Crystalline and salt forms of organic compounds and their pharmaceutical compositions

Abstract

Various salts, including tris(hydroxymethyl)aminomethane salts and sodium salts, as well as various crystalline forms of compounds represented by the following structural formulas, are provided herein. Additionally, pharmaceutical compositions comprising these salts and crystalline forms, methods for preparing the same, and uses thereof for treating conditions, including but not limited to conditions that benefit from the inhibition of dihydroorotate dehydrogenase (DHODH), are provided.

Description

Technology Field

[0001] The present application claims priority to U.S. provisional application No. 62 / 784,083 filed December 21, 2018; U.S. provisional application No. 62 / 791,571 filed January 11, 2019; and U.S. provisional application No. 62 / 882,712 filed August 5, 2019, the full text of each of the disclosures of which is incorporated by reference. Background Technology

[0002] Dihydroorotate dehydrogenase (DHODH) is an enzyme that catalyzes one of the steps of the neopyrimidine nucleotide biosynthesis pathway. It catalyzes the sole oxidation / reduction reaction in the pathway, which is the step of converting DHO (dihydroorotate) to orotate with the help of a flavin cofactor and an electron acceptor. Inhibitors of dihydroorotate dehydrogenase have been found to have a wide range of applications as chemotherapy agents.

[0003] 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid (also referred to hereinafter as "Compound 1" (structural formula shown below)) has been characterized as an inhibitor of DHODH. For example, see International Patent Application Publication No. WO 2014 / 128669 and U.S. Patent No. 9,630,932, the contents of which are incorporated herein by reference.

[0004]

[0005] Compound 1 was developed to treat conditions and disorders that benefit from the inhibition of DHODH, such as, to a non-limiting extent, solid tumors, hematological cancers, viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammatory disorders. Given its therapeutic benefits and the great potential to treat a number of different diseases, there is a need to develop alternative forms of Compound 1 in an effort to facilitate isolation, manufacturing, and the development of formulations for various routes of administration, as well as to enhance storage stability.

[0006] As described in more detail in the following paragraph, the present invention has revealed that the Tris salt of Compound 1 possesses superior properties compared to the free acid and other salt forms of the compound. Furthermore, Tris salt form C has been found to be superior to other Tris salt forms.

[0007] During the salt screening study described herein, over 50 different salt hits of Compound 1, including 10 counterions and 5 different solvents, were evaluated. Twelve different crystalline forms were identified (see Table 8). Among these crystalline salt forms, the Tris salt forms were found to be superior. Specifically, Tris salt forms A and C of Compound 1 stood out as major crystalline salt forms exhibiting sharp XRPD peaks (see Example 3, Table 8, and Fig. 6). The superior crystallinity of a drug substance typically translates into better physical and chemical stability, which is therefore a desirable characteristic of an active pharmaceutical ingredient (API). Furthermore, thermogravimetric analysis (TGA) data showed negligible weight loss for Tris salt forms A and C of Compound 1 (see Table 9), thus exhibiting minimal residual solvent and anhydride polymorphs, which are often preferred over solvated / hydrated forms for the development of oral solid dosage forms. Differential scanning calorimetry (DSC) data for Tris salt forms A and C of Compound 1 (see Table 9) further indicate a single rapid melt endothermic before decomposition, a low probability of polymorphic change, and a low probability of phase transformation, which is often undesirable in terms of the physical stability of API.

[0008] When comparing the tris salt form A and tris salt form C of Compound 1, thermodynamic stability studies using slurry competition experiments indicated that the tris salt form C is thermodynamically more stable (see Example 5). In addition, the tris salt form C of Compound 1 was also found to be less hygroscopic than its tris salt form A counterpart, which causes it to disintegrate more easily in a solvent during formulation development.

[0009] When comparing the pharmacokinetic properties of the free acid and the Tris salt of Compound 1, the Tris salt form has a shorter duration (i.e., lower T maxA higher maximum concentration within ) (i.e., a higher C max It is clearly superior in that it achieves (see Example 8 and Table 13). The initial form of the free acid with low crystallinity and purity exhibits exposure similar to that of the Tris salt, as indicated by the AUC value (see Table 13 and Fig. 10a), but this high AUC value could not be reproduced using the final-approximate form of the free acid with improved crystallinity and purity, despite the reduction in particle size (see Table 13 and Fig. 10b).

[0010] PK data suggest that the Tris salt of Compound 1 exhibits superior exposure as well as faster and higher absorption compared to the free acid form. The relatively clean DSC profile with rapid melt endothermic in the Tris salt form C of Compound 1, coupled with excellent thermodynamic properties and low hygroscopicity, is an indicator of the reliable solid-state properties of this particular salt form in terms of physical stability and suitability for the development of oral solid dosage forms.

[0011] Tris(hydroxymethyl)aminomethane salt, sodium salt, and crystalline form of the compound referred to herein as Compound 1 are provided herein.

[0012] In addition, pharmaceutical compositions comprising tris(hydroxymethyl)aminomethane (tris) salt, sodium salt, and other pharmaceutically acceptable salts and crystalline forms of compound 1, methods for preparing the same, and the use thereof for treating conditions including, but not limited to, conditions that benefit from the inhibition of dihydroorotate dehydrogenase (DHODH) are provided herein.

[0013] In addition, solid dispersions comprising compound 1 or a pharmaceutically acceptable salt thereof, a tris salt of compound 1, or a sodium salt of compound 1 and one or more polymer(s) are provided herein. In addition, pharmaceutical compositions comprising these solid dispersions, methods for preparing the same, and uses thereof for treating conditions including, but not limited to, conditions that benefit from the inhibition of dihydroorotate dehydrogenase (DHODH) are provided herein. Brief explanation of the drawing

[0014] Figure 1 shows the XRPDs for forms A, B, C, and D of compound 1. Figure 2a shows the XRPD pattern for the crystalline form A of compound 1. Figure 2b is a list of XRPD peaks for the crystalline form A of compound 1. Figure 2c shows a combination of DSC temperature records and TGA temperature records for crystalline form A of compound 1. Figure 3a shows the XRPD pattern for the crystalline form B of compound 1. Figure 3b is a list of XRPD peaks for the crystalline form B of compound 1. Figure 3c shows a combination of DSC temperature records and TGA temperature records for crystalline form B of compound 1. Figure 4a shows the XRPD pattern for the crystalline form C of compound 1. Figure 4b is a list of XRPD peaks for the crystalline form C of compound 1. Figure 4c shows a combination of DSC temperature records and TGA temperature records for the crystalline form C of compound 1. Figure 5a shows the XRPD pattern for the crystalline form D of compound 1. Figure 5b is a list of XRPD peaks for the crystalline form D of compound 1. Figure 5c shows a combination of DSC temperature records and TGA temperature records for the crystalline form D of compound 1. Figure 6 shows an overlay of X-ray powder diffraction (XRPD) patterns for three types of crystalline forms of the tris(hydroxymethyl)aminomethane (tris) salt of compound 1. Figure 7a shows the XRPD pattern for the crystalline form A of the Tris salt of compound 1. Figure 7b is a list of XRPD peaks for the crystalline form A of the Tris salt of compound 1. Figure 7c shows a combination of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) temperature records for crystalline form A of the Tris salt of compound 1. FIG. 7d is for the crystalline form A of the Tris salt of compound 1 1 Plot the H NMR pattern. Figure 8a shows the XRPD pattern for the crystalline form B of the Tris salt of compound 1. Figure 8b is a list of XRPD peaks for the crystalline form B of the Tris salt of compound 1. Figure 8c shows a combination of DSC temperature records and TGA temperature records for crystalline form B of the Tris salt of compound 1. FIG. 8d is for the crystalline form B of the Tris salt of compound 1 1 Plot the H NMR pattern. Figure 9a shows the XRPD pattern for the crystalline form C of the tris salt of compound 1. Figure 9b is a list of XRPD peaks for the crystalline form C of the Tris salt of compound 1. Figure 9c shows a combination of DSC temperature records and TGA temperature records for the crystalline form C of the Tris salt of compound 1. Figure 10a shows the pharmacokinetic (PK) profiles of free acid sample compound 1 (lots A and B) and Tris salt sample of compound 1 (lot F). Figure 10b shows the pharmacokinetic (PK) profiles of free acid sample compound 1 (lots C, D, and E) and Tris salt sample of compound 1 (lot F). Specific details for implementing the invention

[0015] definition

[0016] When used alone, the terms "Form A," "Form B," "Form C," and "Form D" refer, respectively, to crystalline forms A, B, C, and D of Compound 1 when describing Compound 1. Additionally, the terms "Form A," "Form B," and "Form C" refer, respectively, to crystalline forms A, B, and C of the tris(hydroxymethyl)aminomethane (tris) salt of Compound 1 when describing the tris(hydroxymethyl)aminomethane (tris) salt of Compound 1. The terms "Form A" and "crystalline form A" referring to crystalline form A of Compound 1 or the tris salt of Compound 1 are used interchangeably. Similarly, "Form B" and "Crystal Form B" and "Form C" and "Crystal Form C" referring to crystalline form B or form C of compound 1 or the Tris salt of compound 1, respectively, as well as "Form D" and "Crystal Form D" referring to crystalline form D of compound 1, are used interchangeably.

[0017] The term "amorphous" refers to a solid existing in a non-crystalline state or form. An amorphous solid is a disordered arrangement of molecules and therefore does not possess a distinguishable crystal lattice or unit cell; consequently, it does not have a definable long-range rule. The solid-state rule of a solid can be determined by standard techniques known in the relevant art, for example, X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids, for example, by birefringence using polarized light microscopy.

[0018] Generally, Compound 1 may contain one or more impurities in any amount(s). In some embodiments, the term “impurity” refers to chemical impurities, e.g., reaction by-products. In this application, this may also be referred to as chemical purity. In other embodiments, the term “impurity” refers to other solid-state forms of Compound 1 or its salt. In these embodiments, other solid-state forms of Compound 1 or its salt may include amorphous or other crystalline forms. As used herein, the term “substantially amorphous” refers to an amorphous form and composition of Compound 1 that is free of impurities and / or lacks the crystalline form of Compound 1 (including the crystalline salt of Compound 1) in a specific weight percentage. A specific weight percentage is such that impurities and / or the crystalline form of Compound 1 are absent in 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 60% and 100%. In some embodiments, substantially amorphous refers to the glass or salt form of at least 90% pure Compound 1. In other embodiments, substantially amorphous refers to the glass or salt form of at least 80% pure Compound 1. In another embodiment, the term substantially amorphous refers to at least 70% pure glass form or salt form. In another embodiment, substantially amorphous refers to a composition comprising compound 1 having about 30%, about 20%, about 15%, about 10%, about 5%, or about 1% of crystalline compound 1.

[0019] As used herein, “crystalline” refers to a solid form of Compound 1 or the Tris salt of Compound 1 in which long-range atomic rules exist at the positions of atoms. The crystalline nature of the solid can be confirmed, for example, by X-ray powder diffraction pattern analysis. If the XRPD shows sharp intensity peaks, the compound is crystalline. Solid forms of Compound 1 or the Tris salt of Compound 1 that are “crystalline” are solids that are completely crystalline or partially crystalline, and include solids that are at least 80 wt% crystalline, 85 wt% crystalline, 90 wt% crystalline, 95 wt% crystalline, and 99 wt% crystalline. Unlike the amorphous solids defined above, crystalline solids are an ordered arrangement of molecules having distinguishable crystal lattices or unit cells, and consequently possess definable long-range rules. In some embodiments, substantially crystalline refers to a solid form of Compound 1 or the Tris salt of Compound 1 that is at least 80% crystalline. In another embodiment, substantially crystalline refers to a solid form that is at least 90% crystalline.

[0020] The chemical purity used herein refers to the degree to which the disclosed form is free of substances having different chemical structures. The chemical purity of the disclosed crystalline form of the compound means dividing the weight of the compound by the sum of the weights of the compound plus the weights of substances / impurities having different chemical structures, and multiplying by 100%, i.e., weight percent. In one embodiment, the disclosed crystalline form of the compound has a chemical purity of at least 60 weight%, at least 70 weight%, at least 80 weight%, at least 90 weight%, at least 95 weight%, or at least 99 weight%.

[0021] The term "solvent" refers to a crystalline compound 1 or a crystalline tris salt of compound 1 in which a stoichiometric or non-stoichiometric amount of solvent, or a mixture of solvents, is incorporated into the crystal structure.

[0022] The term “hydrate” refers to a crystalline compound 1 or a crystalline tris salt of compound 1 in which stoichiometric or non-stoichiometric amounts of water are incorporated into the crystal structure. A hydrate is a solvate in which the solvent incorporated into the crystal structure is water. When used in relation to a compound, the term “anhydrous” means that there is substantially no solvent incorporated into the crystal structure, for example, less than 0.1 weight percent as determined by Karl Fisher analysis. An anhydrous compound is referred to herein as “anhydrous.”

[0023] The term “main peak” as used herein refers to the three strongest peaks of the XRPD data pattern, or a peak having at least 50% of the 100% relative intensity of the strongest peak.

[0024] The single crystalline form of Compound 1 or the tris salt of Compound 1 is that the 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid or 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylate tris salt exists as a single crystal or multiple crystals, wherein each crystal has the same crystalline form (i.e., form A, B, C, or D in the case of a free acid, or form A, B, or C in the case of a tris salt). Where the crystalline form is defined as a specified percentage of one specific single crystalline form of the compound, the remainder consists of an amorphous form and / or a crystalline form other than one or more specified specific forms. In one embodiment, the crystalline form is at least 60 weight% of a single crystalline form, at least 70 weight% of a single crystalline form, at least 80 weight% of a single crystalline form, at least 90 weight% of a single crystalline form, at least 95 weight% of a single crystalline form, or at least 99 weight% of a single crystalline form. The weight percentage of a specific crystalline form is determined by dividing the weight of the specific crystalline form by the sum of the weight of the specific crystal plus the weight of other crystalline forms present plus the weight of the amorphous form present, and multiplying by 100%.

[0025] The 2-theta values ​​of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from instrument to instrument and may also vary depending on variations in sample preparation and batch to batch. Therefore, unless otherwise defined, the XRPD patterns and / or 2-theta peak values ​​mentioned herein should not be interpreted as absolute and may vary by ± 0.2 degrees. The 2-theta values ​​provided herein were obtained using Cu Kα1 radiation.

[0026] For example, the temperature values ​​for the DSC peak temperature and DSC start temperature in this invention may vary slightly from instrument to instrument and may also vary depending on variations in sample preparation, the rate of temperature increase over the experimental process, variations per batch of material, and other environmental factors. Therefore, unless otherwise defined, the temperature values ​​mentioned herein should not be interpreted as absolute and may vary by ± 5 degrees.

[0027] "Substantially identical XRPD pattern" or "substantially similar X-ray powder diffraction pattern" to the defined figure means that, for comparison purposes, at least 90% of the indicated peaks are present. Additionally, for comparison purposes, it should be understood that some variability in the 2-theta peak positions, e.g. ± 0.2 degrees, is allowed from those indicated. Where the expression "characterized by X-ray powder diffraction peaks at 2θ angle (± 0.2°)" follows a list of 2-theta peak positions, it should be understood that ± 0.2 degrees applies to each and all of the listed peak positions.

[0028] The “therapeutic effective dose” of the crystalline form of Compound 1 described herein, or the crystalline Tris salt form of Compound 1, or the salt of Compound 1 (e.g., the amorphous or amorphous or partially crystalline Tris salt or Na salt of Compound 1) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. The terms “therapeutic effective dose” and “effective dose” are used interchangeably. In one aspect, the therapeutic effective dose of a compound means an amount of therapeutic agent or activator, alone or in combination with another therapy, that provides a therapeutic benefit in the treatment of a condition. The terms “therapeutic agent” and “activator” are used interchangeably. The term “therapeutic effective dose” may encompass an amount that improves the overall therapy and / or reduces or avoids the symptoms, signs, or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, the therapeutic effective dose is an amount sufficient to produce a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers as further described herein), viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, or inflammatory disorders. In certain embodiments, the therapeutic effective dose is an amount sufficient to produce a therapeutic effect in the treatment of cancer (including solid tumors and hematological cancers as further described herein), viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, or inflammatory disorders in which the condition is responsive to inhibition of dihydroorotate dehydrogenase (DHODH). In certain embodiments, the therapeutic effective dose is an amount sufficient to improve the overall therapy by regulating DHODH levels, reduce or avoid the symptoms, signs, or causes of the condition, or enhance the therapeutic efficacy of another therapeutic agent. The therapeutically effective dose of the compound is generally in the range of 0.1 to 100 mg / kg body weight per day for the recipient (mammalian), particularly typically in the range of 1 to 10 mg / kg body weight per day.Accordingly, the actual daily dose for an adult mammal weighing 70 kg is typically 70 to 700 mg, where this amount can be administered as an individual daily dose or typically as a series of partial doses per day (e.g., 2, 3, 4, 5, or 6 times) so that the total daily dose is the same.

[0029] The terms “treatment,” “to treat,” and “treating” refer to reversing, alleviating, reducing the likelihood of occurrence, or inhibiting the progression of a disease or disorder or one or more of its symptoms as described herein. In some embodiments, treatment may be administered after one or more symptoms have occurred, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example, to reduce the likelihood of symptom recurrence or to delay symptom recurrence.

[0030] As used herein, the terms “subject” and “patient” are interchangeable and refer to mammals requiring treatment, e.g., companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human requiring treatment. In certain embodiments, the term “subject” refers to a human subject requiring treatment for a disease. In certain embodiments, the term “subject” refers to a human subject requiring treatment by inhibition of DHODH. In certain embodiments, the term “subject” refers to a human adult over the age of 18 requiring treatment for a disease. In certain embodiments, the term “subject” refers to a human child under the age of 18 requiring treatment for a disease.

[0031] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier, ajuvant, or vehicle that does not have an adverse effect on the pharmacological activity of the compound formulated together with it and is also safe for human use.

[0032] The term "pharmaceutical acceptable excipient" refers to a substance or substances that assist in the administration of an active agent to a subject, for example, by modifying the stability of the active agent or by modifying its absorption by the subject upon administration. Pharmaceutically acceptable excipients typically do not have significant toxicological adverse effects on patients.

[0033] In this description, "pharmaceutical acceptable salt" refers to a pharmaceutically acceptable organic or inorganic acid or base salt of the compound described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edicilate, estolate, esylate, fionarate, gluteptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate. Includes lactobionate, laurate, maleate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucarmin ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A constrainedly permissible salt may have more than one charged atom within its structure. In such cases, the constrainedly permissible salt may have multiple counterions. Thus, a constrainedly permissible salt may have one or more charged atoms and / or one or more counterions.

[0034] As used herein, the terms “about” and “approximately” mean that when used in combination with numerical values ​​or ranges of values ​​used to characterize a specific crystalline form, amorphous form, or mixture thereof of a compound, the value or range of values ​​may deviate to an extent that would be considered reasonable to a person skilled in the art when describing the specific crystalline form, amorphous form, or mixture thereof.

[0035] As used herein, "% w / w" is used to mean a weight basis as a percentage of the total weight used as a standard for calculating the weight percentage of individual components. For example, in the case of a bulk composition, the % w / w of an individual component may be calculated as a percentage of the total weight of all components in the bulk composition. As another example, in the case of a single oral dosage form, the % w / w of an individual component may be calculated as a percentage of the total weight of all components in the single oral dosage form. For example, if the single oral dosage form is a capsule, the total weight may be the total weight of all components in the capsule.

[0036] The term "intragranular excipient" refers to a component incorporated into a formulation before granulation, that is, a component located inside the granule structure.

[0037] The term "extragranular excipient" refers to a component incorporated after granulation, that is, a component located outside the granule structure.

[0038] The singular form used herein includes plural subjects unless the context clearly indicates otherwise. For example, the term "intragranular excipient" includes one or more intragranular excipients.

[0039] compound

[0040] Tris(hydroxymethyl)aminomethane salt of Compound 1

[0041] In a first embodiment, the present disclosure relates to a tris(hydroxymethyl)aminomethane (tris) salt of a compound represented by the following formula:

[0042] .

[0043] In a second embodiment, at least 80 weight percent of the Tris salt according to the first embodiment is crystalline. In another embodiment, at least 85 weight percent, at least 90 weight percent, at least 95 weight percent, or at least 99 weight percent of the Tris salt according to the first embodiment is crystalline.

[0044] In the third embodiment, the Tris salt according to the second embodiment is in a single crystalline form of at least 60 weight%, at least 70 weight%, at least 80 weight%, at least 90 weight%, at least 95 weight%, or at least 99 weight%.

[0045] In the fourth embodiment, the Tris salt according to any one of the first, second, and third embodiments has a chemical purity of at least 60 weight%, at least 70 weight%, at least 80 weight%, at least 90 weight%, at least 95 weight%, or at least 99 weight%.

[0046] In the fifth embodiment, the Tris salt according to any one of the first, second, third, and fourth embodiments is anhydrous.

[0047] In the sixth embodiment, the Tris salt according to any one of the first, second, third, fourth, and fifth embodiments is a crystalline form A characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.4°, 15.6°, and 18.9°.

[0048] In the seventh embodiment, the Tris salt according to any one of the first, second, third, fourth, and fifth embodiments is a crystalline form A characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.4°, 15.6°, and 18.9°.

[0049] In the eighth embodiment, the crystalline form A according to either of the sixth and seventh embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 11.5°, 16.4°, 19.6°, and 25.5°.

[0050] In the ninth embodiment, the crystalline form A according to any one of the sixth, seventh, and eighth embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 8.7°, 15.2°, 18.6°, 21.4°, and 25.1°.

[0051] In the 10th embodiment, crystalline form A according to any one of the 6th, 7th, 8th and 9th embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 7a, and XRPD peaks as listed in FIG. 7b.

[0052] In the 11th embodiment, crystalline form A according to any one of the 6th, 7th, 8th and 9th embodiments is characterized by a differential scanning calorimetry (DSC) temperature record including an endothermic peak temperature at about 202.0°C ± 2°C (see FIG. 7c).

[0053] In the 12th embodiment, crystalline form A according to any one of the 6th, 7th, 8th and 9th embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 2.8% up to about 150°C (see FIG. 7c).

[0054] In the 13th embodiment, the Tris salt according to any one of the first, second, third, fourth, and fifth embodiments is a crystalline form B characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) 6.0°, 7.0°, and 7.2°. In one embodiment, the X-ray powder diffraction peaks at 2θ angles (± 0.2°) 6.0°, 7.0°, and 7.2° are the principal peaks.

[0055] In the 14th embodiment, the crystalline form B according to the 13th embodiment further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 9.3° and 12.5°.

[0056] In the 15th embodiment, the crystalline form B according to either the 13th or 14th embodiment is further characterized by at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 15.6° and 19.0°.

[0057] In the 16th embodiment, the crystalline form B according to any one of the 13th, 14th, and 15th embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 8a, and XRPD peaks as listed in FIG. 8b.

[0058] In the 17th embodiment, crystalline form B according to any one of the 13th, 14th, 15th and 16th embodiments is characterized by a differential scanning calorimetry (DSC) thermographic chart including an overlapping endothermic- / exothermic peak temperature at about 129.9°C ± 2°C and an endothermic peak temperature at about 205.8°C ± 2°C (see FIG. 8c).

[0059] In the 18th embodiment, crystalline form B according to any one of the 13th, 14th, 15th, 16th and 17th embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 10.8% up to about 190°C (see FIG. 8c).

[0060] In the 19th embodiment, the Tris salt according to any one of the first, second, third, fourth, and fifth embodiments is a crystalline form C characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.5°, 13.5°, and 18.0°.

[0061] In the 20th embodiment, the Tris salt according to any one of the first, second, third, fourth, and fifth embodiments is a crystalline form C characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.5°, 13.5°, and 18.0°.

[0062] In the 21st embodiment, the crystalline form C according to either of the 19th and 20th embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 14.3°, 18.3°, and 23.5°.

[0063] In the 22nd embodiment, the crystalline form C according to any one of the 19th, 20th and 21st embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 16.3°, 19.0°, 21.2°, 21.4°, 22.5° and 22.8°.

[0064] In the 23rd embodiment, the crystalline form C according to any one of the 19th, 20th, 21st and 22nd embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 9a, and XRPD peaks as listed in FIG. 9b.

[0065] In the 24th embodiment, the crystalline form C according to any one of the 19th, 20th, 21st, 22nd and 23rd embodiments features a differential scanning calorimetry (DSC) thermographic chart including an endothermic peak temperature at about 196.9°C ± 2°C (see FIG. 9c).

[0066] In the 25th embodiment, the crystalline form C according to any one of the 19th, 20th, 21st, 22nd, 23rd and 24th embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 1.2% up to about 150°C (see FIG. 9c).

[0067] In the 26th embodiment, the present disclosure relates to a sodium salt of a compound represented by the following chemical formula:

[0068] .

[0069] The sodium salt of compound 1 is preferably in a solid or solid crystalline form.

[0070] In the 27th embodiment, the present disclosure relates to a crystalline form of a compound represented by the following formula:

[0071] .

[0072] In the 28th embodiment, the crystalline form according to the 27th embodiment is anhydrous.

[0073] In the 29th embodiment, the crystalline form according to the 27th embodiment is a solvate.

[0074] In the 30th embodiment, the crystalline form according to either of the 27th and 28th embodiments is crystalline form A characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.8°, 11.6°, and 12.8°.

[0075] In the 31st embodiment, the crystalline form according to either of the 27th and 28th embodiments is crystalline form A characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.8°, 11.6°, and 12.8°.

[0076] In the 32nd embodiment, the crystalline form A according to either the 30th or 31st embodiment is further characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 8.1° and 16.9°.

[0077] In the 33rd embodiment, the crystalline form A according to any one of the 30th, 31st, and 32nd embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 11.4°, 18.4°, 21.9°, 24.6°, 24.9°, and 25.1°.

[0078] In the 34th embodiment, crystalline form A according to any one of the 30th, 31st, 32nd and 33rd embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 2a, and XRPD peaks as listed in FIG. 2b.

[0079] In the 35th embodiment, crystalline form A according to any one of the 30th, 31st, 32nd, 33rd and 34th embodiments features a differential scanning calorimetry (DSC) thermographic chart including peak temperatures at about 212.1°C ± 2°C (exothermic) and 328.9°C ± 2°C (endothermic) (see FIG. 2c).

[0080] In the 36th embodiment, crystalline form A according to any one of the 30th, 31st, 32nd, 33rd, 34th and 35th embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 1.0% up to about 200°C (see FIG. 2c).

[0081] In the 37th embodiment, the crystalline form according to either of the 27th and 28th embodiments is crystalline form B characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 6.5°, 12.9°, and 25.1°.

[0082] In the 38th embodiment, the crystalline form according to either of the 27th and 28th embodiments is crystalline form B characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 6.5°, 12.9°, and 25.1°.

[0083] In the 39th embodiment, the crystalline form B according to either of the 37th and 38th embodiments further features X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 13.1° and 15.7°.

[0084] In the 40th embodiment, the crystalline form B according to any one of the 37th, 38th, and 39th embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 8.5°, 11.1°, 11.4°, 17.3°, 20.5°, 21.9°, and 25.9°.

[0085] In the 41st embodiment, the crystalline form B according to any one of the 37th, 38th, 39th and 40th embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 3a, and XRPD peaks as listed in FIG. 3b.

[0086] In the 42nd embodiment, crystalline form B according to any one of the 37th, 38th, 39th, 40th and 41st embodiments features a differential scanning calorimetry (DSC) thermographic chart including an endothermic peak temperature at about 325.6°C ± 2°C (see FIG. 3c).

[0087] In the 43rd embodiment, crystalline form B according to any one of the 37th, 38th, 39th, 40th, 41st and 42nd embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 2.9% up to about 200°C (see FIG. 3c).

[0088] In the 44th embodiment, the crystalline form according to either of the 27th and 28th embodiments is a crystalline form C characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.7°, 11.4°, and 25.0°.

[0089] In the 45th embodiment, the crystalline form according to any one of the 27th, 28th, and 29th embodiments is a crystalline form C characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.7°, 11.4°, and 25.0°.

[0090] In the 46th embodiment, the crystalline form C according to either of the 44th and 45th embodiments is further characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 3.2°, 17.4°, and 18.4°.

[0091] In the 47th embodiment, the crystalline form C according to any one of the 44th, 45th, and 46th embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 12.8°, 16.2°, 19.0°, 27.5°, and 31.7°.

[0092] In the 48th embodiment, the crystalline form C according to any one of the 44th, 45th, 46th and 47th embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 4a, and XRPD peaks as listed in FIG. 4b.

[0093] In the 49th embodiment, the crystalline form C according to any one of the 44th, 45th, 46th, 47th and 48th embodiments features a differential scanning calorimetry (DSC) thermographic chart including an endothermic peak temperature at about 326.1°C ± 2°C (see FIG. 4c).

[0094] In the 50th embodiment, the crystalline form C according to any one of the 44th, 45th, 46th, 47th, 48th and 49th embodiments features a thermogravimetric analysis (TGA) temperature record including a weight loss of about 3.6% up to about 200°C (see FIG. 4c).

[0095] In the 51st embodiment, the crystalline form according to either of the 27th and 28th embodiments is a crystalline form D characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.9°, 11.9°, and 17.1°.

[0096] In the 52nd embodiment, the crystalline form according to any one of the 27th, 28th, and 29th embodiments is a crystalline form D characterized by major X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 5.9°, 11.9°, and 17.1°.

[0097] In the 53rd embodiment, the crystalline form D according to either of the 51st and 52nd embodiments further features X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 11.2° and 23.3°.

[0098] In the 54th embodiment, the crystalline form D according to any one of the 51st, 52nd, and 53rd embodiments further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 12.7°, 13.4°, 18.8°, 19.7°, 20.8°, 22.0°, 22.5°, 22.7°, and 24.6°.

[0099] In the 55th embodiment, the crystalline form D according to any one of the 51st, 52nd, 53rd and 54th embodiments features an X-ray powder diffraction pattern substantially similar to that of FIG. 5a, and XRPD peaks as listed in FIG. 5b.

[0100] In the 56th embodiment, the crystalline form D according to any one of the 51st, 52nd, 53rd, 54th and 55th embodiments features a differential scanning calorimetry (DSC) thermographic chart including an endothermic peak temperature of about 329.4°C ± 2°C (see FIG. 5c).

[0101] In the 57th embodiment, the crystalline form D according to any one of the 51st, 52nd, 53rd, 54th, 55th and 56th embodiments is characterized by a thermogravimetric analysis (TGA) temperature record including a weight loss of about 1.0% up to about 200°C (see FIG. 5c).

[0102] In the 58th embodiment, the crystalline form according to any one of the 27th to 57th embodiments is at least 60 weight% single crystalline form, at least 70 weight% single crystalline form, at least 80 weight% single crystalline form, at least 90 weight% single crystalline form, at least 95 weight% single crystalline form, or at least 99 weight% single crystalline form.

[0103] In the 59th embodiment, the crystalline form according to any one of the 27th to 58th embodiments has a chemical purity of at least 60 weight%, at least 70 weight%, at least 80 weight%, at least 90 weight%, at least 95 weight%, or at least 99 weight%.

[0104] Another embodiment of the present invention is an amorphous form of compound 1 or a Tris salt of compound 1.

[0105] Composition and administration

[0106] A pharmaceutical composition is provided herein comprising: i) a tris salt of Compound 1, for example, an amorphous form of the tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1, and a pharmaceutically acceptable carrier. A pharmaceutical composition is also provided comprising: as an active agent, i) a tris salt of Compound 1, for example, an amorphous form of the tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1, and one or more granular excipients. A pharmaceutical composition is also provided comprising: as an active agent, i) a tris salt of Compound 1, for example, an amorphous form of the tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1, and one or more in-granular excipients and one or more ex-granular excipients. A composition is also provided comprising: as part of a solid dispersion, i) a tris salt of Compound 1, for example, an amorphous form of the tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1; or v) a pharmaceutically acceptable salt of Compound 1. In some embodiments, the composition comprises an amorphous solid dispersion. In another embodiment, the composition comprises a substantially amorphous solid dispersion. In yet another embodiment, the composition comprises a partially crystalline solid dispersion. In yet another embodiment, the composition comprises a substantially crystalline solid dispersion.A pharmaceutical composition is also provided comprising: as part of a solid dispersion, i) a tris salt of Compound 1, for example, an amorphous form of the tris salt or one of the disclosed crystalline forms; or ii) one of the disclosed crystalline forms of Compound 1; or iii) an amorphous form of Compound 1; or iv) a sodium salt of Compound 1 or v) a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carrier(s). Suitable pharmaceutical compositions are described in U.S. Patent No. 9,360,932 and below.

[0107] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, transmucosally, or in ophthalmic preparations. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one aspect, the pharmaceutical compositions provided herein may be administered orally in an orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

[0108] The amount of the provided crystalline or amorphous form that may be combined with a carrier material to produce a composition in a single-dose form will depend on the subject to be treated and the specific mode of administration. For example, the specific dosage and therapeutic regimen for any particular subject will depend on various factors including age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the provided crystalline form in the composition will also depend on the specific form in the composition (e.g., forms A, B, C, D of the crystalline form of Compound 1, or forms A, B, C of the crystalline form of the Tris salt of Compound 1). In one aspect, the provided composition may be formulated such that the dose equivalent is about 0.001 to about 100 mg / kg body weight / day of Compound 1.

[0109] In one embodiment, the pharmaceutical composition comprises i) compound 1 or a pharmaceutically acceptable salt thereof; ii) a diluent; iii) a disintegrant; and iv) a lubricant. In another embodiment, the pharmaceutical composition comprises i) compound 1 or a pharmaceutically acceptable salt thereof; ii) a diluent; iii) a disintegrant; iv) a binder; v) a surfactant; vi) a lubricant; and vii) a lubricant. In another embodiment, the pharmaceutical composition comprises i) compound 1 or a pharmaceutically acceptable salt thereof; ii) a diluent; iii) a disintegrant; iv) a binder; and v) a lubricant. In the composition, compound 1 may be provided, for example, as i) one of the disclosed crystalline forms of compound 1; or ii) an amorphous form of compound 1; or iii) a mixture thereof. In another embodiment of the composition, compound 1 is a Tris salt of compound 1, for example, i) in an amorphous form; or ii) as one of the disclosed crystalline forms of the Tris salt, or iii) as a mixture thereof. In another embodiment of the pharmaceutical composition, compound 1 may be provided in a non-salt form, as a Tris salt form, or as a mixture thereof. In one aspect, the pharmaceutical composition is in the form of a capsule. In another aspect, the pharmaceutical composition is in the form of a tablet.

[0110] In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a crystalline form of compound 1 as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises form A of compound 1 as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises form B of compound 1 as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises form C of compound 1 as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises form D of compound 1 as an active agent and one or more granular excipients.

[0111] In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a crystalline form of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises form A of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises form B of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises form C of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises form D of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients.

[0112] In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a Tris salt of Compound 1 as an active agent and one or more granular excipients. In one embodiment, the active agent used in the capsule composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the capsule composition comprises Tris salt form A as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises Tris salt form B as an active agent and one or more granular excipients. In one embodiment, the capsule composition comprises Tris salt form C as an active agent and one or more granular excipients.

[0113] In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a Tris salt of Compound 1 as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the active agent used in the capsule composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the capsule composition comprises Tris salt form A as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Tris salt form B as an active agent, one or more intragranular excipients, and one or more extragranular excipients. In one embodiment, the capsule composition comprises Tris salt form C as an active agent, one or more intragranular excipients, and one or more extragranular excipients.

[0114] In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a sodium salt of compound 1 as an active agent and one or more granular excipients. In a specific embodiment, the pharmaceutical composition is a capsule composition comprising a sodium salt of compound 1 as an active agent, one or more granular excipients and one or more granular excipients.

[0115] In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a crystalline form of compound 1 as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises form A of compound 1 as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises form B of compound 1 as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises form C of compound 1 as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises form D of compound 1 as an active agent and one or more granular excipients.

[0116] In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a crystalline form of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises form A of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises form B of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises form C of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises form D of compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients.

[0117] In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as an active agent and one or more granular excipients. In one embodiment, the active agent used in the tablet composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the tablet composition comprises Tris salt form A as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises Tris salt form B as an active agent and one or more granular excipients. In one embodiment, the tablet composition comprises Tris salt form C as an active agent and one or more granular excipients.

[0118] In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a Tris salt of Compound 1 as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the active agent used in the tablet composition is one of the disclosed crystalline forms of the Tris salt of Compound 1. In one embodiment, the tablet composition comprises Tris salt form A as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Tris salt form B as an active agent, one or more granular excipients, and one or more extragranular excipients. In one embodiment, the tablet composition comprises Tris salt form C as an active agent, one or more granular excipients, and one or more extragranular excipients.

[0119] In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a sodium salt of compound 1 as an active agent and one or more granular excipients. In a specific embodiment, the pharmaceutical composition is a tablet composition comprising a sodium salt of compound 1 as an active agent, one or more granular excipients and one or more granular excipients.

[0120] In certain embodiments, the pharmaceutical composition provided herein comprises compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 90% by weight (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or about 10% to 20% w / w) based on the total weight of the pharmaceutical composition.

[0121] In certain embodiments, the pharmaceutical composition provided herein comprises compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 65% by weight; about 45% to about 65% by weight; or about 15% to about 17% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises compound 1 or a Tris salt of compound 1 in an amount of about 16% by weight, about 45% by weight, about 54% by weight, or about 60% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises compound 1 or the tris salt of compound 1 in an amount of about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, or about 65 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the tris salt of compound 1 is tris salt form C.

[0122] In certain embodiments, the pharmaceutical composition provided herein may comprise one or more intragranular excipients and one or more extragranular excipients. In certain embodiments, the intragranular excipient comprises a diluent, a disintegrant, a binder, a surfactant, a lubricant, and a lubricant. In certain embodiments, the intragranular excipient comprises a diluent, a disintegrant, a binder, a surfactant, and a lubricant. In certain embodiments, the intragranular excipient comprises a diluent, a disintegrant, a binder, a lubricant, and a lubricant. In certain embodiments, the intragranular excipient comprises a diluent, a disintegrant, a binder, and a lubricant. In certain embodiments, the intragranular excipient comprises a diluent, a disintegrant, and a lubricant. In certain embodiments, the extragranular excipient comprises a lubricant and a lubricant. In certain embodiments, the extragranular excipient comprises a lubricant. In certain embodiments, the extragranular excipient comprises a lubricant. In certain embodiments, the extragranular excipient is not used. In other embodiments, intragranular or extragranular excipients are not used.

[0123] 1. Excipients in granules

[0124] In one embodiment, the pharmaceutical composition provided herein comprises one or more granular excipients selected from diluents, disintegrants, binders, surfactants, lubricants, and lubricants.

[0125] A diluent is an excipient used in pharmaceutical formulations in varying amounts to aid in weight increase and to aid in fluidity, solubility, content uniformity, encapsulation, compressibility, reduced stickiness, and stability. The terms diluent(s), filler(s), or bulking agent(s) as used herein should be understood to be used interchangeably unless otherwise explicitly stated. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starch, pre-gelatinized starch, corn starch, partially pre-gelatinized starch, powdered sugar, ethyl cellulose, isomalt, and mixtures thereof. In some embodiments, the diluent is starch, partially pre-gelatinized starch, microcrystalline cellulose, and mannitol, and mixtures thereof. In some embodiments, the diluent is dicalcium phosphate, starch, lactose, isomalt, and a mixture thereof. In some embodiments, the diluent is microcrystalline cellulose and mannitol and a mixture thereof. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is starch. In some embodiments, the diluent is partially pre-gelatinized starch.

[0126] In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5 to about 80 wt% (e.g., about 10% w / w to about 75% w / w; about 15% w / w to about 70% w / w; about 25% w / w to about 65% w / w; about 30% w / w to about 60% w / w; about 35% w / w to about 55% w / w; about 40% w / w to about 50% w / w) based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) in an amount of about 5 wt% to about 15 wt%; about 5 wt% to about 45 wt%; about 25 wt% to about 45 wt%; or about 25 wt% to about 80 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a diluent (or one or more diluents) based on the total weight of the pharmaceutical composition in an amount of about 5 wt%, about 6 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about It contains an amount of 78% by weight, about 79% by weight, or about 80% by weight.

[0127] In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose in an amount of about 5% by weight to about 80% by weight based on the total weight of the pharmaceutical composition, for example, about 5% by weight to about 15% by weight, about 20% by weight to about 40% by weight, or about 20% by weight to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose based on the total weight of the pharmaceutical composition in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about It contains an amount of 65 wt%, about 70 wt%, about 75 wt%, about 78 wt%, about 79 wt%, or about 80 wt%.

[0128] In certain embodiments, the pharmaceutical composition contains mannitol in an amount of about 5% to 80% by weight based on the total weight of the pharmaceutical composition, for example, about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises mannitol based on the total weight of the pharmaceutical composition in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt% or about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about It contains an amount of 65 wt%, about 70 wt%, about 75 wt%, about 78 wt%, about 79 wt%, or about 80 wt%.

[0129] In certain embodiments, the pharmaceutical composition contains starch in an amount of about 5% to about 80% by weight based on the total weight of the pharmaceutical composition, for example, about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises starch based on the total weight of the pharmaceutical composition in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt% or about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt% It contains an amount of weight%, about 70 weight%, about 75 weight%, about 78 weight%, about 79 weight%, or about 80 weight%.

[0130] In certain embodiments, the pharmaceutical composition comprises partially pre-gelatinized starch in an amount of about 5% to about 80% by weight based on the total weight of the pharmaceutical composition, for example, about 5% to about 15% by weight, about 20% to about 40% by weight, or about 20% to about 80% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises partially pre-gelatinized starch in an amount of about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 27 wt%, about 28 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 37 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt% based on the total weight of the pharmaceutical composition. It contains an amount of weight%, about 65 weight%, about 70 weight%, about 75 weight%, about 78 weight%, about 79 weight%, or about 80 weight%.

[0131] Disintegrators are excipients used to improve the disintegration of pharmaceutical formulations; more specifically, they are excipients added to facilitate the release of an active ingredient by absorbing fluid in the body after administration, swelling, and disintegrating the capsule or tablet. In certain embodiments, the amount of disintegrator in the capsules and tablets provided herein is selected so that the disintegration rate and / or dissolution rate of the capsule or tablet falls within a desired range. In certain embodiments, the amount of disintegrator in the capsule or tablet is about 10% by weight or less based on the total weight of the capsule or tablet.

[0132] Exemplary disintegrants include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginate, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pre-gelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. In one embodiment, the disintegrant comprises crospovidone, sodium starch glycolate, sodium croscarmellose, and a mixture thereof. In one embodiment, the disintegrant is crospovidone. In one embodiment, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is sodium croscarmellose.

[0133] In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 0.5% by weight to about 8% by weight, for example, about 0.5% by weight to about 5% by weight or about 2% by weight to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the amount of disintegrant in the pharmaceutical composition is about 2% by weight to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the disintegrant is present in the pharmaceutical composition in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0134] In certain embodiments, the pharmaceutical composition comprises crospovidone in an amount of about 0.5% by weight to about 8% by weight, for example, about 0.5% by weight to about 5% by weight or about 2% by weight to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 2% by weight to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises crospovidone in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0135] In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 0.5% to about 8% by weight, for example, about 0.5% to about 5% by weight or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium starch glycolate in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0136] In certain embodiments, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 0.5% to about 8% by weight, for example, about 0.5% to about 5% by weight or about 2% to about 5% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 2% to about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 3% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 4% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises croscarmellose sodium in an amount of about 5% by weight, based on the total weight of the pharmaceutical composition.

[0137] Binders are classified as excipients that impart the cohesiveness required for the feasibility of manufacturing solid oral dosage forms. The amount of binder in the tablets or capsules provided herein varies, for example, based on the type of binder (characteristics, e.g., molecular weight, solubility, and viscosity), the type and amount of other excipients, the type and amount of complex, the dosage form, and the formulation (granulation method and tableting method).

[0138] Exemplary binders include hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, povidone, corn starch, potato starch, rice starch, and gelatin, and mixtures thereof. In one embodiment, the binder includes hypromellose, povidone, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone / vinyl acetate (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and mixtures thereof. In one embodiment, the binder includes hypromellose. In one embodiment, the binder includes povidone (PVPK-30). In one embodiment, the binder includes methyl cellulose. In one embodiment, the binder includes hydroxypropyl cellulose. In one embodiment, the binder includes polyvinylpyrrolidone / vinyl acetate (PVPVA). In one embodiment, the binder comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0139] In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 0.5 wt% to about 10 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 0.5 wt% to about 5 wt%, about 2 wt% to about 8 wt%, or about 2 wt% to about 5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a binder in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% based on the total weight of the pharmaceutical composition.

[0140] In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 0.5% by weight to about 10% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hypromellose in an amount of about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight based on the total weight of the pharmaceutical composition.

[0141] In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 0.5% by weight to about 10% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 0.5% by weight to about 5% by weight, about 2% by weight to about 8% by weight, or about 2% by weight to about 5% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises povidone in an amount of about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight based on the total weight of the pharmaceutical composition.

[0142] In certain embodiments, the pharmaceutical composition comprises methyl cellulose in an amount of about 0.5 wt% to about 10 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises methyl cellulose in an amount of about 0.5 wt% to about 5 wt%, about 2 wt% to about 8 wt%, or about 2 wt% to about 5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises methyl cellulose in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% based on the total weight of the pharmaceutical composition.

[0143] In certain embodiments, the pharmaceutical composition comprises hydroxypropyl cellulose in an amount of about 0.5 wt% to about 10 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hydroxypropyl cellulose in an amount of about 0.5 wt% to about 5 wt%, about 2 wt% to about 8 wt%, or about 2 wt% to about 5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises hydroxypropyl cellulose in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% based on the total weight of the pharmaceutical composition.

[0144] In certain embodiments, the pharmaceutical composition comprises polyvinylpyrrolidone / vinyl acetate (PVPVA) in an amount of about 0.5 wt% to about 10 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PVPVA in an amount of about 0.5 wt% to about 5 wt%, about 2 wt% to about 8 wt%, or about 2 wt% to about 5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises PVPVA in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% based on the total weight of the pharmaceutical composition.

[0145] In certain embodiments, the pharmaceutical composition comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) in an amount of about 0.5 wt% to about 10 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises HPMCAS in an amount of about 0.5 wt% to about 5 wt%, about 2 wt% to about 8 wt%, or about 2 wt% to about 5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises HPMCAS in an amount of about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt% based on the total weight of the pharmaceutical composition.

[0146] In some embodiments, the pharmaceutical composition also includes a lubricant, which is an excipient used in solid oral dosage forms to increase the fluidity of the powder. Exemplary lubricants include silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, magnesium stearate, magnesium trisilicate, powdered cellulose, talc, starch, and mixtures thereof. In some embodiments, the lubricant is colloidal silicon dioxide, starch, and talc. In one embodiment, the lubricant is colloidal silicon dioxide. In one embodiment, the lubricant is starch. In one embodiment, the lubricant is talc.

[0147] In certain embodiments, the lubricant is present in an amount of about 0.1% to about 2% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of the lubricant is about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight, or about 0.5% to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of the lubricant is about 0.5% by weight, about 0.75% by weight, about 1% by weight, or about 1.5% by weight based on the total weight of the pharmaceutical composition.

[0148] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1 wt% to about 2 wt%; about 0.1 wt% to about 1 wt%, about 0.25 wt% to about 1.5 wt%; or about 0.5 wt% to about 1.0 wt% based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, or about 1.5 wt% based on the total weight of the pharmaceutical composition.

[0149] In certain embodiments, the pharmaceutical composition comprises starch in an amount of about 0.1% to about 2% by weight; about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight; or about 0.5% to about 1.0% by weight, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises starch in an amount of about 0.5% by weight, about 0.75% by weight, about 1% by weight, or about 1.5% by weight, based on the total weight of the pharmaceutical composition.

[0150] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.1% to about 2% by weight based on the total weight of the pharmaceutical composition; about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight; or about 0.5% to about 1.0% by weight. In one embodiment, the pharmaceutical composition comprises talc in an amount of about 0.5% by weight, about 0.75% by weight, about 1% by weight, or about 1.5% by weight based on the total weight of the pharmaceutical composition.

[0151] In some embodiments, the pharmaceutical composition also includes a lubricant, which is an excipient that reduces interparticle friction and adhesion / sticking to the tablet punch and die. Exemplary lubricants include magnesium stearate (vegetable grade), calcium stearate, zinc stearate, sucrose stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, polyvinyl alcohol, magnesium lauryl sulfate, and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate, magnesium stearate, talc, silica, stearic acid, and glyceryl behenate. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is talc. In one embodiment, the lubricant is silica. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0152] In certain embodiments, the lubricant is present in an amount of about 0.25 wt% to about 3 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of the lubricant is about 0.5 wt% to about 2 wt% or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of the lubricant is about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt% or about 2 wt% based on the total weight of the pharmaceutical composition.

[0153] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0154] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0155] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0156] In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0157] In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0158] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.25 wt% to about 3 wt%; about 0.5 wt% to about 2 wt%; or about 0.75 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition.

[0159] Surfactants or wetting agents are excipients that improve wetting properties and aid in the solubilization of active agents. Exemplary surfactants and wetting agents include sodium lauryl sulfate (SLS), vitamin E or its derivatives (e.g., vitamin E TPGS), sodium docusate, sodium dodecyl sulfate, polysorbates (e.g., Tween 20 and Tween 80), poloxamers (e.g., Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, Pluronic copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, the surfactant is sodium lauryl sulfate, poloxamer, Pluronic copolymer, and polysorbate. In one embodiment, the surfactant is sodium lauryl sulfate. In one embodiment, the surfactant is poloxamer. In one embodiment, the surfactant is a Pluronic copolymer. In one embodiment, the surfactant is polysorbate.

[0160] In certain embodiments, the surfactant is present in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of surfactant is about 0.5% to about 1.5% by weight or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the surfactant is present in an amount of about 0.5% by weight, about 1% by weight, about 1.5% by weight, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0161] In certain embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5% to about 1.5% by weight or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises sodium lauryl sulfate in an amount of about 0.5% by weight, about 1% by weight, about 1.5% by weight, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0162] In certain embodiments, the pharmaceutical composition comprises poloxamer in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises poloxamer in an amount of about 0.5% to about 1.5% by weight or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises poloxamer in an amount of about 0.5% by weight, about 1% by weight, about 1.5% by weight, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0163] In certain embodiments, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.5% to about 1.5% by weight or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a Pluronic copolymer in an amount of about 0.5% by weight, about 1% by weight, about 1.5% by weight, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0164] In certain embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.1% to about 3% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises polysorbate in an amount of about 0.5% to about 1.5% by weight or about 1% to about 2% by weight based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises polysorbate in an amount of about 0.5% by weight, about 1% by weight, about 1.5% by weight, or about 2% by weight based on the total weight of the pharmaceutical composition.

[0165] The pharmaceutical compositions provided herein may also contain one or more additional pharmaceutically acceptable granular excipients other than the excipients mentioned above. Examples of such additional excipients include, but are not limited to, solubility enhancers, stabilizers, pH adjusters, coating agents, and pigments.

[0166] In certain embodiments, the pharmaceutical composition provided herein is in tablet form and may include a coating agent, such as polyvinyl alcohol.

[0167] In certain embodiments, the pharmaceutical composition provided herein is in tablet form and may include a pigment, such as titanium dioxide.

[0168] 2. Extragranules

[0169] In certain embodiments, the pharmaceutical composition provided herein comprises one or more excipients other than granules selected from lubricants and lubricants.

[0170] In certain embodiments, the lubricant used in the excipients other than granules is colloidal silicon dioxide, starch, and talc. In one embodiment, the lubricant is colloidal silicon dioxide. In one embodiment, the lubricant is starch. In one embodiment, the lubricant is talc.

[0171] In some embodiments, the lubricant is present in the excipients other than granules in an amount of about 0.1% by weight to about 2% by weight based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of the lubricant in the excipients other than granules is about 0.1% by weight to about 1% by weight, about 0.25% by weight to about 1.5% by weight, or about 0.5% by weight to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the amount of the lubricant in the excipients other than granules is about 0.5% by weight, about 0.75% by weight, or about 1% by weight based on the total weight of the pharmaceutical composition.

[0172] In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.1% to about 2% by weight; about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight; or about 0.5% to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises colloidal silicon dioxide in an amount of about 0.5% by weight, about 0.75% by weight, or about 1% by weight based on the total weight of the pharmaceutical composition.

[0173] In certain embodiments, the pharmaceutical composition comprises starch in an amount of about 0.1% to about 2% by weight; about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight; or about 0.5% to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises starch in an amount of about 0.5% by weight, about 0.75% by weight, or about 1% by weight based on the total weight of the pharmaceutical composition.

[0174] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.1% to about 2% by weight; about 0.1% to about 1% by weight, about 0.25% to about 1.5% by weight; or about 0.5% to about 1.0% by weight based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises talc in an amount of about 0.5% by weight, about 0.75% by weight, or about 1% by weight based on the total weight of the pharmaceutical composition.

[0175] In certain embodiments, the lubricant used in the excipients other than granules is sodium stearyl fumarate, magnesium stearate, talc, silica, stearic acid, and glyceryl behenate. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the lubricant is magnesium stearate. In one embodiment, the lubricant is talc. In one embodiment, the lubricant is silica. In one embodiment, the lubricant is stearic acid. In one embodiment, the lubricant is glyceryl behenate.

[0176] In certain embodiments, the lubricant is present in the excipients other than granules in an amount of about 0.25 weight% to about 1.5 weight% based on the total weight of the pharmaceutical composition. In certain embodiments, the amount of the lubricant in the excipients other than granules is about 0.5 weight%, about 0.75 weight%, about 1 weight%, about 1.25 weight%, or about 1.5 weight% based on the total weight of the pharmaceutical composition.

[0177] In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in excipients outside the granules. In certain embodiments, the pharmaceutical composition comprises sodium stearyl fumarate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, or about 1.5 wt% based on the total weight of the pharmaceutical composition in excipients inside the granules.

[0178] In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules. In certain embodiments, the pharmaceutical composition comprises magnesium stearate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules.

[0179] In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules. In certain embodiments, the pharmaceutical composition comprises talc in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules.

[0180] In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules. In certain embodiments, the pharmaceutical composition comprises silica in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules.

[0181] In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules. In certain embodiments, the pharmaceutical composition comprises stearic acid in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules.

[0182] In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.25 wt% to about 1.5 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules. In certain embodiments, the pharmaceutical composition comprises glyceryl behenate in an amount of about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.25 wt%, about 1.5 wt%, about 1.75 wt%, or about 2 wt% based on the total weight of the pharmaceutical composition in an excipient other than granules.

[0183] The pharmaceutical compositions provided herein may contain various excipients other than the excipients mentioned above that are pharmaceutically acceptable and used as excipients. Examples of other excipients include, but are not limited to, diluents, disintegrants, coloring agents, coating agents, and flavoring agents.

[0184] 3. Pharmaceutical composition

[0185] In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof constitutes about 10% w / w to about 20% w / w of the pharmaceutical composition, diluent(s) constitute about 76.5% w / w to about 83% w / w of the pharmaceutical composition, disintegrant constitutes about 3% w / w to about 5% w / w of the pharmaceutical composition, and lubricant constitutes about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, so that the total is 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a Tris salt.

[0186] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof constitutes about 48% w / w to about 60% w / w of the pharmaceutical composition, diluent(s) constitute about 37.5% w / w to about 44% w / w of the pharmaceutical composition, disintegrant constitutes about 2% w / w to about 6% w / w of the pharmaceutical composition, and lubricant constitutes about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, the total amount of which is 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a Tris salt.

[0187] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof constitutes about 36% w / w to about 54% w / w of the pharmaceutical composition, diluent(s) constitute about 40.5% w / w to about 45% w / w of the pharmaceutical composition, disintegrant constitutes about 2% w / w to about 4% w / w of the pharmaceutical composition, binder constitutes about 2% w / w to about 8% w / w of the pharmaceutical composition, surfactant constitutes about 0.5% w / w to about 3% w / w of the pharmaceutical composition, lubricant constitutes about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, and lubricant constitutes about 0.5% w / w to about 2.0% w / w of the pharmaceutical composition, and the total is 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a Tris salt.

[0188] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof constitutes about 42% w / w to about 63% w / w of the pharmaceutical composition, diluent(s) constitute about 32.5% w / w to about 38% w / w of the pharmaceutical composition, disintegrant constitutes about 2% w / w to about 4% w / w of the pharmaceutical composition, binder constitutes about 2% w / w to about 8% w / w of the pharmaceutical composition, surfactant constitutes about 0% w / w to about 2% w / w of the pharmaceutical composition, lubricant constitutes about 0% w / w to about 3% w / w of the pharmaceutical composition, and lubricant constitutes about 0.5% w / w to about 3.0% w / w of the pharmaceutical composition, and the total is 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a Tris salt.

[0189] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof constitutes about 47% w / w to about 70% w / w of the pharmaceutical composition, diluent(s) constitute about 26.5% w / w to about 32% w / w of the pharmaceutical composition, disintegrant constitutes about 2% w / w to about 4% w / w of the pharmaceutical composition, binder constitutes about 1% w / w to about 9% w / w of the pharmaceutical composition, surfactant constitutes about 0% w / w to about 2% w / w of the pharmaceutical composition, lubricant constitutes about 0% w / w to about 3% w / w of the pharmaceutical composition, and lubricant constitutes about 0.5% w / w to about 3.0% w / w of the pharmaceutical composition, and the total is 100% by weight of the composition. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a Tris salt.

[0190] In certain embodiments, the pharmaceutical composition comprises an intragranular portion and an extragranular portion. In some embodiments, the intragranular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a binder, a surfactant, a lubricant, and a lubricant. In some embodiments, the extragranular portion of the pharmaceutical composition of the present application comprises additional amounts of a lubricant and a lubricant.

[0191] In some embodiments, the granular portion of the pharmaceutical composition of the present application comprises Compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the non-granular portion of the pharmaceutical composition of the present application comprises an additional amount of lubricant.

[0192] In some embodiments, the granular portion of the pharmaceutical composition of the present application comprises compound 1 or a pharmaceutically acceptable salt thereof, a diluent, a disintegrant, and a lubricant. In some embodiments, the extragranular portion of the pharmaceutical composition is not present.

[0193] In some embodiments, the granular portion of the pharmaceutical composition of the present application comprises an amount of about 37% w / w to about 50% w / w of compound 1 or a tris salt of compound 1, an amount of about 41% w / w to about 45% w / w of a diluent (or one or more diluents) of the pharmaceutical composition, an amount of about 2% w / w to about 4% w / w of a disintegrant of the pharmaceutical composition, an amount of about 2% w / w to about 8% w / w of a binder of the pharmaceutical composition, an amount of about 0.5% w / w to about 3% w / w of a surfactant of the pharmaceutical composition, an amount of about 0.5% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition, and an amount of about 0.5% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition.

[0194] In some embodiments, the granular portion of the pharmaceutical composition comprises an amount of about 42% w / w to about 63% w / w of compound 1 or a tris salt of compound 1, an amount of about 32% w / w to about 38% w / w of a diluent (or one or more diluents) of the pharmaceutical composition, an amount of about 2% w / w to about 4% w / w of a disintegrant of the pharmaceutical composition, an amount of about 2% w / w to about 8% w / w of a binder of the pharmaceutical composition, an amount of about 0% w / w to about 2% w / w of a surfactant of the pharmaceutical composition, an amount of about 0% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition, and an amount of about 0.5% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition.

[0195] In some embodiments, the granular portion of the pharmaceutical composition comprises an amount of about 51% w / w to about 68% w / w of compound 1 or a tris salt of compound 1, an amount of about 26% w / w to about 32% w / w of a diluent (or one or more diluents) of the pharmaceutical composition, an amount of about 2% w / w to about 4% w / w of a disintegrant of the pharmaceutical composition, an amount of about 1% w / w to about 9% w / w of a binder of the pharmaceutical composition, an amount of about 0% w / w to about 2% w / w of a surfactant of the pharmaceutical composition, an amount of about 0% w / w to about 1.5% w / w of a lubricant of the pharmaceutical composition, and an amount of about 0.5% w / w to about 2.0% w / w of a lubricant of the pharmaceutical composition.

[0196] In some embodiments, the non-granular portion of the pharmaceutical composition comprises an additional amount of a lubricant in an amount of about 0.5% w / w to about 1% w / w of the pharmaceutical composition, and an additional amount of a lubricant in an amount of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition. In some embodiments, the non-granular portion of the pharmaceutical composition comprises an additional amount of a lubricant in an amount of about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition.

[0197] 4. Solid dispersion

[0198] A pharmaceutical composition comprising a solid dispersion of a therapeutically active compound in a matrix can provide improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of the therapeutically active compound and the matrix material, and then solidifying the mixture by cooling or the removal of the solvent. When administered orally, such a solid dispersion of a therapeutically active compound often exhibits enhanced bioavailability compared to an oral composition containing the undispersed compound.

[0199] As used herein, the term "dispersion" refers to a dispersion system in which one substance (dispersed phase) is distributed in discrete units throughout a second substance (continuous phase or vehicle). Generally, the dispersed phase may be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solid.

[0200] As used herein, the term “amorphous solid dispersion” generally refers to a solid dispersion of two or more components, typically a therapeutically active compound and a polymer (or a plurality of polymers), but possibly contains other components, such as a surfactant or other pharmaceutical excipient, wherein the therapeutically active compound is in the amorphous phase. In some embodiments, the amorphous solid dispersion comprises polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the therapeutically active compound constituting the continuous phase. In some embodiments, the amorphous solid dispersion comprises polymer(s) (and optionally a surfactant) constituting the continuous phase, and the therapeutically active compound constituting the dispersed phase. In some embodiments, the therapeutically active compound is substantially amorphous. In other embodiments, the therapeutically active compound is substantially crystalline.

[0201] In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and one or more polymer(s). In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, one or more polymer(s), and one or more surfactants(s). In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and one polymer. In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, one polymer, and a surfactant. In certain embodiments, the glass form of Compound 1 is used in the solid dispersion. In other embodiments, a pharmaceutically acceptable salt of Compound 1 is used in the solid dispersion. In certain embodiments, the pharmaceutically acceptable salt of compound 1 used in the solid dispersion is the Tris salt of compound 1. In other embodiments, the pharmaceutically acceptable salt of compound 1 used in the solid dispersion is the sodium salt of compound 1.

[0202] In some embodiments, the polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), ethylcellulose, cellulose acetate phthalate, and polyvinylpyrrolidone (PVP), and mixtures thereof. In some embodiments, the polymer is a cellulose-based polymer, such as HPMC, HPMCAS, HPC, and ethylcellulose. In other embodiments, the polymer is HPMCAS.

[0203] In some embodiments, the polymer is present in the solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or about 15% w / w to about 35% w / w). In some embodiments, the polymer (or one or more polymers) is present in the solid dispersion in an amount of about 10% w / w to about 80% w / w, for example, about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, for example, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, or about 54% w / w. In some embodiments, the polymer (or one or more polymers) is present in the solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0204] In some embodiments, compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1 is present in the solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w; about 30% w / w to about 70% w / w; about 40% w / w to about 60% w / w; or about 15% w / w to about 35% w / w). In some embodiments, compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1 is present in the solid dispersion in an amount of about 10% w / w to about 80% w / w, for example, about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, for example, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, or about 60% w / w. In some embodiments, compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1 is present in an amorphous solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0205] In some embodiments, the solid dispersion further comprises a surfactant. In some embodiments, the surfactant is selected from sodium lauryl sulfate (SLS), vitamin E or its derivative (e.g., vitamin E TPGS), sodium docusate, sodium dodecyl sulfate, polysorbate (e.g., Tween 20 and Tween 80), poloxamer (e.g., poloxamer 335 and poloxamer 407), glyceryl monooleate, SPAN 65, SPAN 25, Capriol 90, Pluronic copolymer (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, the surfactant is SLS. In other embodiments, the surfactant is vitamin E or its derivative (e.g., vitamin E TPGS).

[0206] In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w / w to about 10% w / w, for example, about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, about 1% w / w to about 4% w / w, or about 1% w / w to about 5% w / w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, or about 1% w / w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w.

[0207] In some embodiments, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, the solid dispersion essentially consists of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, the solid dispersion consists of Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS. In some embodiments, Compound 1, or a pharmaceutically acceptable salt of Compound 1, or a Tris salt of Compound 1, or a sodium salt of Compound 1, and HPMCAS are present in a weight ratio of about 3:1 to about 1:3, or about 2:1 to about 1:2, or about 1.5:1 to about 1:1.5. In some embodiments, compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1, and HPMCAS are present in a weight ratio of about 1:1.

[0208] In another aspect, the present disclosure relates to a method for preparing a solid dispersion of compound 1, or a pharmaceutically acceptable salt of compound 1, or a Tris salt of compound 1, or a sodium salt of compound 1.

[0209] In some embodiments, the method comprises spray-drying a mixture comprising compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1, a polymer, and a suitable solvent or solvent mixture.

[0210] In some embodiments, the solvent is a volatile solvent (e.g., methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or a mixture thereof). In some embodiments, the solvent is acetone.

[0211] In some embodiments, compound 1, or a pharmaceutically acceptable salt of compound 1, or a tris salt of compound 1, or a sodium salt of compound 1 may be used as a starting material in a spray drying process for preparing a solid dispersion. In some embodiments, one of the crystalline forms described herein may be used as a starting material in a spray drying process.

[0212] Spray drying involves, for example, the atomization of a liquid solution containing a solid and a solvent or a solvent mixture, and the removal of the solvent or solvent mixture. Atomization may be performed, for example, through two types of fluids or pressure or electronic nozzles, or on a rotating disk. The removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., about room temperature to about 200°C). Techniques and methods for spray drying can be found in the literature [Perry's Chemical Engineering Handbook, 6th Ed., RH Perry, DW Green & JO Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954)].

[0213] 5. Exemplary capsule formulation

[0214] Preparations for oral use may also be provided as hard gelatin or hydroxypropylmethylcellulose (HPMC) capsules in which the active ingredient is mixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate, or kaolin and mixtures thereof, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, e.g., peanut oil, liquid paraffin, or olive oil.

[0215] In some embodiments, the capsule composition provided herein comprises an excipient comprising an amount of about 10% w / w to about 20% w / w of a Tris salt of Compound 1 based on the total weight of the capsule, an amount of about 76.5% w / w to about 83% w / w of a diluent (or one or more diluents) based on the total weight of the capsule, an amount of about 3% w / w to about 5% w / w of a disintegrant based on the total weight of the capsule, and an amount of about 0.5% w / w to about 2.0% w / w of a lubricant based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt form C.

[0216] In some embodiments, the capsule composition provided herein comprises an excipient comprising an amount of about 48% w / w to about 60% w / w of the Tris salt of Compound 1 based on the total weight of the capsule, an amount of about 37.5% w / w to about 44% w / w of a diluent (or one or more diluents) of the capsule, an amount of about 2% w / w to about 6% w / w of a disintegrant of the capsule, and an amount of about 0.5% w / w to about 2.0% w / w of a lubricant of the capsule. In one embodiment, the Tris salt comprises Tris salt form C.

[0217] In some embodiments, the capsule composition provided herein comprises, based on the total weight of the capsule, a tris salt of compound 1 of about 37% w / w to about 50% w / w; an excipient within the granule comprising a diluent(s) of about 41% w / w to about 45% w / w, a disintegrant of about 2% w / w to about 4% w / w, a binder of about 2% w / w to about 8% w / w, a surfactant of about 0.5% w / w to about 3% w / w, a lubricant of about 0.5% w / w to about 2.0% w / w, and a lubricant of about 0.5% w / w to about 2.0% w / w; It comprises excipients other than granules, including a lubricant of about 0.5% w / w to about 2.0% w / w and a lubricant of about 0.5% w / w to about 2.0% w / w, all based on the total weight of the capsule. In one embodiment, the Tris salt comprises Tris salt form C.

[0218] In some embodiments, the capsule composition provided herein comprises, based on the total weight of the capsule, an amount of about 42% w / w to about 63% w / w of the tris salt of compound 1; an amount of about 32% w / w to about 38% w / w of a diluent(s), about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a lubricant, and about 0.5% w / w to about 3.0% w / w of a lubricant within the granule; and an amount of about 0% w / w to about 2.0% w / w of a lubricant outside the granule, and about 0.5% w / w to about 2.0% w / w of a lubricant, all of which are based on the total weight of the capsule. In one embodiment, the Tris salt includes Tris salt form C.

[0219] In some embodiments, the capsule composition provided herein comprises, based on the total weight of the capsule, an amount of about 51% w / w to about 68% w / w of the tris salt of compound 1; an amount of about 26% w / w to about 32% w / w of a diluent(s), about 2% w / w to about 4% w / w of a disintegrant, about 1% w / w to about 9% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a lubricant, and about 0.5% w / w to about 3.0% w / w of a lubricant within the granule; and an amount of about 0% w / w to about 2.0% w / w of a lubricant outside the granule, and about 0.5% w / w to about 2.0% w / w of a lubricant, all of which are based on the total weight of the capsule. In one embodiment, the Tris salt includes Tris salt form C.

[0220] 6. Exemplary tablet formulations

[0221] In the case of the tablet composition, Compound 1 or a pharmaceutically acceptable salt thereof, which is a mixture with one or more pharmaceutically acceptable excipients used in the manufacture of the tablet, may be used. Examples of such excipients include, but are not limited to, diluents, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrating agents, e.g., corn starch or alginic acid; binders, e.g., starch, gelatin, or acacia; and lubricants, e.g., magnesium stearate, stearic acid, or talc. The tablet may not be coated, or may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a therapeutic action sustained over a desired period. For example, a time-delaying agent, e.g., glyceryl monostearate or glyceryl distearate, may be used.

[0222] In certain embodiments, the tablet is a coated tablet. In certain embodiments, the coating is a film coating. In certain embodiments, the coating agent is Opadry II. In certain embodiments, the coating agent comprises polyvinyl alcohol.

[0223] Any conventional method for obtaining tablets may be used, and methods described in pharmacopoeias such as the United States Pharmacopoeia and the European Pharmacopoeia may be used, for example.

[0224] In some embodiments, the tablet composition provided herein comprises an excipient comprising an amount of about 10% w / w to about 20% w / w of a Tris salt of Compound 1 based on the total weight of the tablet, an amount of about 76.5% w / w to about 83% w / w of a diluent (or one or more diluents), an amount of about 3% w / w to about 5% w / w of a disintegrant of the tablet, and an amount of about 0.5% w / w to about 2.0% w / w of a lubricant of the tablet, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt form C.

[0225] In some embodiments, the tablet composition provided herein comprises an excipient comprising an amount of about 48% w / w to about 60% w / w of the Tris salt of Compound 1 based on the total weight of the tablet, an amount of about 37.5% w / w to about 44% w / w of a diluent (or one or more diluents) of the tablet, an amount of about 2% w / w to about 6% w / w of a disintegrant of the tablet, and an amount of about 0.5% w / w to about 2.0% w / w of a lubricant of the tablet. In one embodiment, the Tris salt comprises Tris salt form C.

[0226] In some embodiments, the tablet composition provided herein comprises, based on the total weight of the tablet, a tris salt of compound 1 of about 37% w / w to about 50% w / w; a diluent(s) of about 41% w / w to about 45% w / w; a disintegrant of about 2% w / w to about 4% w / w; a binder of about 2% w / w to about 8% w / w; a surfactant of about 0.5% w / w to about 3% w / w; a lubricant of about 0.5% w / w to about 2.0% w / w; and an excipient within the granule comprising a lubricant of about 0.5% w / w to about 2.0% w / w. It comprises excipients other than granules, including a lubricant of about 0.5% w / w to about 2.0% w / w and a lubricant of about 0.5% w / w to about 2.0% w / w, all based on the total weight of the tablet. In one embodiment, the Tris salt comprises Tris salt form C.

[0227] In some embodiments, the tablet composition provided herein comprises, based on the total weight of the tablet, an amount of about 42% w / w to about 63% w / w of the tris salt of compound 1; an amount of about 32% w / w to about 38% w / w of a diluent(s), about 2% w / w to about 4% w / w of a disintegrant, about 2% w / w to about 8% w / w of a binder, about 0% w / w to about 2% w / w of a surfactant, about 0% w / w to about 3.0% w / w of a lubricant, and about 0.5% w / w to about 3.0% w / w of a lubricant within the granules; and an amount of about 0% w / w to about 2.0% w / w of a lubricant outside the granules, and about 0.5% w / w to about 2.0% w / w of a lubricant, all of which are based on the total weight of the tablet. In one embodiment, the Tris salt includes Tris salt form C.

[0228] In some embodiments, the tablet composition provided herein comprises, based on the total weight of the tablet, an amount of about 51% w / w to about 68% w / w of the tris salt of compound 1; an amount of about 26% w / w to about 32% w / w of diluent(s), about 2% w / w to about 4% w / w of disintegrant, about 1% w / w to about 9% w / w of binder, about 0% w / w to about 2% w / w of surfactant, about 0% w / w to about 3.0% w / w of lubricant, and about 0.5% w / w to about 3.0% w / w of lubricant within the granules; and an amount of about 0% w / w to about 2.0% w / w of lubricant outside the granules, and about 0.5% w / w to about 2.0% w / w of lubricant, all of which are based on the total weight of the tablet. In one embodiment, the Tris salt includes Tris salt form C.

[0229] 7. Other preparations

[0230] In the case of an aqueous suspension, the compound of the present disclosure is mixed with an excipient suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum.

[0231] The oral suspension may also contain a dispersant or wetting agent, such as a naturally occurring phosphatid, such as lecithin, or a condensation product of a fatty acid and an alkylene oxide, such as polyoxyethylene stearate, or a condensation product of a long-chain aliphatic alcohol and an ethylene oxide, such as heptadecaethyleneoxycetanol, or a condensation product of a partial ester derived from a fatty acid and hexitol and an ethylene oxide, such as polyoxyethylene sorbitol monooleate, or a condensation product of a partial ester derived from a fatty acid and hexitol anhydride and an ethylene oxide, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0232] An oily suspension may be formulated by suspending the compound of the present disclosure in a vegetable oil, e.g., arachnid oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, e.g., liquid paraffin. The oily suspension may contain a thickener, e.g., beeswax, hard paraffin, or cetyl alcohol.

[0233] Sweeteners and flavoring agents such as those presented above may be added to provide an oral formulation with excellent taste. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0234] Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water may be formulated by providing the compounds of the present disclosure as a mixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, e.g., sweeteners, flavoring agents, and coloring agents may also be present.

[0235] The pharmaceutical composition of the present disclosure may also exist in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, e.g., olive oil or arachnid oil, or a mineral oil, e.g., liquid paraffin and mixtures thereof. Suitable emulsifiers may be naturally occurring gums, e.g., acacia gum or tragacanth gum; naturally occurring phospholipids, e.g., soybean, lecithin; and esters or partial esters derived from fatty acids and hexitol, anhydrides, e.g., sorbitan monooleate; and condensation products of said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0236] Syrups and elixirs may be formulated with sweeteners, e.g., glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain emollients, preservatives, and flavorings and colorings. Pharmaceutical compositions may be in the form of sterile injectables, aqueous suspensions, or oil suspensions. These suspensions may be formulated according to techniques known in the relevant art using one of the more suitable dispersants or wetting agents and suspending agents mentioned above. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, e.g., solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixing oils are typically used as solvents or suspension media. For this purpose, any non-irritating fixation oil containing synthetic mono- or diglycerides may be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0237] Compound 1 or its pharmaceutically acceptable salts may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts at the rectum to release the drug. Such materials are cocoa butter, beeswax, and polyethylene glycol.

[0238] A composition for parenteral administration is administered in a sterile medium. Depending on the vehicle and the concentration of the drug in the formulation used, the parenteral formulation may be a solution or suspension containing the dissolved drug. An ajuvant, such as a local anesthetic, a preservative, and a buffer may also be added to the parenteral composition.

[0239] Another embodiment of the present invention is a liquid formulation comprising the sodium salt of compound 1, suitable for oral or parenteral administration. Typically, the liquid formulation is aqueous. For oral administration, a specific sweetener and / or flavoring agent and / or coloring agent may be added.

[0240] The amount of active ingredient that can be combined with one or more pharmaceutical excipients to form a single dosage form will vary depending on the patient being treated and the specific method of administration. In certain embodiments, the pharmaceutical composition comprises about 10 mg to about 1500 mg of Compound 1 or a pharmaceutically acceptable salt thereof (based on the weight of the free form of Compound 1, excluding the weight of any isoforms, salt-forming agents, hydrated water, solvating solvents, etc.). In some embodiments, the pharmaceutical composition comprises about 90 mg to about 240 mg; about 100 mg to about 240 mg; about 10 mg to about 500 mg; or about 10 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg of compound 1 or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition comprises about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, or about 1450 mg, or about 1500 mg.In certain embodiments, the pharmaceutical composition is in an orally acceptable dosage form, e.g., in the form of a capsule, and comprises about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg of the tris salt of compound 1.

[0241] Treatment methods, uses for the manufacture of medicines, salts or crystalline forms for use in the treatment of diseases

[0242] In one aspect, the crystalline and amorphous forms and pharmaceutical compositions thereof described herein are inhibitors of DHODH (but are not limited thereto) and are generally useful for treating the underlying condition of DHODH. The tris(hydroxymethyl)aminomethane salt of Compound 1 described in the following paragraph comprises any of the tris salts according to the first to 25 embodiments described above. The crystalline form of Compound 1 described in the following paragraph comprises any of the crystalline forms according to any one of the 27 to 59 embodiments described above.

[0243] In one aspect, the present disclosure relates to a method for treating cancer in a subject, comprising administering to the subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof. In another aspect, the present disclosure relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicine for treating cancer. In yet another aspect, the present disclosure relates to the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof for treating cancer.

[0244] In some embodiments, cancer includes solid tumors. In some embodiments, cancer is selected from lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumor, renal cancer or ureteral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasm, tumor angiogenesis, spinal cord tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, environmentally induced cancer, and PTEN mutant cancer. In some embodiments, the cancer is selected from biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and cancer of the upper respiratory and digestive tract. In another embodiment, the cancer is a blood cancer. In one embodiment, the blood cancer is selected from myeloma, lymphoma, and leukemia. In one embodiment, the blood cancer is selected from acute myeloid leukemia, multiple myeloma, B-pre-lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma, bladder cancer, primary CNS lymphoma, and T-cell lymphoma; In one embodiment, the blood cancer is selected from chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary exudative lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double-hit diffuse-B-cell lymphoma, and triple-hit diffuse-B-cell lymphoma.In one embodiment, the blood cancer is selected from angioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastocystic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal B-cell lymphoma, nodular marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenström macroglobulinemia, essential thrombocytopenia, chronic idiopathic myelofibrosis, and polycythemia vera.

[0245] In a further aspect, the present disclosure relates to a method for treating cancer responsive to inhibition of dihydroorotate dehydrogenase in a subject, comprising administering to the subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of its disclosed crystalline forms), the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof. In another aspect, the present application relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicine for treating cancer responsive to inhibition of dihydroorotate dehydrogenase. In yet another aspect, the present disclosure relates to the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof for treating cancer responsive to inhibition of dihydroorotate dehydrogenase. In one embodiment, the arm may be selected from the list of arms described above.

[0246] In a further aspect, the present disclosure relates to a method for treating a condition or disease selected from a virus-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune disease, or inflammatory disorder in a subject, comprising administering to the subject an effective amount of the tris(hydroxymethyl)aminomethane salt of Compound 1 (or one of its disclosed crystalline forms), the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof. In another aspect, the present application relates to the use of the tris(hydroxymethyl)aminomethane salt of Compound 1, the sodium salt of Compound 1, the crystalline form of Compound 1, or a pharmaceutical composition thereof for the manufacture of a medicine for treating a condition or disease selected from a virus-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune disease, or inflammatory disorder. In another aspect, the present disclosure relates to a tris(hydroxymethyl)aminomethane salt of compound 1, a sodium salt of compound 1, a crystalline form of compound 1, or a pharmaceutical composition thereof for treating a selected condition or disease from viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases or inflammatory disorders.

[0247] In another aspect, the present disclosure relates to a method for inhibiting the growth and / or metastasis of tumor cells responsive to the inhibition of dihydroorotate dehydrogenase in a subject, comprising administering to a subject an effective amount of the tris(hydroxymethyl)aminomethane salt of compound 1 (or one of its disclosed crystalline forms), the sodium salt of compound 1, the crystalline form of compound 1, or a pharmaceutical composition thereof.

[0248] In another aspect, the present disclosure relates to a method for inhibiting tumor cells responsive to inhibition of dihydroorotate dehydrogenase in a subject, comprising administering to the subject an effective amount of the tris(hydroxymethyl)aminomethane salt of compound 1 (or one of its disclosed crystalline forms), the sodium salt of compound 1, the crystalline form of compound 1, or a pharmaceutical composition thereof.

[0249] Another embodiment of the present invention is a method for treating a subject having cancer using Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 or a pharmaceutically acceptable salt thereof is preferably provided as i) a Tris salt (e.g., one of the amorphous form or the disclosed crystalline form); ii) a sodium salt of Compound 1; iii) one of the disclosed crystalline forms of Compound 1; or iv) an amorphous form of Compound 1. The cancer to be treated is a hematological cancer selected from myeloma, lymphoma, leukemia, e.g. acute myeloid leukemia (AML), chronic myeloproliferative disease, monoclonal gammaglobulinopathy of unknown meaning, myelodysplastic syndrome, amyloidosis, and myelodysplastic / myeloproliferative neoplasm; and the myeloma to be treated is selected from multiple myeloma, amyloidosis, plasmacytoma, monoclonal gammaglobulinopathy of unknown meaning, asymptomatic myeloma, symptomatic myeloma, and Kaller's disease; The lymphoma to be treated is selected from anaplastic large cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B-cell lymphoma, nodular marginal zone B-cell lymphoma, small lymphoblastic lymphoma, thyroid lymphoma, and Waldenström macroglobulinemia; the chronic myeloproliferative disease to be treated is selected from essential thrombocytopenia, chronic idiopathic myelofibrosis, and polycythemia vera; and the leukemia to be treated is selected from acute myeloid leukemia (AML), hairy cell leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.

[0250] In another aspect, the present disclosure relates to a method for treating cancer in a subject, comprising administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to the subject. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is the tris(hydroxymethyl)aminomethane (tris) salt of compound 1 as described herein (including all partially crystalline or crystalline tris salt forms of compound 1 disclosed herein), the sodium salt of compound 1 as described herein, or free acid compound 1 (including all partially crystalline or crystalline forms of free acid compound 1 disclosed herein), wherein one of the administration regimens described in the following paragraph is implemented. In one embodiment, the subject is treated by administering an effective amount of the crystalline tris salt of compound 1 to the subject. In one specific embodiment, the crystalline tris salt is the crystalline tris salt form C as described herein. In another embodiment, the subject is treated by administering an effective amount of the crystalline form of free acid compound 1 to the subject.

[0251] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) once a week for one or more 28-day or 4-week cycles.

[0252] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of the free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) for a period of 2 to 5 days per week, and one cycle of the regimen is defined as 4 consecutive weeks of treatment.

[0253] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) in one or more cycles of 28 days or 4 weeks for a period of 2 to 4 consecutive days each week, followed by a rest period of 3 to 5 days.

[0254] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) for two consecutive days each week for one or more 28-day or 4-week cycles, followed by a 5-day rest period.

[0255] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of the free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) for three consecutive days each week for one or more 28-day or 4-week cycles, followed by a 4-day rest period.

[0256] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of the free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) for four consecutive days each week for one or more 28-day or 4-week cycles, followed by a three-day rest period.

[0257] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of the free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) in one or more 28-day or 4-week cycles for a period of 2 to 4 consecutive days per week, followed by a rest period of 3 to 5 days, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycles. In another embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) in one or more cycles of 28 days or 4 weeks for a period of 2 to 4 consecutive days each week, followed by a rest period of 3 to 5 days, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0258] In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered to a subject for 2 consecutive days during the first week of a 28-day or 4-week cycle, followed by a 5-day rest period, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycle. In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered to a subject for 2 consecutive days during the first week of a 28-day or 4-week cycle, followed by a 5-day rest period, wherein the number of consecutive treatment days is reduced in at least 1 week of the 28-day or 4-week cycle.

[0259] In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered to a subject for three consecutive days during the first week of a 28-day or 4-week cycle, followed by a 4-day rest period, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycle. In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) is administered to a subject for three consecutive days during the first week of a 28-day or 4-week cycle, followed by a 4-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0260] In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered to a subject for four consecutive days during the first week of a 28-day or 4-week cycle, followed by a three-day rest period, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycle. In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered to a subject for four consecutive days during the first week of a 28-day or 4-week cycle, followed by a three-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0261] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) or orally. In one embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) is administered as an oral capsule. In another embodiment, an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of the free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or the sodium salt of compound 1) is administered as an oral tablet.

[0262] In one embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) once a day (QD). In another embodiment, the administration regimen for the cancer treatment method described in the paragraph comprises administering an effective amount of compound 1 (including the amorphous form and all partially crystalline or crystalline form of free acid compound 1 described herein) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of compound 1 including the amorphous form and all partially crystalline or crystalline Tris salt form of compound 1 disclosed herein, or a sodium salt of compound 1) twice a day (BID).

[0263] In one embodiment, the cancer treated in the method described in the two paragraphs above is selected from the list of solid tumors and hematological cancers provided herein. In one embodiment, the cancer is non-Hodgkin lymphoma or Hodgkin lymphoma. In one specific embodiment, the subject being treated belongs to a subgroup of patients with non-Hodgkin lymphoma or Hodgkin lymphoma, wherein the non-Hodgkin lymphoma or Hodgkin lymphoma has progressed despite prior treatment and further effective (curative or life-prolonging) standard therapy is not possible. That is, the subject being treated belongs to a subgroup of resistant or refractory non-Hodgkin lymphoma or Hodgkin lymphoma. In one embodiment, the standard curative therapy is high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). In one embodiment, the subject's non-Hodgkin lymphoma or Hodgkin lymphoma relapsed after HD-ASCT. That is, the subject being treated belongs to a subgroup of relapsed non-Hodgkin lymphoma or Hodgkin lymphoma (e.g., HD-ASCT-relapsed). In another embodiment, the subject is not eligible for HD-ASCT. In another embodiment, the subject refused HD-ASCT.

[0264] In one embodiment, the lymphoma according to the present disclosure is

[0265] a) Mature B-cell neoplasm

[0266] b) Mature T- and NK-cell neoplasms

[0267] c) Hodgkin lymphoma

[0268] d) It is an immunodeficiency-associated lymphoproliferative disorder.

[0269] The present invention is illustrated by the following examples, which are not intended to be limited.

[0270] example

[0271] As illustrated in the following examples, crystalline and amorphous forms were prepared according to the following general procedure.

[0272] Example 1 - Abbreviation, Solution, Instrument, Synthesis of Compound 1

[0273] Typical abbreviations used are summarized below.

[0274] Table 1. Abbreviations

[0275]

[0276]

[0277] solution

[0278] FaSSGF / SGF (Fasting Artificial Gastric Acid)

[0279] Weigh 100 mg of sodium chloride into a 50-mL volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water to a volume close to the target volume and adjust the pH to 1.6. Weigh 3 mg of FaSSIF / FeSSIF / FaSSGF powder into a volumetric flask and sonicate until the powder is completely dissolved. Dilute to the target volume using purified water and mix well.

[0280] FaSSIF (Fasting Artificial Serum)

[0281] Weigh 0.170 g of monobasic sodium phosphate, 0.021 g of sodium hydroxide, and 0.31 g of sodium chloride into a 50-mL volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water to a volume close to the target volume and adjust the pH to 6.5. Weigh 110 mg of FaSSIF / FeSSIF / FaSSGF powder into the volumetric flask and sonicate until the powder is completely dissolved. Dilute to the target volume using purified water and mix well.

[0282] FeSSIF (postprandial artificial serous fluid)

[0283] Weigh 0.41 mL of glacial acetic acid, 0.202 g of sodium hydroxide, and 0.594 g of sodium chloride into a 50 mL volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Add sufficient purified water to a volume close to the target volume and adjust the pH to 5.0. Weigh 560 mg of FaSSIF / FeSSIF / FaSSGF powder into the volumetric flask and sonicate until the powder is completely dissolved. Dilute to the target volume using purified water and mix well.

[0284] XRPD

[0285] XRPD data panelical expert 3 (PANalytical X'Pert 3 ) It was collected using an X-ray powder diffractometer. The sample was spread in the middle of a zero-background Si holder. The XRPD parameters are listed in Table 2.

[0286] Table 2. Parameters for XRPD

[0287]

[0288] TGA and DSC

[0289] TGA data was collected using a TA Q500 / Q5000 TGA from TA Instruments, and DSC was performed using a TA Q200 / Q2000 DSC from TA Instruments. Detailed parameters are listed in Table 3.

[0290] Table 3. Parameters for TGA and DSC

[0291]

[0292] DVS

[0293] DVS was measured using the SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for the DVS test are listed in Table 4.

[0294] Table 4. Parameters for DVS

[0295]

[0296] HPLC

[0297] An Agilent 1260 HPLC equipped with a DAD detector was used, and detailed chromatographic conditions for solubility analysis are listed in Table 5.

[0298] Table 5. Chromatography conditions for solubility analysis

[0299]

[0300] solution 1 H NMR

[0301] solution 1 1H NMR was collected using DMSO-d6 on a Bruker 400M NMR spectrometer.

[0302] Synthesis of Compound 1

[0303] The synthesis of amorphous compound 1, i.e., amorphous free acid, was previously described in international patent application publication number WO 2014 / 128669 and U.S. patent number 9,630,932.

[0304] Further methods for synthesizing amorphous compound 1 are described in reaction schemes 1 and 2.

[0305] Reaction Equation 1

[0306]

[0307] Reaction Equation 2

[0308]

[0309] The tetrasubstituted aromatic compound S3 was synthesized starting from S1 according to previous precedents. Refer to International Patent Application Publication No. WO2012 / 142513 and the document [Chi-Linh et al., J. Agricultural & Food Chem. 2016, 64(18) 3533, supplementary info, page S7]. S3 was aminated to methylamine by nucleophilic aromatic substitution of the chloride group in the presence of an aqueous base and ethyl acetate to obtain S4. The nitro functional group in S4 was reduced using iron in the presence of an acid (e.g., acetic acid), carbon-phase platinum (in the presence or absence of vanadium), or carbon-phase palladium. In some cases, the use of carbon-phase palladium induces debromination. The intermediate diamine (S5) can be used directly in a subsequent step as shown in Reaction Scheme 1, or isolated as a salt (HCl or H2SO4) as shown in Reaction Scheme 2. S5 as a free base or salt is converted to bromotriazole S6 by reaction with sodium nitrite in aqueous hydrogen chloride.

[0310] In parallel, 2-methylboronic acid (S7) was coupled to 4-iodo-bromobenzene (S8) under Suzuki coupling conditions to obtain biphenyl S9. The bromide in S9 was replaced with a boronic acid functional group by low-temperature lithium-halogen exchange and reaction with tri-isopropylborate (S10).

[0311] A solution of bromotriazole (S6) and boronic acid (S10) in toluene was coupled (Suzuki coupling) under Pd-catalyzed conditions in the presence of aqueous potassium carbonate to obtain S11. The methyl ester of S11 was hydrolyzed into a carboxylic acid using aqueous sodium hydroxide in methanol to obtain the free acid form of compound 1.

[0312] Example 2 - Amorphous solid dispersion of Compound 1

[0313] Compound 1 and hypromellose acetate succinate-MG (hypromellose acetate succinate, MG grade, Shin-Etsu Chemical Co.) (HPMCAS) (50% / 50%, w / w) are weighed, dissolved in methanol, and spray-dried over a Buechi B-290 to prepare an amorphous solid dispersion of Compound 1 and hypromellose acetate succinate (HPMCAS). The spray-drying parameters include nitrogen as the drying gas, an inlet temperature of about 80°C to 95°C, an outlet temperature of about 37°C to 45°C, and a spray solution concentration of about 15% w / w / . The amorphous solid dispersion is further dried in a vacuum oven at 40°C for 12 to 18 hours and then screened. The amorphous solid dispersion can be packaged in a double polyethylene bag using a twist nylon tie, placed in a high-density polyethylene (HDPE) container containing a desiccant, and stored at 2-8°C until a subsequent processing step.

[0314] Example 3 - Polymorph and Salt Screening of Compound 1

[0315] Polymorph screening

[0316] A total of 74 polymorph screening experiments were performed using different solution crystallization and solid-state transition methods as listed in Table 6. The isolated solids were characterized using XRPD, TGA, and DSC (see Table 7), and the pattern comparison results in Figure 2 indicated that four different crystal forms were obtained.

[0317] Table 6. Summary of Polymorph Screening Experiments for Free Acid Compound 1

[0318]

[0319] Table 7. Summary of Solid-State Characterization of Free Acid Forms A / B / C / D

[0320]

[0321] *: For glass form type C, no change in solid form was observed with a 2.3% reduced weight loss upon heat treatment at 150°C. **: Exothermic peak, peak temperature.

[0322] Characterization of the identified crystalline form of free acid compound 1

[0323] Representative samples of each identified morphology (morphology A / B / C / D) were characterized using TGA and DSC. Heating experiments were also performed to investigate the relationships between the different morphologies.

[0324] Glassy acid form A

[0325] The XRPD pattern of free acid form A is shown in Fig. 2a, and the peak list is shown in Fig. 2b. The TGA / DSC curve in Fig. 3c showed a weight loss of 1.0% up to 200°C and a weak exothermic reaction at 212.1°C (peak temperature), followed by a rapid endothermic reaction at 326.8°C (start temperature). The heat treatment did not show any change in form for free acid form A after heating to 150°C and then cooling to ambient conditions. Form A converted to form B after heating to 220°C. Based on the low TGA weight loss and the results of the heating experiment, it was assumed that the free form type A is an anhydrous form.

[0326] Glassy acid form B

[0327] Free acid form B can be obtained by heating experiments and slurrying at room temperature / 50°C. Free acid form B was obtained by heating the starting material of free acid form A to 220°C and then cooling it to ambient conditions; the XRPD pattern is shown in Fig. 3a, the peak list is shown in Fig. 3b, and the TGA / DSC curve in Fig. 3c showed a weight loss of 2.9% up to 200°C and a single abrupt endothermic at 321.9°C (starting temperature). By combining the prepared method (conversion from anhydrous free acid form A) and the pure TGA / DSC curve, it was assumed that free acid form B is a hygroscopic anhydrous form.

[0328] Glassy acid form C

[0329] Free acid form C can be obtained by reverse solvent addition, evaporation, slow cooling, and slurrying. Free acid form C was obtained by slurrying starting material compound 1 in 1,4-dioxane at room temperature for ~2 days, the XRPD pattern is shown in Fig. 4a, and the corresponding peak list is provided in Fig. 4b. The TGA / DSC curve in Fig. 4c showed a weight loss of 3.6% up to 200°C and a single abrupt endothermic at 322.5°C (start temperature). Heat treatment did not show a change in form for free acid form C after heating to 150°C, and it converted to form B after heating to 300°C. Further TGA characterization was performed on the heated free acid form C, and a decrease in TGA weight loss (3.6% to 2.3% up to 200°C) was observed. Based on the results of TGA / DSC and heating experiments, it was assumed that the free acid form C is a hygroscopic anhydrous form.

[0330] Glassy acid form D

[0331] Free acid form D can be obtained by slurrying in a multisolvent system. Free acid form D was obtained by slurrying starting material compound 1 in EtOAc at room temperature for ~7 days, the XRPD pattern is shown in Fig. 5a, and the corresponding peak list is shown in Fig. 5b. The TGA / DSC curve in Fig. 5c showed a weight loss of 1.0% up to 200°C and a weak endothermic at 286.7°C (starting temperature), followed by a rapid endothermic at 327.4°C (starting temperature). The heat treatment indicated that free acid form D was converted to form B after heating to 305°C. Based on the low TGA weight loss and the results of the heating experiment, it was assumed that free acid form D is an anhydrous form.

[0332] Thermodynamic stability research

[0333] To investigate and compare the thermodynamic stability among the four identified crystalline forms (free acid forms A / B / C / D) of Compound 1, a two-stage slurry competition experiment was performed, the first stage of which was to study anhydrous solvent systems, and the second stage was to study different water activities (a w It was a solvent system having ).

[0334] In the first step, ~2 mg of each solid form (free acid forms A / B / C / D) was first physically mixed, and then 0.5 mL of solvent was added to form a suspension. Under various slurrying conditions, a small amount of solid was isolated after ~7 days for XRPD testing. According to XRPD characterization, free acid forms A / B / C converted to form D after slurrying at room temperature, 50°C, and 70°C, indicating that form D is thermodynamically more stable than forms A / B / C from room temperature to 70°C.

[0335] To further investigate the arbitrary effect of water content on the conversion relationship, six conditions with different water activities and temperatures were applied. Approximately 2 mg of each solid form (free acid forms A / B / C / D) were mixed and suspended in 1.0 mL of the corresponding solvent system. After slurrying for ~1 month, the solids were isolated for XRPD testing. XRPD characterization revealed that free acid forms A / B / C converted to form D after slurrying at room temperature, 50°C, and 70°C, indicating that form D has different water activities (a w : Indicates that it is more stable than form A / B / C in solvent mixtures having 0~1).

[0336] Salt screening

[0337] Solvent-mediated reaction crystallization was applied to salt screening. A total of 55 salt screening experiments involving 10 counterions and 5 different solvents, as well as 5 blank experiments, were performed. The specific experimental procedures are described below:

[0338] 1. Weigh ~15 mg and molar equivalents of glass form type A counter-ions into respective HPLC vials;

[0339] 2. Add 0.5 to 1.0 mL of a corresponding solvent to form a suspension or solution;

[0340] 3. Magnetically stir the mixture at room temperature (25±3℃) for ~2 days (~1000 rpm);

[0341] 4. The residual solid is isolated by centrifugation (10,000 rpm, 2 min);

[0342] 5. The solid was dried at 50°C for ~2 hours and then characterized by XRPD.

[0343] As summarized in Table 8, 12 potential salt hits were identified, including 5 Na salt hits (Types A–E), 3 Ca salt hits (Types A–C), 1 Mg salt hit (Type A), 2 Tris salt hits (Types A and B), and 1 betaine salt hit (Type A) (highlighted in bold in Table 8). The solid-state characteristics of the identified salt hits are described in Table 9.

[0344] Table 8. Summary of salt screening results for Compound 1

[0345]

[0346] *: After slurrying at room temperature or 5°C, transfer to room temperature and evaporate to isolate any solid, and then obtain a clear solution.

[0347] Table 9. Summary of Characterization of Different Potential Salt Hits

[0348]

[0349] 1 This Tris salt form A was prepared as a ~15 mg batch during salt screening using the procedure described above. 2 This Tris salt form A was remanufactured as a ~200.7 mg batch.

[0350] *: Onset temperature. **: Na salt type A was obtained by humidity-induced conversion of amorphous Na salt. N / A: Since a weak degree of crystallization was observed for the isolated solid, no further characterization was performed.

[0351] Example 4 - Polymorph screening and characterization of Tris salt forms A, Tris salt forms B, and Tris salt forms C of Compound 1

[0352] Polymorph screening

[0353] As listed in Table 10, a total of 107 polymorph screening experiments were performed using 11 solution crystallization or solid-state transition methods, utilizing the Tris salt form of Compound 1 and the free acid form of Compound 1. Solids for XRPD characterization were isolated from a total of 105 experiments. No new forms for the free acid were obtained other than the crystalline free acid forms A / B / C / D identified in Example 3. In addition to the crystalline Tris salt forms A / B identified in Example 3, a new crystalline form C for the Tris salt was obtained. The isolated solids were characterized using XRPD, TGA, and DSC (see Table 9), and the pattern comparison results in Figure 6 indicated that three different crystalline forms were obtained.

[0354] Table 10. Summary of Polymorph Screening Experiments for Free Acid Compound 1 and Tris Salt of Compound 1

[0355]

[0356]

[0357] Characterization of the identified crystalline form of Tris salt compound 1

[0358] Representative samples of each identified morphology (morphology A / B / C) were characterized using XRPD, TGA, and DSC. Heating experiments were also performed to investigate the relationships between the different morphologies.

[0359] Tris salt form A

[0360] Tris salt form A was obtained by slurrying free acid form A with Tris in acetone at room temperature for ~2 days. The XRPD pattern is shown in Fig. 7a, and the list of corresponding peaks is shown in Fig. 7b. The TGA / DSC curve in Fig. 7c showed a weight loss of 2.8% up to 150°C and a sharp endothermic reaction at 198.6°C (start temperature). Fig. 7d 1Based on the H NMR results, the stoichiometry of Tris salt form A was determined to be 1.0:1.1 (free acid / Tris).

[0361] Tris salt form B

[0362] Tris salt form B was obtained by slurrying free acid form A with Tris in EtOH at room temperature for ~2 days. The XRPD pattern is shown in Fig. 8a, and the corresponding peak list is shown in Fig. 8b. The TGA / DSC curve in Fig. 8c showed a two-step weight loss of 10.8% up to 190°C and a rapid endothermic reaction at 201.4°C (start temperature) following an overlapping endothermic / exothermic reaction at 125.3°C (start temperature). Tris salt form B was converted to Tris salt form A after being heated to 150°C and subsequently cooled to ambient conditions. Fig. 8d 1 Based on the H NMR results, the stoichiometry of Tris salt type B was determined to be 1.0:1.0 (free acid / Tris).

[0363] Tris salt form C

[0364] Tris salt form C was obtained by slurrying the free acid form of Compound 1 with Tris in DMSO at room temperature for ~2 days. The resulting slurry was heated to 100°C and stirred for 30 minutes, after which the reaction product became a clear solution. Subsequently, the reaction solution was cooled to room temperature, and no solid was formed at room temperature. Then, 320 mL of EtOH was slowly added to the reaction solution and stirred at room temperature for 30 minutes. This step was repeated. After the second addition of EtOH and stirring, a solid was formed. The reaction mixture containing the formed solid was stirred overnight at 20-25°C and then filtered. The filtrate cake was washed with 2 x 320 mL of EtOH and dried under vacuum at 50°C to obtain a white solid. Subsequently, 150 mL of EtOH was added to the white solid, and the slurry was mechanically stirred at 65°C for 4 hours. The reaction solution was allowed to cool to room temperature for about 1 hour, stirred at room temperature for 3 hours, and then filtered. The filtrate cake was washed with 2 x 32 mL of EtOH and dried under vacuum at 50°C for 20 hours to obtain 29.8 g of grayish-white or white powder. Subsequently, 150 mL of EtOH was added to the white solid, and the slurry was mechanically stirred at 65°C for 4 hours. As an additional final purification step, the obtained grayish-white / white powder was redissolved in DMSO (45 mL) at 100°C for 15 minutes. Subsequently, the solution was cooled to 45°C, and then EtOH (500 mL) was added dropwise. After adding 150 mL of EtOH, the reaction mixture began to become turbid. The resulting slurry was stirred at 25–30°C for 20 hours and then filtered. The filtrate cake was washed with 2 x 100 mL EtOH. The resulting Tris salt was softened in 20 volumes of EtOH at 70°C for 5 hours, then cooled to 25-30°C over 2 hours, and stirred at the same temperature for 3 hours.After repeating this procedure three times, 28 g of Tris salt form C was obtained as a grayish-white solid. The XRPD pattern of Tris salt form C is shown in Fig. 9a, and the corresponding peak list is shown in Fig. 9b. The TGA / DSC curve in Fig. 9c showed a weight loss of 1.2% up to 150°C, a rapid endothermic reaction at 193.1°C (onset temperature), and a peak at 196.9°C. The stoichiometry is. 1 It was confirmed to be 1.00:1.02 (free acid / tris) by ¹H NMR (data not presented).

[0365] Additional procedures that can be used to obtain Tris salt form C are described below. 4 grams of the free acid form of Compound 1 were slurried at room temperature using 1.5 g of Tris in 10 mL of DMSO. The reaction solution was cooled to approximately 30°C, and 20 mL of EtOH was added. 10 mg of Tris salt form A was added and stirred for 5 minutes to form a turbid solution. The mixture was stirred for 2 hours and diluted with 60 mL of EtOH to form a slurry. The slurry was stirred overnight at 28-32°C. The solid was collected by filtration, washed with 2 x 20 mL of EtOH, and dried to obtain Tris salt form C as a grayish-white solid.

[0366] The free acid form of Compound 1 and 1.05 equivalents of Tris were mixed in a flask in 2.5 volumes of DMSO. The mixture was heated to ~100°C and stirred for 0.5 to 1 hour to form a clear solution. The solution was cooled to 60-70°C and slowly diluted with an additional volume of EtOH (which may be in the range of 5-15 volumes). Seeds of Tris salt form C were added, followed by slowly adding an additional volume of EtOH (which may be in the range of 5-15 volumes) over 2 hours. The mixture was stirred at 60-70°C for 16-24 hours and cooled to 20-30°C. The mixture was stirred at 20-30°C for 2-4 hours. The solid was collected by filtration, washed with EtOH, and dried under vacuum at 40-50°C for 8-12 hours to obtain Tris salt form C as a grayish-white solid.

[0367] Example 5 - Thermodynamic stability study comparing Tris salt form A and Tris salt form C

[0368] The thermodynamic stability relationship between Tris salt forms A and C was investigated through slurry competition experiments under four temperature conditions (5°C / room temperature / 50°C / 75°C) using two process-related solvent systems: DMSO / EtOH (1:8, v / v) and EtOH. Two stages of slurry competition experiments were performed, the first stage including temperature as a variable, and the second stage using newly opened reagents to minimize the effect of absorbed moisture. Typical experimental procedures are described below.

[0369] Approximately 5-10 mg of crystalline Tris salt form C was first dissolved in ~1.0 mL of the corresponding solvent to form a nearly saturated solution at the corresponding temperature (equilibration method: magnetic stirring, ~1000 rpm, ~2 hours). Subsequently, ~15 mg of each form (crystalline Tris salt forms A and C) were physically mixed, and then the nearly saturated solution was added to form a suspension. The suspension was then stirred at the corresponding temperature for 7 days (~1000 rpm) (a small amount of solid was sampled at the 2nd day of the second stage experiment). The obtained solid was isolated by centrifugation (10000 rpm, 2 min) and the form was confirmed by XRPD.

[0370] Tris salt form A was shown to be converted to Tris salt form C, which indicates that Tris salt form C is thermodynamically more stable at 5°C to 50°C.

[0371] Example 6 - Dynamic Solubility Study Comparing Free Acid Form D, Tris Salt Form A, and Tris Salt Form C

[0372] The kinetic solubility of Tris salt form A and free acid form D was measured at 37°C in three bio-related media (SGF, FaSSIF, and FeSSIF). Specifically, ~30 mg of solid was initially suspended in 4.0 mL of each medium and equilibrated by shaking (500 rpm) at 37°C. Approximately 0.8 mL of the suspension was extracted at 15 / 30 / 60 / 120 minutes and 24 hours, respectively. The supernatant and precipitate were separated by centrifugation (10,000 rpm, 3 min) followed by concentration (HPLC), the pH of the supernatant was measured, and the corresponding solid form was characterized by XRPD.

[0373] As indicated by the data summarized in Table 11, the solubility of free acid form D was measured to be 3–8 μg / mL in FaSSIF and FeSSIF, and < 1 μg / mL in SGF. Compared to free acid form D, enhanced solubility for Tris salt form A was observed in all SGF / FaSSIF / FeSSIF media during equilibration (> 100 μg / mL at 24 hours). Meanwhile, pH changes were observed in all three media, particularly in SGF (pH: 1.8), where it changed to 7.4 (at 24 hours), which may have caused the enhancement in solubility because this free form exhibited acidity in the aqueous phase.

[0374] Table 11. Summary of kinetic solubility data for free acid form D and Tris salt form A in SGF / FaSSIF / FeSSIF

[0375]

[0376] Due to the thermodynamic stability of Tris salt form C, further evaluations were performed, including kinetic solubility in three bio-related media (FaSSGF / FaSSIF / FeSSIF) and H2O at 37°C. The solubility of Tris salt form C was also found to be significantly higher than that of the free acid form in artificial serous media (FaSSIF and FeSSIF) reflecting both fasting and feeding conditions, and similar to that of Tris salt form A, with a gradual decrease in API concentration values ​​detected in FaSSIF / FeSSIF / H2O (FaSSIF: from 0.39 mg / mL to 0.17 mg / mL; FeSSIF: from 0.33 mg / mL to 0.04 mg / mL; H2O: from 0.81 mg / mL to 0.40 mg / mL).

[0377] Table 12. Summary of kinetic solubility data for Tris salt form C in SGF / FaSSIF / FeSSIF

[0378]

[0379] *: Precipitation occurred during the HPLC / pH test (samples for the HPLC test were diluted to be clear).

[0380] Example 7 - Hygroscopicity Study Comparing Free Acid Form D, Tris Salt Form A, and Tris Salt Form C

[0381] To evaluate the hygroscopicity of the free acid form D, Tris salt form A, and Tris salt form C of Compound 1, dynamic vapor adsorption (DVS) data for each sample were collected at 25°C. At 25°C, when humidity varied from 0% RH to 80% RH, ~5 wt% moisture absorption was observed for both the free form type D and the Tris salt form A. The Tris salt form C was less hygroscopic, with only ~0.04 wt% moisture absorption observed within the same humidity range. The solid form remained as the Tris salt form C after the DVS test, as confirmed by XRPD (data not shown).

[0382] Example 8 - Pharmacokinetic Study Comparing Free Acid and Tris Salt

[0383] The purpose of the pharmacokinetic (PK) study was to determine the pharmacokinetics of different forms of Compound 1 after oral (PO) administration in uninjured Sprague Dawley rats. Briefly, free acid of Compound 1 from several lots with different particle size distributions from different manufacturing batches (crystallization was not tested), and the tris salt of Compound 1 (crystallization was not tested) were formulated with 0.5% (w / v) methylcellulose and 0.2% (v / v) Tween 80 in water at a concentration of 100 mg / mL. Food and water were freely available to all animals, and Compound 1 or the tris salt of Compound 1 was administered orally at a dose of 100 mg / kg (100 mL / kg). Approximately 110 μL of whole blood was collected via tail vein hemorrhage into tubes containing the anticoagulant K2EDTA at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours before and after administration, processed to obtain plasma, and stored at approximately -70°C until analysis. The concentrations of the active pharmaceutical component in the plasma samples were quantified using an unverified, high-performance liquid chromatography (LC-MS / MS) method accompanied by tandem mass spectrometry. Pharmacokinetic analysis of individual plasma concentration data was performed using WinNonlin® (Version 6.4; Pharsight Corporation, Mountain View, California, USA). Pharmacokinetic parameters were estimated using a non-compartmental extravascular model method. The area under the concentration-time curve (AUC) was calculated using the linear trapezoidal rule. For the calculation of PK parameters, concentrations of AG-636 below the limit of quantification (BLQ) at the end stage were excluded. Concentrations <80% of the LLOQ were designated as BLQ.

[0384] The results from PK experiments using SD male rats are summarized in Table 13 below, and the PK profiles for both the Tris salt and free base of Compound 1 are shown in Figures 10a-10b. Among the free acid forms evaluated, Lot A and Lot B achieved some of the highest exposures, as can be seen in Figure 10a. However, Lot A and Lot B were initial batches of the free acid of Compound 1 that were only partially crystalline and were characterized by the presence of a larger amount of residual organic solvent; therefore, they were not suitable for use in formulation development. Furthermore, Lot A and Lot B were produced by a process not considered suitable for large-scale synthesis.

[0385] Therefore, to identify a final form that would provide exposure similar to Lots A and B, a new glassy form of Compound 1 with superior crystallinity and acceptable levels of residual solvent was synthesized using an improved method. This new glassy form of Compound 1 was also synthesized as Lots C, Lot D, and Lot E with different particle size distributions, as summarized in Table 13, to evaluate the effect of particle size reduction on glassy form exposure in the PK study. Unfortunately, despite enhanced crystallinity and purity, none of Lots C, Lot D, and Lot E exhibited exposure equivalent to that previously observed (see Fig. 10b).

[0386] Referring to Table 13 for a summary, T of the Tris salt of Compound 1 represents the time at which the maximum API concentration occurs and the maximum API concentration itself, respectively. max and C max is clearly superior to the corresponding parameter observed in the free acid. Specifically, low values ​​of T max and higher value C maxAs indicated by [Figure], faster absorption of higher maximum API concentrations for Tris salt could be observed compared to all batches of free acid. Significantly, even when comparing Tris salt to the best free acid batch of Lot B, T max is ~2 times lower, and C max It is approximately 1.5 times higher. Based on in vivo PK data, the in vitro solubility and / or dissolution rate of Tris salt is expected to be significantly higher.

[0387] Table 13. PK parameters of free acid and Tris salt of Compound 1

[0388]

[0389] Example 9 - Capsule composition

[0390] 10 mg dose strength capsules (glass-form equivalents) can be manufactured using a dry granulation method and a direct encapsulation method as described in Table A.

[0391] Table A: Batch formulation composition

[0392]

[0393] 50, 100, and 125 mg dose strength capsules (glass-form equivalents) can be manufactured using a dry granulation method and a direct encapsulation method as described in Table B.

[0394] Table B: Batch formulation composition

[0395]

[0396] 100 and 125 mg dose strength capsules (glass-form equivalents) can be manufactured as described in Tables C and D using the dry granulation and direct encapsulation methods described below.

[0397] Table C: Batch formulation composition

[0398]

[0399] Table D: Batch formulation composition

[0400]

[0401] The Tris salt of Compound 1 and the excipients listed in Tables C and D were weighed, sieved, and blended. The Tris salt of Compound 1 and the granule components (diluent(s), disintegrant, binder, surfactant, lubricant, and lubricant) were mixed in a suitable blender. The granule blend was roller-pressed (Capsules E, F, H, I, J, M, and N), and the pressed material was resized to produce granules. For Capsules K and L, the granule blend was granulated, and the granulated blend was resized.

[0402] The non-granular components (lubricants and lubricants) were weighed, sieved, and blended. The non-granular components and crushed granules were screened, added to a suitable blender, and blended.

[0403] Next, the blended material was encapsulated into size 1 capsules by manually filling the capsules. The capsules were stored under ambient conditions (15-25℃).

[0404] Although numerous embodiments have been described, the scope of this disclosure is defined by the appended claims and not by the specific embodiments shown as examples. The contents of all references cited throughout this application (including references, granted patents, published patent applications, and pending patent applications) are hereby expressed by reference in their entirety. Unless otherwise defined, all technical and technological terms used herein are consistent with their meanings as commonly known to a person skilled in the art.

Claims

Claim 1 Tris(hydroxymethyl)aminomethane salt of the compound represented by the chemical formula of Compound 1 below: . Claim 2 In paragraph 1, an anhydrous tris(hydroxymethyl)aminomethane salt. Claim 3 In claim 2, tris(hydroxymethyl)aminomethane salt of crystalline form A characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.4°, 15.6°, and 18.9°. Claim 4 Tris(hydroxymethyl)aminomethane salt according to claim 3, wherein the crystalline form A is further characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 11.5°, 16.4°, 19.6°, and 25.5°. Claim 5 Tris(hydroxymethyl)aminomethane salt according to claim 3, wherein the crystalline form A further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 8.7°, 15.2°, 18.6°, 21.4°, and 25.1°. Claim 6 In claim 2, a tris(hydroxymethyl)aminomethane salt having crystalline form C characterized by X-ray powder diffraction peaks at 2θ angles (± 0.2°) of 4.5°, 13.5°, and 18.0°. Claim 7 Tris(hydroxymethyl)aminomethane salt according to claim 6, wherein the crystalline form C further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 14.3°, 18.3°, and 23.5°. Claim 8 The tris(hydroxymethyl)aminomethane salt of claim 7, wherein the crystalline form C further features at least one X-ray powder diffraction peak at a 2θ angle (± 0.2°) selected from 16.3°, 19.0°, 21.2°, 22.5° and 22.8°. Claim 9 A pharmaceutical composition for treating cancer comprising a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is optionally combined with additional therapeutic agents, and optionally (i) cancer is lung cancer, breast cancer, triple-negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, head and neck cancer, skin cancer, cutaneous or intraocular malignant endometrium, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumor, renal cancer or ureteral cancer, renal pelvis carcinoma, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal cord tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, environmentally induced Cancer, and PTEN mutant cancer; and selected from biliary tract cancer or ampullary carcinoma, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, ovarian cancer, and upper respiratory and gastrointestinal cancer; or (ii) cancer is acute myeloid leukemia, multiple myeloma, B-pro-lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's disease lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma, bladder cancer, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, primary exudative lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double-hit diffuse large B-cell lymphoma, and triple-hit diffuse large B-cell lymphoma;A pharmaceutical composition comprising a hematological cancer selected from angioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastocystic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal-to-B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenström macroglobulinemia, essential thrombocytopenia, chronic idiopathic myelofibrosis, and polycythemia vera.; Claim 10 A pharmaceutical composition comprising a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients for treating (i) cancer responsive to inhibition of dihydroorotate dehydrogenase; or (ii) a condition or disease selected from virus-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases or inflammatory disorders. Claim 11 A pharmaceutical composition comprising a tris(hydroxymethyl)aminomethane salt according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients for inhibiting the growth and / or metastasis of tumor cells responsive to the inhibition of dihydroorotate dehydrogenase. 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