present in the first heat by DSC with an initiation at 120.9°C and a peak at 143.6°C, corresponding to desolvation (Figure 18). Subsequently, no significant thermal events were present during the cooling of the DSC or in the second heat (Figures 19-20).

[0417] Although a clear crystalline morphology was not visualized by PLM analysis, small, highly birefringent particles were present (Figure 21). 1 ¹H NMR revealed 1.4 equivalents of IPA in a sample with an 8.6H peak at 1.04 ppm (Figure 16). The FT-IR spectrum was consistent with the expected diacetate structure, with the water peak at 3257.32 cm⁻¹ in Figure 22. -1 It exists.

[0418] DVS analysis of Form 3 revealed that the substance was converted to Form 9, which was hydrated at 50% RH with a loss of approximately 4 wt.% (loss of 0.3 equivalents of IPA or 1.0 equivalent of water). Form 9 is hygroscopic in DVS containing 8% mass uptake (2.0 equivalents of water) at 90% RH, with dehydration at less than 10% RH (Figure 23). The conversion of Form 3 to Form 9 is evident in the DVS dynamics plot, as the sample weight stabilizes over time at the 50-60% RH stage (Figure 24). The solid recovered after DVS analysis was analyzed by XRPD to confirm the conversion to Form 9.

[0419] The results of the 1-week stability evaluation of Form 3 are summarized in Table 16. The substance under normal temperature and humidity conditions, at 40°C / 75% RH, showed conversion to Form 1 after 1 week, but no change was observed at 80°C after 1 week. The substance was heated to 150°C using TG / DSC, resulting in an 11.0% weight loss (0.8 equivalents of IPA or 3.2 equivalents of water) with associated endothermic events starting at 132.5°C and peaking at 137.9°C (Figure 25), confirming desolvation. The recovered solid was then analyzed by XRPD to confirm conversion to Form 1.

[0420] Form 3 was the solvated form of compound A diacetate, which readily converts to thermodynamically stable form 1 upon desolvation, as observed in the 1-week stability assessment and desolvation / XRPD test. This also converts to hydrated form 9 under high humidity conditions, as observed in the DVS analysis.

[0421] In summary, Form 3 was solvated, and TG / DSC identified a mass loss of 11.7% (0.9 equivalents of IPA or 3.0 equivalents of water) with melting at 192.2°C. 11H NMR identified 1.4 equivalents of IPA. DSC identified an endothermic event at 120.9°C, corresponding to desolvation. PLM analysis of the substance did not reveal a clear morphology, but visualized small, highly birefringent particles. It was found that form 3 was converted to form 1 during desolvation above 150°C. Similarly, it was found that the substance converted to form 1 during storage at room temperature and humidity at 40°C / 75% RH. DVS analysis (Figures 23-24) showed that the substance converted to form 9 (dihydrate) at 50% RH. Therefore, form 3 appears to be a low-risk solvate as it is easily converted to form 1. Preparation and Characterization of Morphology 8

[0422] Form 8 was scaled up using the following procedure with amorphous input material prepared by the process described above. 27.2 mL of ethanol was added to lyophilized compound A diacetate to form a slurry. The slurry was then circulated between room temperature and 40°C in 4-hour cycles with stirring for approximately 24 hours. The slurry was then filtered through Buchner filtration, and the isolated solid was collected in a scintillation vial. After analyzing the subsamples with XRPD, the XRPD plates were placed in an oven at 40°C for 1 hour, and the samples were re-analyzed with XRPD to check for loss of crystallinity upon high-temperature drying. The vials were left uncapped to allow the solid to dry at room temperature for approximately 24 hours, and then re-analyzed with XRPD. The solid was characterized using the same technique as used in Form 3 above.

[0423] The scale-up of Form 8 was successful, and the form was maintained after drying at room temperature for approximately 24 hours. The bulk material was not dried at high temperatures, as a significant loss of crystallinity was observed when the solid was dried on an XRPD plate at 40°C for 1 hour. TG analysis identified a moderate 6.7% weight loss (0.7 equivalents of ethanol) from the onset of exothermic reactions. Subsequently, a large endothermic event occurred in association with a further 30.6% weight loss, corresponding to salt disproportionation / melting, with an onset at 196.0°C and a peak at 218.5°C (Figure 44). Two broad endothermic events were present with the first heat by DSC due to the moderate drying of the material. The first event had an onset at 32.5°C and a peak at 55.6°C, and the second event had an onset at 78.8°C and a peak at 103.2°C (Figure 45). Subsequently, no significant thermal events were present with the cooling of the DSC or with the second heat (Figures 46-47).

[0424] Although a clear crystalline morphology was not visualized by PLM analysis, small, highly birefringent particles were present (Figure 48). 1 ¹H NMR confirmed the diacetate structure, and 1.8 equivalents of ethanol were found in a sample with a 5.51H peak at 1.06 ppm (Figure 43). The FT-IR spectrum was consistent with the expected structure. The shoulder was approximately 3000 cm². -1 This can be seen across a wide range of peaks, which may be due to water peaks (Figure 49).

[0425] DVS analysis of the substance in form 8 revealed that the substance desolvated and was converted to form 1 at 50% RH via a loss of 8.2 wt.% (0.9 equivalents of ethanol), as seen in the isotherm plot in Figure 50. The substance in form 1 then exhibited slight hygroscopicity with a 1.8% mass increase at 90% RH (consistent with the initial characterization). The morphological change is evident in the dynamics plot in Figure 51, which shows the sample weight that takes considerable time to stabilize initially before proceeding rapidly through the DVS cycle after conversion to form 1. XRPD after DVS confirmed the conversion of form 8 to form 1.

[0426] The results of the one-week stability assessment are summarized in Table 16. Similar to the substance in Form 3, the solid in Form 8 underwent conversion to Form 1 during storage at room temperature and humidity, at 40°C / 75% RH. No change in form was observed during storage at 80°C, although a significant loss of crystallinity was observed. The substance in Form 8 was heated to 150°C before XRPD analysis. TG / DSC identified a two-step mass loss of 2.3% (0.2 equivalents of ethanol or 0.6 equivalents of water) followed by 8.6% (1.0 equivalent of ethanol or 2.2 equivalents of water), accompanied by two related endothermic events at 34.2°C and 67.0°C (Figure 52). XRPD analysis of the recovered solid revealed a substance with significantly reduced crystallinity, but no conversion to Form 1 was observed during desolvation with Form 3.

[0427] Based on the results obtained, Form 8 appears to be a metastable solvated form of compound A diacetate that readily converts to Form 1 during a one-week stability assessment and DVS analysis under high humidity and ambient conditions. Upon drying, the substance becomes less crystalline but does not convert to Form 1.

[0428] In summary, form 8 was also found to be a solvated form of the diacetate, and TG / DSC identified a 6.7% mass loss (0.7 equivalents of ethanol or 1.7 equivalents of water) with melting at 196.0°C. 1 1H NMR also identified 1.8 equivalents of ethanol present in the sample. Two broad endothermic reactions were observed on DSC at 32.5°C and 78.8°C, corresponding to the desolvation of the sample. No distinct morphology was present on PLM, but small, highly birefringent particles were visualized. Drying the substance to 150°C did not convert this solvate to form 1. However, the substance was converted to form 1 during storage at 40°C / 75% RH and 50% RH during the DVS cycle (Figures 50-51). Partial conversion to form 1 was also observed when storing the substance at room temperature and humidity. Preparation and Characterization of Morphology 9

[0429] Form 9 was scaled up using the following procedure with the amorphous input material prepared by the process described above. 3.2 mL of water was added to the lyophilized compound A diacetate to form a slurry. The slurry was then circulated between room temperature and 40°C in 4-hour cycles with stirring for approximately 24 hours. The slurry was then filtered by centrifugation, and the isolated solid was collected in a scintillation vial and analyzed by XRPD. The saturated mother liquor was allowed to stand at room temperature and evaporated. Subsamples were analyzed by XRPD after evaporation, and the solid was dried in a 40°C oven for approximately 24 hours and then re-analyzed by XRPD. The solid was characterized using the same technique as used in Forms 3 and 8.

[0430] In the thermal circulation of amorphous compound A diacetate in water, we successfully produced form 2 (consistent with primary polymorph screening), which is converted to form 9 when dried at 40°C. Evaporation of the saturated mother liquor solution yielded form 2, which was successfully dried again to form 9 at 40°C. TG analysis identified a combined initial mass loss of 9.4% (0.3 equivalents of water followed by 2.3 equivalents of water) associated with an endothermic event with an initiation at 55.6°C and a peak at 74.2°C, likely due to dehydration. A small exothermic event occurred before the disproportionation of the salt, with an initiation at 146.7°C and a peak at 156.1°C. Subsequently, a 31.7% weight loss (2.1 equivalents of acetate) occurred with a large endothermic event corresponding to the disproportionation of the salt, with an initiation at 194.9°C and a peak at 214.2°C (Figure 55). In the first heat phase of the DSC, a large endothermic event was identified, beginning at 88.8°C and including a shoulder peak at 98.0°C, with a peak at 88.9°C (Figure 56). Subsequently, no significant thermal events were observed during the cooling of the DSC or in the second heat phase (Figures 57-58).

[0431] 1 The 1H NMR spectrum is shown in Figure 54. The spectrum was consistent with the diacetate structure containing the identified significant water content. PLM analysis identified a large, highly birefringent rod-like morphology (Figure 59). The FTIR spectrum was obtained at approximately 3000 cm⁻¹. -1The structure was consistent with the expected diacetate structure, accompanied by a water peak hidden beneath a broad peak due to the stretching of OH groups (Figure 60).

[0432] The DVS isotherm plot is shown in Figure 61. The substance underwent a transformation to form 2 in the first adsorption cycle at 80% RH, involving a 5.2 wt.% increase (1.4 equivalents of water), and then transformed back to form 9 at 50% RH. Form 9 is then stable until dehydrated at less than 10% RH, with a 7.3 wt.% loss (2.0 equivalents of water). The dynamics plot shows that the sample weight stabilizes longer at the 80–90% RH stage, but the substance transforms from form 9 back to form 2 (Figure 62). XRPD analysis of the recovered solid revealed a sample that was a mixture of phases, with a peak corresponding to form 9 and a new peak that did not correspond to the other peaks observed. VHXRPD confirmed that the solid in form 9 was transformed back to form 2 at 90% RH, but when the substance was dried at 0% RH, the substance became poorly crystalline and did not transform back to form 9 when the humidity increased to 80% RH.

[0433] The results of the one-week stability evaluation are shown in Table 16. Form 9 remained unchanged in XRPD after storage at room temperature and humidity at 40°C / 75% RH, but conversion to Form 1 was observed when stored at 80°C. The material was dried by TG / DSC, and an 8.3% mass loss (2.1 equivalents of water) associated with a large and broad endothermic event with an initiation at 60.7°C and a peak at 81.6°C was identified (Figure 63). XRPD analysis of the recovered solid revealed a poorly crystalline material with several small peaks corresponding to Form 1 and several new peaks.

[0434] Based on the results obtained, form 9 appears to be a dihydrate that converts to form 2 of the tetrahydrate under high humidity (RH over 80%). The substance showed conversion to form 1 when stored at 80°C for one week, but it does not appear to dehydrate to form 1 when dried.

[0435] In summary, morphology 9 was isolated from water and exhibited good crystallinity according to XRPD analysis. Similarly, PLM analysis revealed a large, highly birefringent rod-like morphology. The material was found to be hydrated, and TG / DSC showed a two-step mass loss at 1.3% (0.3 equivalents of water) followed by 8.1% (2.3 equivalents of water) and melting at 194.9°C. DSC identified a sharp endothermic event corresponding to dehydration at 88.8°C. The material in morphology 9 was observed to be converted to morphology 2 at 80% RH in a DVS cycle and converted back to morphology 9 at 50% RH (Figures 61-62). This was confirmed by VH-XRPD. VH-XRPD analysis revealed dehydration of morphology 9 at less than 10% RH, the material became poorly crystallinity, and morphology 1 could not be obtained. When humidity increased from 0% RH, morphology 9 did not reformulate even at 80% RH for 1 hour.

[0436] A summary of further characterizations of forms 1, 3, 8, and 9 is shown in Table 16 below. [Table 17] Thermodynamic evaluation of solubility

[0437] The results of the thermodynamic solubility tests are summarized in Table 17. In the whole-solid slurry prepared in water, XRPD analysis revealed that it was amorphous after maturation. Form 1 was found to be the most soluble form at 49.5 mg / mL, while Form 3 was the least soluble at 38.5 mg / mL. In the whole-solid slurry prepared in pH 7.4 phosphate buffer, XRPD analysis revealed a new, less crystalline form shown as Form 12 (Figure 65). The substance appears to be highly insoluble in phosphate buffer, with all forms having a solubility of 0.3 mg / mL except for Form 2, which had a solubility of 0.2 mg / mL. [Table 18] Competitive slurry testing

[0438] Approximately 5 mg of compound A diacetate forms 1, 3, 8, and 9 were combined in an 8 × 4 mL vial. A suitable solvent was added to form a slurry, and the sample was shaken at room temperature or 60°C for approximately 48 hours. The sample was then removed from the shaker and filtered by centrifugation. The isolated solid was analyzed by XRPD and found to contain a mixture of forms. The solid was recovered from the XRPD plate, returned, and shaken for a further 3 days as before, and then re-analyzed by XRPD.

[0439] The results of the initial competitive slurry test are summarized in Table 18. Except for the ethanol sample, which had been converted to a mixture of Forms 1 and 8, all samples remained as a mixture of polymorphs of all input compound A diacetate after approximately 48 hours of stirring. After a further 72 hours of stirring, the ethanol in the surrounding sample had been converted to Form 8, while all other samples remained unchanged. [Table 19]

[0440] Approximately 5 mg of compound A diacetate forms 1, 3, 8, and 9 were weighed into 6 × 4 mL vials, and approximately 10 mg of forms 1 and 9 were weighed into 3 × 2 mL vials. A suitable solvent was then added to form a slurry, the samples were sealed with Parafilm, and shaken at room temperature, 40°C, or 60°C for approximately 9 days. After stirring for 5 and 9 days, the solids were analyzed by XRPD.

[0441] The results of additional competitive slurry tests are summarized in Table 19. After stirring for 9 days, the majority of the tests remained as mixtures, except for 95% IPA and 5% water, which returned to Form 1, and 85% IPA and 15% water, which also returned to Form 1. [Table 20] Reactivity precipitation test

[0442] Approximately 500 mg of compound A diacetate was weighed and dissolved in 20 mL of water. The solution was added to a separatory funnel, and 20 mL of saturated sodium bicarbonate solution was added. Precipitation was immediately observed. The slurry was washed with 3 × 40 mL of ethyl acetate, and the organic phase (containing the precipitate) was collected. This slurry was filtered using a Buchner filter, and the isolated solid was dried in a vacuum oven at 40°C for approximately 2 hours. 1 Analysis was performed using 1H NMR.

[0443] Approximately 20 mg of free base of compound A was weighed into a 13 × 1.5 mL vial, and an appropriate volume of solvent was added to form a slurry. Next, 2.05 equivalents of acetic acid were added to the slurry, the sample was sealed with Parafilm, and placed in an incubator shaker, where the temperature was circulated between room temperature and 40°C in 4-hour cycles while stirring for approximately 48 hours. Then, the sample was removed from the shaker, the observations were recorded, and the slurry was centrifuged and filtered. After analyzing the isolated solid with XRPD, the XRPD plate was dried in an oven at 40°C for approximately 72 hours, and the sample was re-analyzed to check for any changes in morphology. If a new morphology was obtained, the solid was subjected to TG / DSC, as far as the amount of substance allowed. 1 Analysis was performed using 1H NMR, PLM, and FT-IR.

[0444] The results of the reactive precipitation tests are summarized in Table 20. One novel diffractogram was identified, shown as Form 13 from NMP and as Form 3 from THF when dried. Most of the solvent systems yielded predictable forms from the primary polymorph screening. The XRPD diffractogram of Form 13 is shown in Figure 66. [Table 21] [Example 11] Preparation of a formulation containing form 1 of compound A

[0445] Batches of 30 mg and 120 mg strength capsules containing form 1 of compound A diacetate were prepared. The compositions of the 30 mg and 120 mg capsules are described in Table 21 below. The 30 mg strength capsules were filled into size 2 HPMC capsules with a white body and a flesh-colored cap. The 120 mg strength capsules were filled into size 0 Swedish orange capsules. [Table 22]

[0446] The capsules were prepared by the process described in Scheme 2 below. [ka]

[0447] First, the required amounts of pre-sieved silicified microcrystalline cellulose (SMCC), lactose, and colloidal silicon dioxide were weighed into a PE bag and manually mixed for approximately 3 minutes. The mixture was then sieved through a 60-mesh screen. Next, form 1 of compound A diacetate was added to the mixture, and the mixture was manually blended for approximately 3 minutes. The mixture was then sampled for blend uniformity (targeting 95–100% of the indicated amount, with a %RSD of less than 5.0%). Next, magnesium stearate was added, and the mixture was manually blended for approximately 2 minutes. The capsule shells were then manually filled with the blend. Weight checks were then performed (n=60 capsules). For 30 mg capsules, the target weight was 214 ± 7.62 mg. For 120 mg capsules, the target weight was 422 ± 16.4 mg. The capsules were then packaged in HDPE bottles with a heat-conductive seal and a child-safe cap.

[0448] In addition, all references cited herein, including U.S. patents, published U.S. patent applications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications, are incorporated herein by reference in their entirety to the extent that they do not contradict this description. In the event of any conflict between this application and the references cited herein, this application shall prevail.

[0449] Even if a foreign invention is described in detail in the description and examples for the purpose of clear understanding, a person skilled in the art will understand that certain changes and modifications can be made within the scope of the attached claims.

[0450] It should be understood that the present invention is not limited to the embodiments illustrated and described in the above specification, and the right to illustrated embodiments and all modifications within the scope of the claims is reserved.

Claims

1. 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate or its solvate in crystalline form.

2. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate is not solvated.

3. The crystalline form according to claim 1, which is substantially anhydrous.

4. The crystalline form according to any one of claims 1 to 3, characterized by having an X-ray powder diffraction (XRPD) pattern containing a peak at an angle of approximately 17.86° with a 2-theta angle.

5. The crystal morphology according to claim 4, wherein the XRPD pattern further includes a peak at an angle of approximately 24.29° with a 2-theta angle.

6. The crystalline morphology according to claim 4 or 5, wherein the XRPD pattern further includes a peak at an angle of approximately 24.21° with a 2-theta angle.

7. The crystalline morphology according to any one of claims 4 to 6, wherein the XRPD pattern further includes a peak at an angle of 2 theta of approximately 25.87°.

8. The crystal morphology according to any one of claims 1 to 7, characterized by having an XRPD pattern substantially as shown in Figure 1.

9. The crystal morphology according to any one of claims 1 to 8, characterized by having an endothermic peak at approximately 217.7°C as determined by DSC.

10. The crystalline morphology according to any one of claims 1 to 9, characterized by exhibiting a weight loss of approximately 31.9% as determined by TGA.

11. The crystal morphology according to any one of claims 1 to 10, characterized by having a TG / DSC graph substantially as shown in Figure 2.

12. The crystal morphology according to any one of claims 1 to 11, characterized by having a DVS graph substantially as shown in Figure 8.

13. The crystalline form according to any one of claims 1 to 12, characterized by having an FT-IR spectrum substantially as shown in Figure 10.

14. In essence, as shown in Figure 11 １ A crystalline form according to any one of claims 1 to 13, characterized by having a 1H NMR spectrum.

15. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidolphenoxy)pentyl)oxy)picolinimidoamide diacetate is a solvate of isopropyl alcohol (IPA).

16. The crystal morphology according to claim 15, characterized by having an XRPD pattern that includes a peak at an angle of approximately 25.35° with a 2-theta angle.

17. The crystal morphology according to claim 16, wherein the XRPD pattern further includes a peak at an angle of approximately 9.95° 2-theta.

18. The crystalline morphology according to claim 16 or 17, wherein the XRPD pattern further includes a peak at an angle of 2 theta of approximately 17.88°.

19. The crystalline morphology according to any one of claims 1 and 15 to 18, characterized by having an XRPD pattern substantially as shown in Figure 15.

20. The crystalline morphology according to any one of claims 1 and 15 to 19, characterized by having an endothermic peak at approximately 126.6°C as determined by DSC.

21. The crystalline morphology according to any one of claims 1 and 15 to 20, characterized by exhibiting a weight loss of approximately 29.4% as determined by TGA.

22. The crystalline morphology according to any one of claims 1 and 15 to 21, characterized by having a TG / DSC graph substantially as shown in Figure 17.

23. The crystalline form according to any one of claims 1 and 15 to 22, characterized by having an FT-IR spectrum substantially as shown in Figure 22.

24. In essence, as shown in Figure 16 １ The crystalline form according to any one of claims 1 and 15 to 23, characterized by having a 1H NMR spectrum.

25. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate is a solvate of N-methyl-2-pyrrolidone (NMP).

26. The crystal morphology according to claim 25, characterized by having an XRPD pattern that includes a peak at an angle of approximately 18.14° 2 theta.

27. The crystal morphology according to claim 26, wherein the XRPD pattern further includes a peak at an angle of approximately 25.23° with a 2-theta angle.

28. The crystalline morphology according to claim 26 or 27, wherein the XRPD pattern further includes a peak at an angle of 2 theta of approximately 22.85°.

29. The crystalline morphology according to any one of claims 1 and 25 to 28, characterized by having an XRPD pattern substantially as shown in Figure 27.

30. The crystalline morphology according to any one of claims 1 and 25 to 29, characterized by having an endothermic peak at approximately 161.0°C as determined by DSC.

31. The crystalline morphology according to any one of claims 1 and 25 to 30, characterized by exhibiting a first weight loss of approximately 18.2% as determined by TGA.

32. The crystalline morphology according to any one of claims 1 and 25 to 31, characterized by having a TG / DSC graph substantially as shown in Figure 29.

33. The crystalline form according to any one of claims 1 and 25 to 32, characterized by having an FT-IR spectrum substantially as shown in Figure 31.

34. In effect, as shown in Figure 28 １ A crystalline form according to any one of claims 1 and 25 to 33, characterized by having a 1H NMR spectrum.

35. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidolphenoxy)pentyl)oxy)picolinimidoamide diacetate is a solvate of toluene.

36. The crystal morphology according to claim 35, characterized by having an XRPD pattern that includes a peak at an angle of approximately 5.69° 2 theta.

37. The crystal morphology according to claim 36, wherein the XRPD pattern further includes a peak at an angle of approximately 18.49° with a 2-theta angle.

38. The crystalline morphology according to claim 36 or 37, wherein the XRPD pattern further includes a peak at an angle of 2 theta of approximately 18.27°.

39. The crystalline morphology according to any one of claims 1 and 35 to 38, characterized by having an XRPD pattern substantially as shown in Figure 32.

40. The crystalline morphology according to any one of claims 1 and 35 to 39, characterized by having an endothermic peak at approximately 113.6°C as determined by DSC.

41. The crystalline morphology according to any one of claims 1 and 35 to 40, characterized by exhibiting a first weight loss of approximately 13.6% as determined by TGA.

42. The crystalline morphology according to any one of claims 1 and 35 to 41, characterized by having a TG / DSC graph substantially as shown in Figure 34.

43. The crystalline form according to any one of claims 1 and 35 to 42, characterized by having an FT-IR spectrum substantially as shown in Figure 36.

44. In essence, as shown in Figure 33 １ A crystalline form according to any one of claims 1 and 35 to 43, characterized by having a 1H NMR spectrum.

45. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate is a hydrate.

46. The crystal morphology according to claim 45, characterized by having an XRPD pattern that includes a peak at an angle of approximately 10.14° 2 theta.

47. The crystal morphology according to claim 46, wherein the XRPD pattern further includes a peak at an angle of approximately 26.27° with a 2-theta angle.

48. The crystalline morphology according to claim 46 or 47, wherein the XRPD pattern further includes a peak at an angle of 2 theta of approximately 24.77°.

49. The crystalline morphology according to any one of claims 1 and 45 to 48, characterized by having an XRPD pattern substantially as shown in Figure 37.

50. The crystalline morphology according to any one of claims 1 and 45 to 49, characterized by having an endothermic peak at approximately 147.9°C as determined by DSC.

51. The crystalline morphology according to any one of claims 1 and 45 to 50, characterized by exhibiting a weight loss of approximately 4.6% after heating to approximately 147.7°C to approximately 147.9°C, as determined by TGA.

52. The crystalline morphology according to any one of claims 1 and 45 to 51, characterized by having a TG / DSC graph substantially as shown in Figure 39.

53. The crystalline form according to any one of claims 1 and 45 to 52, characterized by having an FT-IR spectrum substantially as shown in Figure 41.

54. In effect, as shown in Figure 38 １ A crystalline form according to any one of claims 1 and 45 to 53, characterized by having a 1H NMR spectrum.

55. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidolphenoxy)pentyl)oxy)picolinimidoamide diacetate is a solvate of ethanol.

56. The crystal morphology according to claim 55, characterized by having an XRPD pattern that includes a peak at an angle of approximately 5.53° 2 theta.

57. The crystal morphology according to claim 56, wherein the XRPD pattern further includes a peak at an angle of approximately 19.01° with a 2-theta angle.

58. The crystalline morphology according to claim 56 or 57, wherein the XRPD pattern further includes a peak at an angle of approximately 24.63° with a 2-theta angle.

59. The crystalline form according to any one of claims 1 and 55 to 58, characterized by having an XRPD pattern substantially as shown in Figure 42.

60. The crystalline morphology according to any one of claims 1 and 55 to 59, characterized by having an endothermic peak at approximately 218.5°C as determined by DSC.

61. The crystalline morphology according to any one of claims 1 and 55 to 60, characterized by exhibiting a first weight loss of approximately 6.7% as determined by TGA.

62. The crystalline morphology according to any one of claims 1 and 55 to 61, characterized by having a TG / DSC graph substantially as shown in Figure 44.

63. The crystalline form according to any one of claims 1 and 55 to 62, characterized by having an FT-IR spectrum substantially as shown in Figure 49.

64. In essence, as shown in Figure 43 １ A crystalline form according to any one of claims 1 and 55 to 63, characterized by having a 1H NMR spectrum.

65. The crystalline form according to claim 1, wherein 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate is a hydrate.

66. The crystal morphology according to claim 65, characterized by having an XRPD pattern that includes a peak at an angle of approximately 23.63° 2 theta.

67. The crystal morphology according to claim 66, wherein the XRPD pattern further includes a peak at an angle of approximately 26.06° with a 2-theta angle.

68. The crystalline morphology according to claim 66 or 67, wherein the XRPD pattern further includes a peak at an angle of approximately 23.28° with a 2-theta angle.

69. The crystalline form according to any one of claims 1 and 65 to 68, characterized by having an XRPD pattern substantially as shown in Figure 53.

70. The crystalline morphology according to any one of claims 1 and 65 to 69, characterized by having an endothermic peak at approximately 74.2°C as determined by DSC.

71. The crystalline morphology according to any one of claims 1 and 65 to 70, characterized by exhibiting a first weight loss of approximately 9.4% as determined by TGA.

72. The crystalline morphology according to any one of claims 1 and 65 to 71, characterized by having a TG / DSC graph substantially as shown in Figure 55.

73. The crystalline form according to any one of claims 1 and 65 to 72, characterized by having an FT-IR spectrum substantially as shown in Figure 60.

74. In essence, as shown in Figure 54 １ A crystalline form according to any one of claims 1 and 65 to 73, characterized by having a 1H NMR spectrum.

75. a. Contacting 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate with a solvent selected from the group consisting of 1,4-dioxane, 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, methanol, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, toluene, water, DCM, or a mixture thereof. b. Crystallization of 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide diacetate or its solvate. The crystalline form according to claim 1, produced by a process including the process.

76. A pharmaceutical composition comprising the crystalline form described in any one of claims 1 to 74, and a pharmaceutically acceptable carrier or additive.

77. a. A crystalline form according to any one of claims 1 to 73, in an amount of approximately 0.1% to approximately 60% w / w. b. Silicified microcrystalline cellulose containing approximately 10% to 70% w / w c. Lactose monohydrate in an amount of approximately 5% to approximately 30% w / w, d. Colloidal silicon dioxide in an amount of approximately 0.1% to approximately 5% w / w, and e. Approximately 0.1% to 5% w / w magnesium stearate The pharmaceutical composition according to claim 76, which is a capsule containing the above.

78. a. A crystalline form according to any one of claims 1 to 73, with an alcohol content of approximately 27% w / w. b. Approximately 47.25% w / w silicified microcrystalline cellulose, c. Approximately 23.6% w / w lactose monohydrate, d. Approximately 1.6% w / w colloidal silicon dioxide, and e. Approximately 0.5% w / w magnesium stearate The pharmaceutical composition according to claim 76, which is a capsule containing the above.

79. a. A crystalline form according to any one of claims 1 to 73, with an alcohol content of approximately 50.8% w / w. b. Approximately 31.4% w / w silicified microcrystalline cellulose, c. Approximately 15.7% w / w lactose monohydrate, d. Approximately 1.6% w / w colloidal silicon dioxide, and e. Approximately 0.5% w / w magnesium stearate The pharmaceutical composition according to claim 76, which is a capsule containing the above.

80. The pharmaceutical composition according to any one of claims 76 to 79, wherein the crystalline form is the crystalline form of any one of claims 2 to 14.

81. A process for producing 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide, 1. 4-hydroxybenzonitrile 【Chemistry 1】 And it will react, 【Chemistry 2】 To form, [wherein, R １ and R ２ are each independently halogen] 2. From Step (1) 【Transformation 3】 Reacting with 5-hydroxypicolinonitrile to form 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinonitrile, 3. Treat the 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinonitrile from step (2) sequentially with sodium methoxide and ammonium acetate to form 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinimidoamide acetate.

4. Treat the 5-((5-(4-cyanophenoxy)pentyl)oxy)picolinimidoamide acetate from step (3) with ethanolic HCl to form ethyl 4-((5-((6-carbamimidolpyridine-3-yl)oxy)pentyl)oxy)benzimidate, 5. Convert the ethyl 4-((5-((6-carbamimidylpyridine-3-yl)oxy)pentyl)benzimidate from step (4) to form 5-((5-(4-carbamimidylphenoxy)pentyl)oxy)picolinimidoamide. A process that includes this.

82. 6. Treat the 5-((5-(4-carbamimidoidylphenoxy)pentyl)oxy)picolinimidoamide from step (5) with ammonium acetate to form 5-((5-(4-carbamimidoidylphenoxy)pentyl)oxy)picolinimidoamide diacetate. The process according to claim 81, further comprising: 【Request Item 83】 【Chemistry 4】 The process according to claim 81 or 82, wherein is 1,5-dibromopentane or 1-bromo-5-chloropentane. 【Request Item 84】 【Chemistry 5】 The process according to any one of claims 81 to 83, wherein the molar ratio of to 4-hydroxybenzonitrile is about 5:

1. 【Request Item 85】 【Chemistry 6】 The process according to any one of claims 81 to 84, wherein the molar ratio of to 5-hydroxypicolinonitrile is about 1:

1.

86. The process according to any one of claims 81 to 85, wherein step (1), step (2), or both are carried out in the presence of potassium carbonate.

87. The process according to any one of claims 81 to 86, wherein step (1) is carried out in N,N-dimethylformamide (DMF).

88. The process according to any one of claims 81 to 87, wherein step (5) is carried out using ammonium carbonate.

89. The process according to any one of claims 81 to 88, wherein steps (3), (5), and (6) are carried out in methanol.

90. The process according to any one of claims 81 to 89, comprising slurring 5-((5-(4-carbamimidolphenoxy)pentyl)oxy)picolinimidoamide diacetate from step (6) and washing with n-heptane.

91. A kit comprising the crystal form described in any one of claims 1 to 74.

92. The kit according to claim 91, further comprising instructions for the treatment of cancer.

93. A method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of the crystalline form described in any one of claims 1 to 74.

94. The method according to claim 93, wherein the cancer is liver cancer.

95. The method according to claim 94, wherein the liver cancer is hepatocellular carcinoma (HCC).

96. The method according to claim 93, wherein the cancer is lung, pancreatic, colon, kidney, cholangiocarcinoma, or breast cancer.

97. The method according to claim 93, wherein the cancer originates in the lungs, colon, kidneys, bile ducts, pancreas, or breast, and then metastasizes to and grows in the liver.

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