Preparations of 19-nor-C3,3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Abstract

To provide a formulation of 19-nor C3,3-disubstituted C21-N-pyrazolyl steroid and a method for using the same. [Solution] The present invention relates to a 19-nor-C3,3-disubstituted C21-pyrazolylsteroid of formula (I) and a pharmaceutical composition thereof. The Specified also discloses a method for producing a pharmaceutical composition of a 19-nor-C3,3-disubstituted C21-pyrazolylsteroid of formula (I), as well as a method for using the 19-nor-C3,3-disubstituted C21-pyrazolylsteroid of formula (I) or in crystalline solid form, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable composition thereof.

Description

[Background technology]

[0001] Brain excitability is defined as the level of arousal in animals, spanning a continuum from coma to seizure, and is regulated by various neurotransmitters. Generally, neurotransmitters play a role in regulating the conductance of ions across the nerve membrane. The nerve cell membrane has a potential (i.e., membrane voltage) of approximately -70 mV at rest, and the inside of the cell is negative relative to the outside. The potential (voltage) is a result of the balance of ions (K+, Na+, Cl-, organic anions) across the semipermeable membrane of the nerve cell. Neurotransmitters are stored in presynaptic vesicles and released under the influence of the nerve cell's action potential. Upon release into the synaptic cleft, excitatory chemotransmitters (e.g., acetylcholine) cause membrane depolarization (a potential change occurs from -70 mV to -50 mV). This action is mediated by postsynaptic nicotinic receptors, which, when stimulated by acetylcholine, increase membrane permeability to Na+ ions. The reduced membrane potential stimulates nerve cell excitability in the form of a postsynaptic action potential.

[0002] In the case of GABA receptor complexes (GRCs), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Since up to 40% of nerve cells in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual nerve cells by modulating the conductance of chloride ions across the nerve membrane. GABA interacts with recognition sites on GRCs to facilitate the flow of chloride ions down the electrochemical gradient of GRCs into the cell. An increase in the intracellular level of this anion leads to hyperpolarization of the transmembrane potential, reducing the nerve cell's sensitivity to excitatory input (i.e., decreasing nerve cell excitability). In other words, higher intracellular chloride ion concentrations result in lower levels of brain excitability and arousal.

[0003] GRCs have been shown to mediate anxiety, seizure activity, and sedation. Therefore, GABA, or drugs that act like GABA or enhance the action of GABA (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs), e.g., Valium®), exert therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Current evidence indicates that GRCs contain not only binding sites for benzodiazepines and barbiturates, but also intrinsic sites for neuroactive steroids. See, for example, Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0004] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnane-20-one and 3α-21-dihydroxy-5-reduced pregnane-20-one, which are metabolites of hormonal steroids such as progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986), Harrison, N Let al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0005] The neuroactive steroid compounds of formula (I) described herein are synaptic and extrasynaptic GABA. A GABA that targets receptors A Compound 1 was shown to be a positive allosteric modulator of the receptor. Compound 1 is GABA A As a positive allosteric modulator of receptors, it functions as a therapeutic agent for central nervous system disorders, such as depression (e.g., postpartum depression and major depressive disorder) and anxiety disorders.

[0006] There is a need for neuroactive steroids, particularly 19-NOR C3,3-disubstituted C21-N-pyrazolyl steroids, that exhibit desirable physicochemical properties (e.g., pleomorphism, melting point, solubility), are easy to manufacture, and have a bioavailability profile that provides sufficient drug exposure to treat diseases.

[0007] Thus, the development and manufacture of pharmaceutical formulations possessing the bioavailability, chemical stability, physical stability, and material properties necessary for the production of safe and effective oral formulations for treating brain and / or central nervous system-related diseases and disorders remains a significant challenge. Therefore, there remains an unmet need to develop pharmaceutical compositions containing neuroactive steroids and methods for manufacturing such compositions to have the efficacy and safety profiles required by regulatory authorities for the production of commercially viable formulations. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-Patent Document 2] Majewska, MDet al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison,NLet al.,J.Pharmacol.Exp.Ther.241:346-353(1987) [Overview of the project] [Means for solving the problem]

[0009] In one embodiment, this specification provides pharmaceutical compositions of compounds of formula (I). [ka]

[0010] In various embodiments, as used herein, a pharmaceutical composition comprising a plurality of particles of a crystalline form of a compound of formula (I),

Chemical formula

[0011] In various embodiments, as used herein, a pharmaceutical composition comprising a crystalline form of a compound of formula (I),

Chemical formula

[0012] In various embodiments, herein is provided a pharmaceutical composition comprising (i) a crystalline form of a compound of formula (I), and [Chemical formula] (ii) a filler, (iii) a lubricant, and (iv) a glidant.

[0013] In various embodiments, herein is provided a pharmaceutical composition comprising (i) from about 0.4% (w / w) to about 60% (w / w) of a crystalline form of a compound of formula (I), and [Chemical formula] (ii) from about 0% (w / w) to about 90% (w / w) of a brittle filler, (iii) from about 0% (w / w) to about 90% (w / w) of a ductile filler, (iv) from about 0% (w / w) to about 15% (w / w) of a disintegrant, (v) from about 0.1% (w / w) to about 5% (w / w) of a lubricant, and (vi) from about 0.1% (w / w) to about 5% (w / w) of a glidant.

[0014] In various embodiments, herein is provided a pharmaceutical composition comprising (i) from about 0.4% (w / w) to about 36% (w / w) of a crystalline form of a compound of formula (I), and [Chemical formula] (ii) from about 15% (w / w) to about 75% (w / w) of a brittle filler, (iii) Approximately 10% (w / w) to approximately 60% (w / w) of ductile filler, (iv) Approximately 3% (w / w) to approximately 12% (w / w) of disintegrant, (v) Approximately 0.25% (w / w) to approximately 5% (w / w) of a fluidizing agent, (vi) A pharmaceutical composition is provided which contains approximately 0.5% (w / w) to approximately 3% (w / w) of a lubricant.

[0015] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of the compound of formula (I) at approximately 10% (w / w) to approximately 15% (w / w), [ka] (ii) A brittle filler of approximately 60% (w / w) to approximately 70% (w / w), (iii) Approximately 10% (w / w) to approximately 20% (w / w) of ductile filler, (iv) Approximately 4% (w / w) to approximately 8% (w / w) of disintegrant, (v) Approximately 0.5% (w / w) to approximately 2% (w / w) of a fluidizing agent, (vi) A pharmaceutical composition is provided which contains approximately 1% (w / w) to approximately 2% (w / w) of a lubricant.

[0016] In various embodiments, this specification provides for a pharmaceutical composition comprising (i) about 20 mg of a compound of formula (I) in crystalline form, [ka] (ii) Approximately 105.9 mg of mannitol and (iii) Approximately 26.2 mg of silicified microcrystalline cellulose, (iv) Approximately 10 mg of croscarmellose sodium, (v) Approximately 1.7 mg of colloidal silicon dioxide, (vi) A pharmaceutical composition is provided which contains approximately 2.9 mg of sodium stearyl fumarate.

[0017] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of approximately 25 mg of the compound of formula (I), [ka] (ii) Approximately 132 mg of mannitol and (vii) Approximately 32.7 mg of silicified microcrystalline cellulose, (viii) Approximately 12.5 mg of croscarmellose sodium, (ix) Approximately 2.1 mg of colloidal silicon dioxide, (x) A pharmaceutical composition is provided comprising approximately 3.6 mg of sodium stearyl fumarate.

[0018] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of approximately 30 mg of the compound of formula (I), [ka] (ii) Approximately 159 mg of mannitol and (iii) Approximately 39.3 mg of silicified microcrystalline cellulose, (iv) Approximately 15 mg of croscarmellose sodium, (v) Approximately 2.5 mg of colloidal silicon dioxide, (vi) A pharmaceutical composition is provided which contains approximately 4.4 mg of sodium stearyl fumarate.

[0019] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of approximately 40 mg of the compound of formula (I), [ka] (ii) Approximately 212 mg of mannitol and (vii) Approximately 52.4 mg of silicified microcrystalline cellulose, (viii) Approximately 20 mg of croscarmellose sodium, (ix) Approximately 3.3 mg of colloidal silicon dioxide, (x) A pharmaceutical composition is provided comprising approximately 5.8 mg of sodium stearyl fumarate.

[0020] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of approximately 50 mg of the compound of formula (I), [ka] (ii) Approximately 265 mg of mannitol and (iii) Approximately 65.5 mg of silicified microcrystalline cellulose, (iv) Approximately 25 mg of croscarmellose sodium, (v) Approximately 4.2 mg of colloidal silicon dioxide, (vi) A pharmaceutical composition is provided which contains approximately 7.3 mg of stearyl sodium fumarate.

[0021] In various embodiments, this specification provides for a pharmaceutical composition comprising (i) about 60 mg of a compound of formula (I) in crystalline form, [ka] (ii) Approximately 317.7 mg of mannitol and (iii) Approximately 78.6 mg of silicified microcrystalline cellulose, (iv) Approximately 30 mg of croscarmellose sodium, (v) Approximately 5 mg of colloidal silicon dioxide, (vi) A pharmaceutical composition is provided which contains approximately 8.8 mg of sodium stearyl fumarate.

[0022] In various embodiments, this specification provides for a pharmaceutical composition comprising a plurality of particles in crystalline form of the compound of formula (I), [ka] Multiple particles of the crystalline form of the compound of formula (I) A pharmaceutical composition is provided having a particle size distribution defined by D90 ranging from approximately 1 μm to approximately 100 μm.

[0023] In various embodiments, this specification describes a pharmaceutical composition, (i) Multiple particles of the crystalline form of the compound of formula (I), [ka] (ii) Filler and (vii) A pharmaceutical composition is provided comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, wherein the plurality of particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 of about 1 μm to about 20 μm.

[0024] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (vii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, The provided pharmaceutical composition has a bulk density of approximately 0.2 g / cc to approximately 0.8 g / cc and a tap density of approximately 0.3 g / cc to approximately 1.1 g / cc, wherein the tap density of the pharmaceutical composition is higher than the bulk density.

[0025] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, The provided pharmaceutical composition has an average flow index (FRI) of approximately 0.05 to approximately 3.1 kg / second.

[0026] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, When the pharmaceutical composition is tested using a USP1 or USP2 apparatus, A pharmaceutical composition is provided which releases at least about 50% of the compound of formula (I) after about 20 minutes.

[0027] In various embodiments, this specification describes a pharmaceutical composition, (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, A pharmaceutical composition is provided which exhibits the following solubility profile: When tested in a USP2 instrument at approximately 37°C in approximately 500 mL to 900 mL of 50 mM sodium phosphate buffer with pH 6.8 and approximately 0.2% to 0.6% SDS, at least approximately 70% of the compound of formula (I) was released after approximately 20 minutes. At least about 80% of the compound of formula (I) is released after about 30 minutes.

[0028] In another embodiment, the Specified Provision provides a dosage form intended for oral administration, comprising a pharmaceutical composition described herein.

[0029] In another embodiment, this specification provides a method for producing the pharmaceutical compositions described herein.

[0030] In various embodiments, this specification describes a process for preparing a pharmaceutical composition, (a) In order to obtain a micronized crystalline form of the compound of formula (I), the crystalline form of the compound of formula (I) is micronized, [ka] The microparticle crystal form of the compound of formula (I) is The process involves creating fine particles with a particle size distribution defined by D90 ranging from approximately 1 μm to approximately 100 μm. (b) To obtain a blend, blend the particulate crystalline form of the compound of formula (I) with one or more pharmaceutically acceptable excipients, (c) To obtain granules, the blend is granulated, (d) In order to obtain the granular internal phase, the granules are crushed, (e) A process is provided which involves blending a granular internal phase with one or more extragranular pharmaceutical excipients in order to obtain a pharmaceutical composition.

[0031] In another embodiment, the Specified Provisions provide a pharmaceutical composition comprising a compound of formula (I) useful for the treatment of various conditions, diseases, and disorders described herein. In various embodiments, the condition, disease, or disorder is insomnia. In various embodiments, the condition, disease, or disorder is major depressive disorder. In various embodiments, the condition, disease, or disorder is bipolar disorder. In various embodiments, the condition, disease, or disorder is insomnia. In various embodiments, the condition, disease, or disorder is postpartum depression. In various embodiments, the condition, disease, or disorder is anxiety. In various embodiments, the condition, disease, or disorder is treatment-resistant depression. [Brief explanation of the drawing]

[0032] [Figure 1A] This is an exemplary X-ray powder diffraction pattern of crystalline form A of compound 1. [Figure 1B] Exemplary thermogravimetric (top) and differential scanning calorimetry (bottom) curves for crystalline form A of compound 1 are shown. [Figure 2A] This is an exemplary X-ray powder diffraction pattern of crystalline form C of compound 1. [Figure 2B] Exemplary thermogravimetric (top) and differential scanning calorimetry (bottom) curves for crystalline form C of compound 1 are shown. [Figure 3] This shows a jet mill filled with particles of crystalline form A of compound 1. [Figure 4A] This is an exemplary particle size distribution in the particles of compound 1 in crystalline form C. [Figure 4B] This is an exemplary particle size distribution in the particles of compound 1 in crystalline form C. [Figure 4C] This is an exemplary particle size distribution in the particles of compound 1 in crystalline form C. [Figure 5] This is an exemplary particle size distribution in particles of compound 1 in crystalline form A. [Figure 6]This image shows the superimposed pharmacokinetic profiles of non-particulate particles of compound 1 in crystalline form C and particulate particles of compound 1 in crystalline form C, administered orally to male Sprague-Dawley rats. [Figure 7] This is an exemplary flowchart of the present invention for preparing the capsules described herein using a direct blending process. [Figure 8] As described in Example 21, the pharmacokinetic profiles of three direct-blend, manually filled 5 mg capsule formulations administered orally to dogs were superimposed. [Figure 9] This is an exemplary flowchart of the present invention for preparing the capsules described herein using a dry granulation process. [Figure 10] As further described in Example 33, this is a superimposed collection of dissolution data collected for exemplary manually filled capsules (30 mg dose strength) containing various amounts of crystalline form A to crystalline form C of compound 1. [Figure 11] As further described in Example 34, this is a superimposed collection of dissolution data collected for exemplary manually filled capsules containing 30 mg of compound 1 in crystalline form C, each with a different particle size distribution. [Figure 12A] This is an exemplary DSC thermogram of compound 1a in particulate form C. [Figure 12B] This is an exemplary DSC thermogram of compound 1b in particulate form C. [Figure 12C] This is an exemplary DSC thermogram of compound 1c in particulate form C. [Figure 12D] This is an exemplary DSC thermogram of compound 1d in particulate form C. [Figure 13] This is an exemplary particle size distribution in the micronized crystalline form C of compound 1a. [Figure 14A] This is an exemplary particle size distribution in the micronized crystalline form C of compound 1b. [Figure 14B] This is an exemplary particle size distribution in the non-micronized crystalline form C of compound 1b. [Figure 15A] This is an exemplary particle size distribution in the microparticle crystalline form C of compound 1c. [Figure 15B] This is an exemplary particle size distribution in the non-micronized crystalline form C of compound 1c. [Figure 16A] This is an exemplary particle size distribution in the micronized crystalline form C of compound 1d. [Figure 16B] This is an exemplary particle size distribution in non-micronized crystalline form C of compound 1d. [Modes for carrying out the invention]

[0033] As generally described herein, this disclosure relates to a pharmaceutical composition comprising a neuroactive steroid (e.g., a compound of formula (I)), [ka] The present invention provides a method for preparing the pharmaceutical composition and a method for treating medical conditions, diseases, and disorders (e.g., central nervous system disorders) using the pharmaceutical composition.

[0034] definition To facilitate understanding of the present invention, several terms and expressions are defined below.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains. Abbreviations used herein have their conventional meanings within the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0036] In the overall modes for carrying out the invention, where compositions and kits are described as having specific components, including, or comprising, specific components, or where processes and methods are described as having specific steps, including, or comprising, it is further intended that there exist compositions and kits of the present invention that are essentially composed of or comprise the listed components, and processes and methods according to the present invention that are essentially composed of or comprise the listed processing steps.

[0037] Where it is stated in this application that an element or component is included in and / or selected from the list of elements or components, it should be understood that the element or component may be any one of the listed elements or components, or that the element or component may be selected from a group consisting of two or more of the listed elements or components.

[0038] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly, can be combined in various ways without departing from the spirit and scope of the invention. For example, where a particular compound is mentioned, that compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention, unless otherwise understood from the context. In other words, while embodiments within this application are described and illustrated in a manner that enables the description and creation of a clear and concise application, it is intended and to be understood that embodiments can be combined and separated in various ways without departing from the teachings and inventions. For example, it should be understood that all features described and illustrated herein may be applicable to all embodiments of the inventions described and illustrated herein.

[0039] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article, unless the context is inappropriate. For example, "element" means one or more elements.

[0040] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0041] The expression "at least one of ~" should be understood to include each of the items listed after it and any various combinations of two or more of the listed items, unless otherwise understood from the context and usage. The expression "and / or" relating to three or more listed items should be understood to have the same meaning, unless otherwise understood from the context.

[0042] The use of the terms "include / includes / including," "have," or "contain / contains / containing" (including their grammatical equivalents) should be understood to be generally unrestrictive and non-exclusive, unless otherwise specified or understood from the context, and should not exclude, for example, further elements or steps not listed.

[0043] When "approximately" is used before a quantitative value, unless otherwise specified, the present invention also includes the specific quantitative value itself. As used herein, the term "approximately" refers to a variation of ±10% from the nominal value, unless otherwise indicated or inferred from the context.

[0044] In various places in this specification, variables or parameters are disclosed in groups or ranges. In embodiments for carrying out the invention, it is specifically intended to include any partial combination of members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to disclose individually 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to disclose individually 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0045] Any use of any example or illustrative term in this specification (e.g., "such as" or "including") is intended merely to better illustrate the invention and does not imply any limitation to the scope of the invention unless otherwise claimed. No term in this specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0046] As a general rule, compositions specifying percentages are based on weight unless otherwise specified. Furthermore, if a variable is not defined, its previous definition prevails. As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD pattern is an xy graph in which 2θ (diffraction angle) is plotted on the x-axis and intensity is plotted on the y-axis. These are diffraction peaks used to characterize crystalline materials. Since diffraction peak intensity can be particularly sensitive to sample orientation, diffraction peaks are usually represented and referred to by their position on the x-axis rather than their intensity on the y-axis (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, typically, those skilled in the art do not use intensity to characterize crystalline materials. As with any data measurement, variability can exist in XRPD data. In addition to variability in diffraction peak intensity, variability can also exist in the position of the diffraction peaks on the x-axis. However, this variability can typically be taken into account when reporting the position of the diffraction peaks for characterization purposes. Such variability in the position of diffraction peaks along the x-axis can stem from several causes. One such cause is sample preparation. When samples of the same crystalline material are prepared under different conditions, slightly different diffractograms may be obtained. Factors such as particle size, water content, solvent content, temperature, and orientation can all affect the X-ray diffraction of a sample. Another cause of variability is due to the parameters of the instrument. Different X-ray powder diffractometers operate with different parameters, which can result in slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data differently, which can also introduce variability. These and other causes of variability are known to those skilled in the art. Because of these causes of variability, the term "approximately" is sometimes used before the value of each X-ray diffraction peak, followed by an appropriate range to define the experimental variability (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.).

[0047] When referring to the peaks in the XRPD pattern of a given chemical entity's crystalline form (e.g., the crystalline form of the compound of formula (I)), the term "characteristic peaks" refers to a specific set of diffraction peaks whose values ​​span a range of 2θ values ​​(e.g., 0° to 40°) and which, as a whole, are characteristic of that particular crystalline form.

[0048] As used herein, "crystalline" refers to the solid phase of a given chemical entity in which the three-dimensional structural order is clearly defined. Atoms, ions, and / or molecules are arranged regularly and periodically within a repeating three-dimensional lattice. In various embodiments, the crystalline material may include one or more discrete crystalline forms.

[0049] As used herein, “crystalline form,” “crystalline solid form,” “crystalline form,” “solid form,” and related terms herein refer to crystalline modifiers comprising a given substance (e.g., the compound of formula (I)), which include, but are not limited to, single-component crystalline forms and multi-component crystalline forms, as well as polymorphs, solvates, hydrates, and salts.

[0050] The term "substantially crystalline" refers to a solid form that is crystalline to at least a specific weight percentage. A specific weight percentage may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In a particular embodiment, the weight percentage of a particular degree of crystallinity is at least 90%. In a particular other embodiment, the weight percentage of a particular degree of crystallinity is at least 95%. In some embodiments, the compound of formula (I) may be a substantially crystalline sample of any crystalline solid form described herein (e.g., crystal forms A and C).

[0051] The term “substantially pure” relates to the composition of a particular crystalline solid form (e.g., the crystalline form of the compound of formula (I)) that may not contain at least a certain weight percentage of impurities and / or other solid forms. A particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In certain embodiments, the compound of formula (I) may be a substantially pure sample of any crystalline solid form described herein (e.g., crystalline forms A and C). In certain embodiments, the compound of formula (I) may be a substantially pure form A. In certain embodiments, the compound of formula (I) may be a substantially pure form C.

[0052] As used herein, the terms “anhydrous” or “anhydrous” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) mean the absence of water molecules that form part of the unit cell of the crystalline form. An anhydrous crystalline form may still contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., as residual solvent molecules left over from the production of the crystalline form). In a preferred embodiment, water may constitute about 0.5% by weight of the total composition of the anhydrous form sample. In a more preferred embodiment, water may constitute about 0.2% by weight of the total composition of the anhydrous form sample. In some embodiments, a sample of the anhydrous crystalline form of the compound of formula (I) does not contain water molecules (e.g., does not contain a detectable amount of water).

[0053] As used herein, the terms “desolvated” or “solvated” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) mean that there are no solvent molecules that form part of the unit cells of the crystalline form. A solvated crystalline form may still contain solvent molecules that do not form part of the unit cells of the solvated crystalline form (e.g., as residual solvent molecules left over from the production of the crystalline form). In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the sample in the solvated form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the sample in the solvated form. In some embodiments, a sample of the solvated crystalline form of the compound of formula (I) does not contain solvent molecules (e.g., does not contain a detectable amount of solvent).

[0054] As used herein, “polymorph (singular),” “polymorphic form (singular),” “polymorph (plural),” “polymorphic form (plural),” and related terms refer to two or more crystalline forms that essentially consist of the same molecule (singular or plural) or ion (e.g., the compound of formula (I)). Different polymorphs may exhibit different physicochemical properties, such properties including, but are not limited to, melting temperature, solubility, dissolution rate, and physical stability as a result of differences in the arrangement or stereochemistry of molecules or ions within the crystal lattice.

[0055] When referring to the crystalline form of the compound of formula (I), the term "solvate" means that the solvent molecules (e.g., organic solvents and water) form part of the unit cell of the crystalline form. Solvates containing water as a solvent are also referred to herein as "hydrates."

[0056] As used herein, the terms “particle size” or “particle size distribution (PSD)” when referring to the compound of formula (I) are a list of numerical values ​​that define the relative amount (typically mass or volume) of particles present according to their size. Distribution data can be reported as a cumulative distribution and / or as a density distribution by volume or mass (e.g., D(v,0.1), D(v,0.5), and D(v,0.9)). In various embodiments, the particle size of the compound of formula (I) can be measured using laser diffraction techniques (e.g., by scattering light at various angles to disperse particles in a sample and irradiating the sample with a parallel laser beam). Larger particles produce high scattering intensity at relatively narrow angles relative to the incident beam, while smaller particles produce lower intensity signals, but at a much wider angle. A laser diffraction analyzer uses a series of detectors to record the pattern of scattered light produced by the sample. By applying an appropriate optical behavior model, the particle size distribution of the sample can be determined from the scattering data via a deconvolution step.

[0057] As used herein, “yield pressure” can refer to, for example, the pressure at which a material (e.g., the compound of formula (I)) begins to deform irreversibly (plastically or by brittle fracture), or the pressure at which the material exhibits nonlinear deformation (a sum of elastic and irreversible deformation). Yield pressure is the reciprocal of the slope of ln(1 / (1-D)) with respect to P in a Haeckel plot, where D is the relative molding density of the tablet, P is the applied compressive pressure, and the slope is determined by the pressure at which plastic flow first occurs. A very low yield pressure of 50 MPa is typical of the ductile Avicel PH 101 (MCC), while a very high yield pressure of over 959 MPa is typical of the extremely brittle dicalcium phosphate (DCP) (Pharmaceutical Powder Compaction Technology, 2nd Edition, Volume 197, Drugs and Pharmaceutical Sciences, Edited by Metin Celik, (copyright) 2011). (by CRC Press)

[0058] As used herein, “strain rate” refers to the change in strain (i.e., the rate at which the material expands or contracts, and also the rate at which it progressively shears and deforms without changing its volume) of a material (e.g., the compound of equation (I)) as a function of time.

[0059] As used herein, “contact angle” refers to the angle formed by a liquid at a three-phase boundary where a solid (e.g., the compound of formula (I)), a liquid, and a vapor intersect. Measurements of the contact angle can be used to quantify the wettability of a solid surface (e.g., the smooth surface of a compressed tablet prepared using the crystalline form of the compound of formula (I)) by a given liquid or solution. The contact angle can be measured, for example, using the droplet technique. Other methods are commonly used and found in surface chemistry textbooks (JT Davies and EK Rideal, “Interfacial Phenomena”, Academic Press, 1963 or AWAdamson and AP Gast, “The Physical Chemistry of Surfaces”, Wiley, 1997), and include, for example, the ring method, droplet weight method, Wilhemy plate method, pendant drop method, ripple method, capillary rise method, and maximum bubble pressure method. The measurements reported in this application were obtained using the droplet method.

[0060] As used herein, “true density” or “particle density” refers to a measured volume of a particle (e.g., powder, particulate solid) excluding porous regions both within and between particles. Typically, this is measured using a gas hydrometer (e.g., Accupyc), with helium used as the gas to allow permeability through the smallest pores.

[0061] As used herein, "bulk density" refers to the mass of particles per unit of the total volume occupied by the particles. The total volume includes, for example, the particle volume, the interparticle void volume, and the internal void volume.

[0062] As used herein, “tap density,” “volume density,” or “apparent density” refers to the increased bulk density of a powder or particulate material (e.g., a pharmaceutical composition as described herein) after a container containing the powder or particulate material has been mechanically “tapped.”

[0063] As used herein, the "Carr index" or "Carr compressibility index" is a measure of the tendency of a powder or particulate material to be compressed (e.g., the pharmaceutical compositions described herein), and is a function of both the bulk density and tap density of the material.

[0064] As used herein, the "Flow Index (FRI)" can be defined as the velocity at which a solid flows through a given hopper outlet diameter when completely degassed. A low FRI value usually indicates that the powder is fine and highly compressible. Particles larger than 400 μm are usually incompressible, highly permeable, and have a high FRI. Variations in this index value can signal separation or changes in composition of the powder mixture during processing. This can be measured using a flow rate indicator system.

[0065] As used herein, “envelope density” refers to the volume of particles including pores or spaces between particles, and is measured, for example, by Geopyc, by flowing particles around a sample with a rigid sphere to establish a controlled dry flow.

[0066] As used herein, “solids content” refers to the ratio of envelope density to true density, and is essential for understanding and controlling the roller compression or compression process. It is typically measured for ribbons, granules, and / or final powder blends prior to encapsulation or tableting. It is also measured for uncoated tablets.

[0067] As used herein, “dissolution profile” refers to dissolution tests of an active pharmaceutical ingredient (API) or formulation at multiple time points. Dissolution profiles of APIs (e.g., compounds of formula (I)) or formulations (e.g., pharmaceutical compositions described herein) may be performed for characterization and quality control to ensure that the drug is released at a specified rate in at least a well-defined aqueous dissolution medium that is the sink condition for the drug, or in a bio-related medium (e.g., simulated gastric or intestinal fluid corresponding to either fasting or feeding). Dissolution tests may, in certain cases, predict or provide insight into the in vivo bioavailability of an API, but not in other cases. Dissolution tests may be performed using USP test protocols and dissolution equipment.

[0068] As used herein, “granulation” refers to the process of forming granules from powdered or particulate materials. As used herein, “dry granulation” refers to the process of forming granules without the presence of a solution and may be useful in the preparation of granules of materials sensitive to heat, moisture, or solvents. Roller compression is an example of a dry granulation process. As used herein, “wet granulation” refers to the formation of granules by binding particles together using a binder or solution. Examples of wet granulation include high-shear granulation and fluidized bed granulation.

[0069] As used herein, “pharmaceutical composition” or “pharmaceutical preparation” means a combination of a therapeutically active agent and an inactive or active pharmaceutically acceptable excipient that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0070] "Medically acceptable" means a compound, molecular entity, composition, material, and / or dosage form that, when administered to animals or humans as necessary, does not produce adverse reactions, allergic reactions, or other unfavorable reactions, or a means that is approved or eligible for approval by a federal or state regulatory agency or a corresponding agency in a country other than the United States, or a means that is listed in the United States Pharmacopeia or other widely recognized pharmacopoeias for use in animals, more specifically in humans.

[0071] As used herein, “pharmaceutically acceptable salt” means any salt of an acidic or basic group that may be present in the compound of the present invention (e.g., the compound of formula (I)) and is suitable for pharmaceutically acceptable administration.

[0072] As is known to those skilled in the art, “salts” of compounds can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, may be used in the preparation of salts that are useful as intermediate products in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts, even though they themselves are not pharmaceutically acceptable.

[0073] Examples of bases, though not limited to them, include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and formula NW4. + The compound (wherein W is C) 1~4 Examples include alkyl groups.

[0074] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention formulated with suitable cations (e.g., Na + , K + , Ca 2+ , NH4 + , and NW4 + (where W can be a C 1~4 alkyl group)).

[0075] With respect to therapeutic use, salts of the compounds of the present invention are contemplated to be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0076] As used herein, “pharmaceutically acceptable excipients” means substances that can be included in the compositions of the present invention without causing serious and harmful toxic effects to the patient, and which assist in the administration and / or absorption of the active agent to the target. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents or fillers (e.g., brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavorings, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxypropyl methylcellulose, polyvinylpyrrolidine, and colorants. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975), or Rowe, Shesky, and Quinn, Handbook of Pharmaceutical Excipients, 6 th See Ed. Pharmaceutical Press, London, UK (2009).

[0077] Examples of diluents or fillers include, but are not limited to, sugars (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, polydextrose, and combinations thereof), inorganic materials (e.g., dicalcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, starch (e.g., pregelatinized starch), microcrystalline cellulose, silicified microcrystalline cellulose, polysaccharides, cellulose (e.g., hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose), dextrin, maltodextrin, alginic acid, collagen, polyvinylpyrrolidone, polyvinyl acrylate, polyethylene oxide, and polyethylene glycol. Sugars are defined herein to include sugar alcohols.

[0078] Examples of disintegrants include, but are not limited to, alginic acid, alginates, Primogel, cellulose (e.g., hydroxypropylcellulose), potassium polaritrin, sodium starch glycolate, croscarmellose sodium, polyplasdone (e.g., crospovidone), and starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0079] Examples of binders include, but are not limited to, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (e.g., low viscosity hydroxypropylmethylcellulose), sugars, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polydextrose, chitosan, carrageenan, carbophyll, microcrystalline cellulose, tragacanth gum, guar gum, gellan gum, gelatin, and starch (e.g., corn starch).

[0080] Examples of wetting agents include, but are not limited to, poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polydimethylsiloxane, polysorbate (e.g., polyoxyethylene 20 sorbitan monooleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholic acid, polyethoxylated castor oil, cetyltrimethylammonium bromide, nonoxynol, α-tocopherol polyethylene glycol 1000 succinate, and sodium doxart.

[0081] Examples of lubricants and fluidizers include, but are not limited to, waxes, glycerides, diesel fuel, polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oils (e.g., hydrogenated vegetable oils), alkyl sulfates, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0082] Examples of fluidizing agents, though not limited to them, include colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0083] Examples of colorants, though not limited to them, include titanium dioxide, aluminum lake, iron oxide, and carbon black.

[0084] Examples of coating agents, though not limited to them, include film-forming polymers (e.g., hypromellose, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, Eudragit / acrylate) and plasticizers (e.g., triacetin, polyethylene glycol, propylene glycol).

[0085] Pharmaceutical compositions for oral administration (for example, pharmaceutical compositions of the compounds of formula (I) described herein) may be in the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, compositions are presented in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to physically separate units suitable as unit drug doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms for solid compositions include pills, tablets, capsules, etc.

[0086] The "targets" to which administration is intended include, but are not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the target is human. In certain embodiments, the target is a non-human animal.

[0087] As used herein, “solid dosage form” means a drug dose(s) in solid form, such as tablets, capsules, granules, powders, minitablets, sachets, stick packs, reconstituted powders, dry powder inhalers, lozenges, and chewables.

[0088] As used herein, “administer” means oral administration, pulmonary administration, suppository administration, intramuscular administration, intrathecal administration, intranasal or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini osmotic pump) to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palate, gingival, nasal cavity, vagina, rectum, or). Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations. “Concurrent administration” means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anticancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compounds of formula (I) may be administered to a patient alone or concurrently. Concurrent administration is intended to include administering the compounds individually or in combination (multiple compounds or drugs) simultaneously or over time. Therefore, the formulation can also be combined with other active substances if desired (for example, to reduce metabolic degradation).

[0089] In this specification, the terms “disease,” “disorder,” and “condition” are used interchangeably.

[0090] As used herein, and unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to an action that occurs while the subject is suffering from a specified disease, disorder, or condition, and which is intended to reduce the severity of the disease, disorder, or condition, or to delay or slow the progression of the disease, disorder, or condition (e.g., “therapeutic treatment”).

[0091] Generally, the “effective dose” of a compound refers to the amount sufficient to elicit a desired biological response (e.g., to treat a disease or disorder of the brain and / or central nervous system). As those skilled in the art will understand, the effective dose of a compound in this disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject.

[0092] As used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to produce a therapeutic benefit in the treatment of a disease, disorder, or condition, or sufficient to delay or minimize one or more symptoms associated with the disease, disorder, or condition. “Therapeutic dose” of a compound means the amount of a therapeutic agent, either alone or in combination with other therapies, that produces a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall therapy, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0093] In alternative embodiments, the present invention intends to administer the compounds of the present invention or pharmaceutically acceptable salts or compositions thereof as prophylactic agents to subjects before they contract a specified disease, disorder, or condition. As used herein, and unless otherwise specified, “prophylactic effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. The prophylactic effective dose of a compound means the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic effect of another prophylactic agent.

[0094] As used herein, “episodic dosing regimen” is a dosing regimen in which a compound of formula (I) or a composition containing a compound of formula (I) is administered to a subject for a limited period of time in response to a diagnosis of a disorder or its symptoms (e.g., a diagnosis or symptoms of depression, an episode of major depressive disorder, bipolar depression, anxiety, or postpartum depression). In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosing units, each unit comprising the compound of formula (I) and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of several weeks (e.g., about 8 weeks). In contrast to chronic dosing as defined herein, episodic dosing of the compound is performed over a limited period (e.g., about 2 to about 8 weeks) in response to a diagnosis of a disorder (e.g., depression) or its symptoms. In some embodiments, the episodic dosing is performed once daily over several weeks (e.g., about 2 to about 6 weeks). In one embodiment, the duration of an epidural administration is two weeks. In some embodiments, one or more epidural regimens are administered to the subject, for example, two or more epidural regimens are administered over the subject's lifetime.

[0095] compound This invention relates to the compound of formula (I). [ka]

[0096] Methods for chemically synthesizing the compound of formula (I) (including Example 1 provided herein) (sometimes referred to herein as Compound 1) are described in U.S. Patent No. 9,725,481 and PCT Publication No. WO2014169831, which are incorporated herein by reference in their entirety. Several crystalline forms of the compound of formula (I) (including crystalline forms A and C described herein) and methods for preparing such forms are described in U.S. Patent Publication No. US20190177359 and PCT Publication No. WO2018039378, which are incorporated herein by reference in their entirety.

[0097] The compound of formula (I) has a solubility of approximately 0.8–3 μg / mL in water and similar solubility in artificial gastric fluid at pH 1.2. Its solubility in fasting artificial intestinal fluid (FaSSIF) reflects its solubility in these media, and the compound of formula (I) is considered substantially insoluble in aqueous media. The compound of formula (I) belongs to the high-permeability, low-solubility drug classification (BCS2) described in the Biopharmaceutics Classification System (BCS). In the improved and widely accepted Developability Classification System (DCS) (discussed by Butler and Dressman), the high-permeability, low-solubility category is further divided into two subcategories. Specifically, the degree of human absorption can be predicted using the dose-to-solubility ratio of the drug in FaSSIF. Class 2a represents compounds with good permeability, low solubility, and a small dose-to-solubility ratio. Class 2b compounds represent compounds that pose significant challenges to formulations because they have a higher dose-to-solubility ratio, potentially leading to incomplete absorption unless the drug is formulated in an already solubilized form. The dose-to-solubility ratio in FaSSIF is over 10,000 for a 10 mg dose, over 20,000 for a 20 mg dose, over 30,000 for a 30 mg dose, over 90,000 for a 90 mg dose, and over 100,000 for a 100 mg dose. This means that even a 10 mg dose may only dissolve in a glass of water or FaSSIF at approximately 1.2% of the drug dose. For Class 2b compounds, system predictions suggest that particle reduction should not affect bioavailability. Martinez and Amidon state: "In cases of absorption with limited solubility, particle size has minimal influence on the proportion of drug absorbed. In this situation, improvement in the proportion of drug absorbed can only be achieved by increasing the solubility of the drug (for example, by including a surfactant in the drug formulation). Conversely, particle size has the maximum influence when solubility is not an issue." (Martinez and Amidon; J. Clin. Pharmacol.; 2002; 42; 620-643).Given the very high solubility relative to dose of the compound of formula (I), oral absorption of the compound of formula (I) is limited by its solubility, and particle size reduction should not affect its bioavailability. Surprisingly, however, as described herein, particle size reduction of the compound of formula (I) results in an increase in bioavailability.

[0098] In one embodiment, the Specified herein provides compounds of formula (I) or pharmaceutically acceptable salts thereof for preparing pharmaceutical compositions for use in subjects requiring the treatment of various diseases and disorders of the brain and / or central nervous system.

[0099] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable salt thereof is any crystalline form disclosed in PCT application publication WO2018039378.

[0100] In a particular embodiment, the crystalline form of the compound of formula (I) is anhydrous crystalline form A. In a particular embodiment, form A has an XRPD pattern with characteristic peaks between the following 2θ (degree) values ​​(including both endpoints): 9.3–9.7 (e.g., 9.5±0.2), 10.6–11.0 (e.g., 10.8±0.2), 13.0–13.4 (e.g., 13.2±0.2), 14.7–15.1 (e.g., 14.9± 0.2), 15.8-16.2 (e.g., 16.0±0.2), 18.1-18.5 (e.g., 18.3±0.2), 18.7-19.1 (e.g., 18.9±0.2), 20.9-21.3 (e.g., 21.1±0.2), 21.4-21.8 (e.g., 21.6±0.2), and 23.3-23.7 (e.g., 23.5±0.2). In a particular embodiment, form A has an XRPD pattern with characteristic peaks between the following 2θ (degree) values ​​(including the endpoints): 9.3–9.7 (e.g., 9.5±0.2), 10.6–11.0 (e.g., 10.8±0.2), 13.0–13.4 (e.g., 13.2±0.2), 18.7–19.1 (e.g., 18.9±0.2), and 21.4–21.8 (e.g., 21.6±0.2). In a particular embodiment, form A has an XRPD pattern with characteristic peaks at the following 2θ (degree) values: 9.5±0.2, 10.8±0.2, 13.2±0.2, 14.9±0.2, 16.0±0.2, 18.3±0.2, 18.9±0.2, 21.1±0.2, 21.6±0.2, and 23.5±0.2. In a particular embodiment, the X-ray powder diffraction pattern of form A may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the peaks at 9.5±0.2, 10.8±0.2, 13.2±0.2, 14.9±0.2, 16.0±0.2, 18.3±0.2, 18.9±0.2, 21.1±0.2, 21.6±0.2, and 23.5±0.2 with respect to 20. In a particular embodiment, form A has an XRPD pattern with characteristic peaks at the following 2θ (degree) values: 9.5±0.2, 10.8±0.2, 13.2±0.2, 18.9±0.2, and 21.6±0.2.

[0101] In a particular embodiment, the crystalline form of the compound of formula (I) is anhydrous crystalline form C. In a particular embodiment, form C may have an XRPD pattern with characteristic peaks between the following 2θ (degree) values ​​(including both endpoints): 9.7~10.1 (e.g., 9.9±0.2), 11.6~12.0 (e.g., 11.8±0.2), 13.2~13.6 (e.g., 13.4±0.2), 14.2~14.6 (e.g., 1 4.4±0.2), 14.6~15.0 (e.g., 14.8±0.2), 16.8~17.2 (e.g., 17.0±0.2), 20.5~20.9 (e.g., 20.7±0.2), 21.3~21.7 (e.g., 21.5±0.2), 21.4~21.8 (e.g., 21.6±0.2), and 22.4~22.8 (e.g., 22.6±0.2). In a particular embodiment, form C may have an XRPD pattern with characteristic peaks between the following 2θ (degree) values ​​(including the endpoints): 9.7–10.1 (e.g., 9.9±0.2), 14.6–15.0 (e.g., 14.8±0.2), 16.8–17.2 (e.g., 17.0±0.2), 20.5–20.9 (e.g., 20.7±0.2), and 21.3–21.7 (e.g., 21.5±0.2). In a particular embodiment, form C may have an XRPD pattern with characteristic peaks at the following 2θ (degree) values: 9.9±0.2, 11.8±0.2, 13.4±0.2, 14.4±0.2, 14.8±0.2, 17.0±0.2, 20.7±0.2, 21.5±0.2, 21.6±0.2, and 22.6±0.2. In a particular embodiment, the X-ray powder diffraction pattern of form C may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the peaks at 9.9±0.2, 11.8±0.2, 13.4±0.2, 14.4±0.2, 14.8±0.2, 17.0±0.2, 20.7±0.2, 21.5±0.2, 21.6±0.2, and 22.6±0.2 with respect to 20. In a particular embodiment, form C may have an XRPD pattern with characteristic peaks at the following 2θ (degree) values: 9.9±0.2, 14.8±0.2, 17.0±0.2, 20.7±0.2, and 21.5±0.2.

[0102] In certain embodiments, the crystalline form of the compound of formula (I) includes a mixture of two or more crystalline forms. In certain embodiments, the crystalline form of the compound of formula (I) includes anhydrous crystalline form A and anhydrous crystalline form C.

[0103] Pharmaceutical composition As described herein, in one embodiment, the present invention provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0104] In various embodiments, the pharmaceutical composition comprises a plurality of particles in crystalline form of the compound of formula (I), [ka] Multiple particles of the crystalline form of the compound of formula (I) include at least one of the following features: (i) Particle size distribution defined by D90 from approximately 1 μm to approximately 100 μm, (ii) Yield pressure of approximately 40 MPa to approximately 200 MPa, (iii) strain rate sensitivity of less than approximately 10%, and (iv) Contact angle of approximately 60 to 110 degrees (measured using droplet technology).

[0105] In a particular embodiment, multiple particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 as follows: approximately 1 μm to approximately 100 μm, approximately 5 μm to approximately 100 μm, approximately 10 μm to approximately 100 μm, approximately 15 μm to approximately 100 μm, approximately 20 μm to approximately 100 μm, approximately 25 μm to approximately 100 μm, approximately 30 μm to approximately 100 μm, approximately 35 μm to approximately 100 μm, approximately 40 μm to approximately 100 μm, approximately 45 μm to approximately 100 μm, approximately 50 μm to approximately 100 μm, approximately 60 μm to approximately 100 μm, approximately 70 μm to approximately 100 μm, approximately 80 μm to approximately 100 μm, approximately 90 μm to approximately 1 00μm, about 1μm to about 90μm, about 1μm to about 80μm, about 1μm to about 70μm, about 1μm to about 60μm, about 1μm to about 50μm, about 1 μm to approx. 45 μm, approx. 1 μm to approx. 40 μm, approx. 1 μm to approx. 35 μm, approx. 1 μm to approx. 30 μm, approx. 1 μm to approx. 25 μm, approx. 1 μm to approx. 20 μm m, about 1 μm to about 15 μm, about 1 μm to about 10 μm, about 1 μm to about 5 μm, about 5 μm to about 90 μm, about 5 μm to about 80 μm, about 5 μm to about 70μm, about 5μm to about 60μm, about 5μm to about 50μm, about 5μm to about 45μm, about 5μm to about 40μm, about 5μm to about 35μm, about 5 μm ~ approx. 30 μm, approx. 5 μm ~ approx. 25 μm, approx. 5 μm ~ approx. 20 μm, approx. 5 μm ~ approx. 15 μm, approx. 5 μm ~ approx. 10 μm, approx. μm, about 10 μm to about 80 μm, about 10 μm to about 70 μm, about 10 μm to about 60 μm, about 10 μm to about 50 μm, about 10 μm to about 45 μm , about 10 μm to about 40 μm, about 10 μm to about 35 μm, about 10 μm to about 30 μm, about 10 μm to about 25 μm, about 10 μm to about 20 μm, about 10μm to about 15μm, about 15μm to about 90μm, about 15μm to 80μm, about 15μm to about 70μm, about 15μm to about 60μm, about 15μm m~about 50μm, about 15μm~about 45μm, about 15μm~about 40μm, about 15μm~about 35μm, about 15μm~about 30μm, about 15μm~ Approximately 25μm, approximately 15μm to approximately 20μm, approximately 20μm to approximately 90μm, approximately 20μm to approximately 80μm, approximately 20μm to approximately 70μm, approximately 20μm to approximately 6 0 μm, about 20 μm to about 50 μm, about 20 μm to about 45 μm, about 20 μm to about 40 μm, about 20 μm to about 35 μm, about 20 μm to about 30 μm m, about 20 μm to about 25 μm, about 30 μm to about 90 μm, about 30 μm to about 80 μm, about 30 μm to about 70 μm, about 30 μm to about 60 μm,Approximately 30μm to approximately 50μm, approximately 30μm to approximately 45μm, approximately 30μm to approximately 40μm, approximately 30μm to approximately 35μm, approximately 35μm to approximately 90μm, approximately 35μm to approximately 80μm, approximately 35μm to approximately 70μm, approximately 35μm to approximately 60 μm, approximately 35 μm to approximately 50 μm, approximately 35 μm to approximately 45 μm, approximately 35 μm to approximately 40 μm, approximately 40 μm to approximately 90 μm, approximately 40 μm to approximately 80 μm, approximately 40 μm to approximately 70 μm, approximately 40 μm to approximately 50 μm, approximately 40 μm to approximately 45 μm, approximately 45 μm to approximately 90 μm, approximately 45 μm to approximately 80 μm, approximately 45 μm to approximately 70 μm, approximately 45 μm to approximately 60 μm, approximately 45 μm to approximately 50 μm, approximately 50 μm to approximately 90 μm, approximately 50 μm to approximately 80 μm, approximately 50 μm to approximately 70 μm, approximately 50 μm to approximately 60 μm, approximately 60 μm to approximately 90 μm, approximately 60 μm to approximately 80 μm, approximately 60 μm to approximately 70 μm, approximately 70 μm to approximately 90 μm, approximately 70 μm to approximately 80 μm, or approximately 80 μm to approximately 90 μm. In a particular embodiment, multiple particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 ranging from approximately 1 μm to approximately 20 μm.

[0106] In certain embodiments, a plurality of particles of the crystalline form of the compound of formula (I) are from about 1 μm to about 20 μm, from about 2 μm to about 20 μm, from about 3 μm to about 20 μm, from about 4 μm to about 20 μm, from about 5 μm to about 20 μm, from about 6 μm to about 20 μm, from about 7 μm to about 20 μm, from about 8 μm to about 20 μm, from about 9 μm to about 20 μm, from about 10 μm to about 20 μm, from about 11 μm to about 20 μm, from about 12 μm to about 20 μm, from about 13 μm to about 20 μm, from about 14 μm to about 20 μm, from about 15 μm to about 20 μm, from about 16 μm to about 20 μm, from about 17 μm to about 20 μm, from about 18 μm to about 20 μm, from about 2 μm to about 19 μm, from about 1 μm to about 19 μm, from about 1 μm to about 18 μm, from about 1 μm to about 17 μm, from about 1 μm to about 16 μm, from about 1 μm to about 15 μm, from about 1 μm to about 14 μm, from about 1 μm to about 13 μm, from about 1 μm to about 12 μm, from about 1 μm to about 11 μm, from about 1 μm to about 10 μm, from about 1 μm to about 9 μm, from about 1 μm to about 8 μm, from about 1 μm to about 7 μm, from about 1 μm to about 6 μm, from about 1 μm to about 5 μm, from about 1 μm to about 4 μm, from about 1 μm to about 3 μm, from about 1 μm to about 2 μm, from about 2 μm to about 19 μm, from about 2 μm to about 18 μm, from about 2 μm to about 17 μm, from about 2 μm to about 16 μm, from about 2 μm to about 15 μm, from about 2 μm to about 14 μm, from about 2 μm to about 13 μm, from about 2 μm to about 12 μm, from about 2 μm to about 11 μm, from about 2 μm to about 10 μm, from about 2 μm to about 9 μm, from about 2 μm to about 8 μm, from about 2 μm to about 7 μm, from about 2 μm to about 6 μm, from about 2 μm to about 5 μm, from about 2 μm to about 4 μm, from about 2 μm to about 3 μm, from about 3 μm to about 19 μm, from about 3 μm to about 18 μm, from about 3 μm to about 17 μm, from about 3 μm to about 16 μm, from about 3 μm to about 15 μm, from about 3 μm to about 14 μm, from about 3 μm to about 13 μm, from about 3 μm to about 12 μm, from about 3 μm to about 11 μm, from about 3 μm to about 10 μm, from about 3 μm to about 9 μm, from about 3 μm to about 8 μm, from about 3 μm to about 7 μm, from about 3 μm to about 6 μm, from about 3 μm to about 5 μm, from about 3 μm to about 4 μm, from about 4 μm to about 19 μm, from about 4 μm to about 18 μm, from about 4 μm to about 17 μm, from about 4 μm to about 16 μm, from about 4 μm to about 15 μm, from about 4 μm to about 14 μm, from about 4 μm to about 13 μm, from about 4 μm to about 12 μm, from about 4 μm to about 11 μm, from about 4 μm to about 10 μm, from about 4 μm to about 9 μm, from about 4 μm to about 8 μm, from about 4 μm to about 7 μm, from about 4 μm to about 6 μm, from about 4 μm to about 5 μm, from about 5 μm to about 19 μm, from about 5 μm to about 18 μm, from about 5 μm to about 17 μm, from about 5 μm to about 16 μm,Approximately 5μm to approximately 15μm, approximately 5μm to approximately 14μm, approximately 5μm to approximately 13μm, approximately 5μm to approximately 12μm, approximately 5μm to approximately 11μm, approximately 5μm to approximately 10μm, approximately 5μm to approximately 9μm, approximately 5μm to approximately 8μm, approximately 5μm to approximately 7μm, approximately 5μm to approximately 6μm, approximately 6μm to approximately 19μm, approximately 6μm to approximately 18μm, approximately 6μm to approximately 17μm, approximately 6μm to approximately 16μm, approximately 6μm to approximately 15μm, approximately 6μm to approximately 14μm, approximately 6μm to approximately 13μm, approximately 6μm to approximately 12μm, approximately 6μm to approximately 11μm, approximately 6μm to approximately 10μm, approximately 6μm to approximately 9μm, approximately 6μm to approximately 8μm, approximately 6μm to approximately 7μm, approximately 7μm~approx. 19μm, approx. 7μm~approx. 18μm, approx. 7μm~approx. 17μm, approx. 7μm~approx. 16μm, approx. 7μm~approx. 15μm, approx. 7μm~approx. 14μm, approx. 7μm~approx. 13μm, approx. 7μm~approx. 12μm, approx. 7μm~approx. 11μm, approx. 7μm~approx. 10μm, approx. 7μm~approx. 9μm, approx. 7μm~ Approximately 8μm, approximately 8μm to approximately 19μm, approximately 8μm to approximately 18μm, approximately 8μm to approximately 17μm, approximately 8μm to approximately 16μm, approximately 8μm to approximately 15μm, approximately 8μm to approximately 14μm, approximately 8μm to approximately 13μm, approximately 8μm to approximately 12μm, approximately 8μm to approximately 11μm, approximately 8μm to approximately 10μm, approximately 8μm to approximately 9μm Approximately 9μm to 19μm, approximately 9μm to 18μm, approximately 9μm to 17μm, approximately 9μm to 16μm, approximately 9μm to 15μm, approximately 9μm to 14μm, approximately 9μm to 13μm, approximately 9μm to 12μm, approximately 9μm to 11μm, approximately 9μm to 10μm, approximately 10μm to 19μm. Approximately 10μm to approximately 18μm, approximately 10μm to approximately 17μm, approximately 10μm to approximately 16μm, approximately 10μm to approximately 15μm, approximately 10μm to approximately 14μm, approximately 10μm to approximately 13μm, approximately 10μm to approximately 12μm, approximately 10μm to approximately 11μm, approximately 11μm to approximately 19μm, approximately 11μm to approximately 18μm, approximately 11μm m ~ approximately 17μm, approximately 11μm ~ approximately 16μm, approximately 11μm ~ approximately 15μm, approximately 11μm ~ approximately 14μm, approximately 11μm ~ approximately 13μm, approximately 11μm ~ approximately 12μm, approximately 12μm ~ approximately 19μm, approximately 12μm ~ approximately 18μm, approximately 12μm ~ approximately 17μm, approximately 12μm ~ approximately 16μm, approximately 12μm ~ approximately 1 5μm, approximately 12μm to approximately 14μm, approximately 12μm to approximately 13μm, approximately 13μm to approximately 19μm, approximately 13μm to approximately 18μm, approximately 13μm to approximately 17μm, approximately 13μm to approximately 16μm, approximately 13μm to approximately 15μm, approximately 13μm to approximately 14μm, approximately 14μm to approximately 19μm, approximately 14μm to approximately 18μm,It has a particle size distribution defined by D90, approximately 14 μm to 17 μm, 14 μm to 16 μm, 14 μm to 15 μm, 15 μm to 19 μm, 15 μm to 18 μm, 15 μm to 17 μm, 15 μm to 16 μm, 16 μm to 19 μm, 16 μm to 18 μm, 16 μm to 17 μm, 17 μm to 19 μm, 17 μm to 18 μm, or 18 μm to 19 μm.

[0107] In a particular embodiment, the crystalline particles of the compound of formula (I) are approximately 5 μm to 10 μm, 5.5 μm to 10 μm, 6 μm to 10 μm, 6.5 μm to 10 μm, 7 μm to 10 μm, 7.5 μm to 10 μm, 8 μm to 10 μm, 8.5 μm to 10 μm, 9 μm to 10 μm, 9.5 μm to 10 μm, 5 μm to 9.5 μm, 5 μm to 9 μm, and 5 μm to about 8.5 μm, about 5 μm to about 8 μm, about 5 μm to about 7.5 μm, about 5 μm to about 7 μm, about 5 μm to about 6.5 μm, about 5 μm to about 6 μm, about 5 μm to about 5.5 μm, about 5.5 μm to about 9.5 μm, Approximately 5.5μm to approximately 9μm, approximately 5.5μm to approximately 8.5μm, approximately 5.5μm to approximately 8μm, approximately 5.5μm to approximately 7.5μm, approximately 5.5μm to approximately 7μm, approximately 5.5μm to approximately 6.5μm, approximately 5.5μm to approximately 6μm, Approximately 6μm to 9.5μm, approximately 6μm to 9μm, approximately 6μm to 8.5μm, approximately 6μm to 8μm, approximately 6μm to 7.5μm, approximately 6μm to 7μm, approximately 6μm to 6.5μm, approximately 6.5μm to 9.5μm, approximately 6.5μm to 9μm, approximately 6.5μm to 8.5μm, approximately 6.5μm to 8μm, approximately 6.5μm to 7.5μm, approximately 6.5μm to 7μm, approximately 7μm to 9.5μm, approximately 7μm to 9μm, approximately 7 It has a particle size distribution defined by D90, ranging from approximately μm to 8.5 μm, approximately 7 μm to 8 μm, approximately 7 μm to 7.5 μm, approximately 7.5 μm to 9.5 μm, approximately 7.5 μm to 9 μm, approximately 7.5 μm to 8.5 μm, approximately 7.5 μm to 8 μm, approximately 8 μm to 9.5 μm, approximately 8 μm to 9 μm, approximately 8 μm to 8.5 μm, approximately 8.5 μm to 9.5 μm, approximately 8.5 μm to 9 μm, or approximately 9 μm to 9.5 μm.

[0108] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0109] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0110] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0111] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0112] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0113] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0114] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0115] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0116] In a particular embodiment, multiple particles of the crystalline form of the compound of formula (I) have an average particle size defined by D90 of about 11 μm.

[0117]

[0118] In a particular embodiment, multiple particles of the crystalline form of the compound of formula (I) are located at approximately 40 MPa to 200 MPa, 50 MPa to 200 MPa, 60 MPa to 200 MPa, 70 MPa to 200 MPa, 80 MPa to 200 MPa, 90 MPa to 200 MPa, 95 MPa to 200 MPa, 100 MPa to 200 MPa, 150 MPa to 200 MPa, and 40 MPa. Pa ~ about 150MPa, about 40MPa - about 100MPa, about 40MPa - about 95MPa, about 40MPa - about 90MPa, about 40MPa - about 80MPa, about 40MPa - about 70MPa, about 40MPa ~Approx. 60MPa, approx. 40MPa ~ approx. 50MPa, approx. 50MPa ~ approx. 150MPa, approx. 50MPa ~ approx. 100MPa, approx. 50MPa ~ approx. 95MPa, approx. 80 MPa, approximately 50 MPa to 70 MPa, approximately 50 MPa to 60 MPa, approximately 60 MPa to 150 MPa, approximately 60 MPa to 100 MPa, approximately 60 MPa to 95 MPa, approximately 60 MPa to 90 MPa, approximately 60 MPa to 80 MPa, approximately 60 MPa to 70 MPa, approximately 70 MPa to 150 MPa, approximately 70 MPa to 100 MPa, approximately 70 MPa to 95 MPa, approximately 70 MPa to 90 MPa a. It has a yield pressure of approximately 70 MPa to 80 MPa, approximately 80 MPa to 150 MPa, approximately 80 MPa to 100 MPa, approximately 80 MPa to 95 MPa, approximately 80 MPa to 90 MPa, approximately 90 MPa to 150 MPa, approximately 90 MPa to 100 MPa, approximately 90 MPa to 95 MPa, approximately 95 MPa to 150 MPa, approximately 95 MPa to 100 MPa, or approximately 100 MPa to 150 MPa.

[0119] In certain embodiments, a plurality of particles in the crystalline form of the compound of formula (I) have a yield pressure of about 60 MPa to about 100 MPa. In certain embodiments, a plurality of particles in the crystalline form of the compound of formula (I) have a yield pressure of about 70 MPa to about 95 MPa. In certain embodiments, a plurality of particles in the crystalline form of the compound of formula (I) have a yield pressure of about 80 MPa to about 90 MPa.

[0120] In certain embodiments, multiple particles of the crystalline form of the compound of formula (I) have strain rate sensitivity of less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, or less than about 20%. In certain embodiments, multiple particles of the crystalline form of the compound of formula (I) have strain rate sensitivity of less than about 10%.

[0121] In a particular embodiment, multiple particles of the crystalline form of the compound of formula (I) are located at approximately 60° to 110°, 65° to 110°, 70° to 110°, 75° to 110°, 80° to 110°, 90° to 110°, 100° to 110°, 60° to 100°, 60° to 90°, 60° to 80°, 60° to 75°, 60° to 70°, 60° to 65°, and 65° to 80°. The contact angles are 100 degrees, approximately 65 to 90 degrees, approximately 65 to 80 degrees, approximately 65 to 75 degrees, approximately 65 to 70 degrees, approximately 70 to 100 degrees, approximately 70 to 90 degrees, approximately 70 to 80 degrees, approximately 70 to 75 degrees, approximately 75 to 100 degrees, approximately 75 to 90 degrees, approximately 75 to 80 degrees, approximately 80 to 100 degrees, approximately 80 to 90 degrees, or approximately 90 to 100 degrees, where the contact angle is measured using droplet technology. In certain embodiments, multiple particles of the crystalline form of the compound of formula (I) have a contact angle of approximately 70 to 80 degrees. In certain embodiments, multiple particles of the crystalline form of the compound of formula (I) have a contact angle of approximately 70 to 75 degrees.

[0122] In various embodiments, the pharmaceutical composition comprises a plurality of particles in crystalline form of the compound of formula (I), [ka] Multiple particles of the crystalline form of the compound of formula (I) are, (v) Particle size distribution defined by D90, ranging from approximately 1 μm to approximately 100 μm. (vi) Yield pressure of approximately 80 MPa to approximately 90 MPa, (vii) strain rate sensitivity of less than approximately 10%, and (viii) Includes a contact angle of approximately 70 to 75 degrees (measured using droplet technology).

[0123] In various embodiments, the pharmaceutical composition comprises a plurality of particles in crystalline form of the compound of formula (I), [ka] Multiple particles of the crystalline form of the compound of formula (I) are, (i) Particle size distribution defined by D90, ranging from approximately 6.1 μm to approximately 7.7 μm. (ii) Yield pressure of approximately 80 MPa to approximately 90 MPa, (iii) strain rate sensitivity of less than approximately 10%, and (iv) Includes a contact angle of approximately 70 to 75 degrees (measured using droplet technology).

[0124] In various embodiments, the pharmaceutical composition comprises a plurality of particles in crystalline form of the compound of formula (I), [ka] Multiple particles of the crystalline form of the compound of formula (I) are, (i) Particle size distribution defined by D90, ranging from approximately 4.2 μm to approximately 11.6 μm. (ii) Yield pressure of approximately 80 MPa to approximately 90 MPa, (iii) strain rate sensitivity of less than approximately 10%, and (iv) Includes a contact angle of approximately 70 to 75 degrees (measured using droplet technology).

[0125]

[0126] In various embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (I), [ka] The pharmaceutical composition includes at least one of the following characteristics: (i) True density of approximately 1.0 g / cc to approximately 2.5 g / cc, (ii) having a bulk density of approximately 0.2 g / cc to approximately 0.8 g / cc and a tap density of approximately 0.3 g / cc to approximately 1.1 g / cc, with the tap density of the pharmaceutical composition being higher than the bulk density, (iii) having a Carr index of approximately 10 to approximately 38, (iv) When the pharmaceutical composition is passed through a 710 / 25 (micron / mesh) sieve, approximately 0.2% to approximately 90% of the pharmaceutical composition is retained; when the pharmaceutical composition is passed through a 425 / 40 (micron / mesh) sieve, approximately 0.2% to approximately 75% of the material is retained; and when the pharmaceutical composition is passed through a 63 / 230 (micron / mesh) sieve, approximately 0.1% to approximately 55% of the pharmaceutical composition is retained. (v) Solid content ratio of approximately 0.5 to approximately 0.95, (vi) Flow index (FRI) of approximately 0.05 kg / sec to approximately 4 kg / sec, and (vii) The pharmaceutical composition releases at least about 50% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus.

[0127] In certain embodiments, the pharmaceutical composition has a density of from about 1.0 g / cc to about 2.5 g / cc, from about 1.1 g / cc to about 2.5 g / cc, from about 1.2 g / cc to about 2.5 g / cc, from about 1.3 g / cc to about 2.5 g / cc, from about 1.4 g / cc to about 2.5 g / cc, from about 1.5 g / cc to about 2.5 g / cc, from about 1.6 g / cc to about 2.5 g / cc, from about 1.7 g / cc to about 2.5 g / cc, from about 1.8 g / cc to about 2.5 g / cc, from about 1.9 g / cc to about 2.5 g / cc, from about 2.0 g / cc to about 2.5 g / cc, from about 2.2 g / cc to about 2.5 g / cc, from about 1.0 g / cc to about 2.2 g / cc, from about 1.0 g / cc to about 2.0 g / cc, from about 1.0 g / cc to about 1.9 g / cc, from about 1.0 g / cc to about 1.8 g / cc, from about 1.0 g / cc to about 1.7 g / cc, from about 1.0 g / cc to about 1.6 g / cc, from about 1.0 g / cc to about 1.5 g / cc, from about 1.0 g / cc to about 1.4 g / cc, from about 1.0 g / cc to about 1.3 g / cc, from about 1.0 g / cc to about 1.2 g / cc, from about 1.0 g / cc to about 1.1 g / cc, from about 1.1 g / cc to about 2.2 g / cc, from about 1.1 g / cc to about 2.0 g / cc, from about 1.1 g / cc to about 1.9 g / cc, from about 1.1 g / cc to about 1.8 g / cc, from about 1.1 g / cc to about 1.7 g / cc, from about 1.1 g / cc to about 1.6 g / cc, from about 1.1 g / cc to about 1.5 g / cc, from about 1.1 g / cc to about 1.4 g / cc, from about 1.1 g / cc to about 1.3 g / cc, from about 1.1 g / cc to about 1.2 g / cc, from about 1.2 g / cc to about 2.2 g / cc, from about 1.2 g / cc to about 2.0 g / cc, from about 1.2 g / cc to about 1.9 g / cc, from about 1.2 g / cc to about 1.8 g / cc, from about 1.2 g / cc to about 1.7 g / cc, from about 1.2 g / cc to about 1.6 g / cc, from about 1.2 g / cc to about 1.5 g / cc, from about 1.2 g / cc to about 1.4 g / cc, from about 1.2 g / cc to about 1.3 g / cc, from about 1.3 g / cc to about 2.2 g / cc, from about 1.3 g / cc to about 2.0 g / cc, from about 1.3 g / cc to about 1.9 g / cc, from about 1.3 g / cc to about 1.8 g / cc, from about 1.3 g / cc to about 1.7 g / cc, from about 1.3 g / cc to about 1.6 g / cc, from about 1.3 g / cc to about 1.5 g / cc, from about 1.3 g / cc to about 1.4 g / cc, from about 1.4 g / cc to about 2.2 g / cc, from about 1.4 g / cc to about 2.0 g / cc, from about 1.4 g / cc to about 1.9 g / cc, from about 1.4 g / cc to about 1.8 g / cc, from about 1.4g / cc~about 1.7g / cc, about 1.4g / cc~about 1.6g / cc, about 1.4g / cc~about 1.5g / cc, about 1.5g / cc~about 2.2g / cc, about 1.5g / cc~about 2.0g / cc, about 1.5g / cc~about 1.9g / cc, about 1.5g / cc ~ approx. 1.8g / cc, approx. 1.5g / cc ~ approx. 1.7g / cc, approx. 1.5g / cc ~ approx. 1.6g / cc, approx. 1.6g / cc ~ approx. 2.2g / cc, approx. 1.6g / cc ~ approx. 2.0g / cc, approx. 1.6g / cc ~ approx. 1.9g / cc, approx. 1.6g / cc c ~ about 1.8g / cc, about 1.6g / cc - about 1.7g / cc, about 1.7g / cc - about 2.2g / cc, about 1.7g / cc - about 2.0g / cc, about 1.7g / cc - about 1.9g / cc, about 1.7g / cc - about 1.8g / cc, about 1.8g / cc It has a true density of about 2.2 g / cc, about 1.8 g / cc to about 2.0 g / cc, about 1.8 g / cc to about 1.9 g / cc, about 1.9 g / cc to about 2.2 g / cc, about 1.9 g / cc to about 2.0 g / cc, or about 2.0 g / cc to about 2.2 g / cc. .

[0128] In certain embodiments, the pharmaceutical composition has a true density of about 1.1 g / cc to about 2.0 g / cc. In certain embodiments, the pharmaceutical composition has a true density of about 1.2 g / cc to about 1.6 g / cc.

[0129] In certain embodiments, the pharmaceutical composition is about 0.2 g / cc to about 0.8 g / cc, about 0.3 g / cc to about 0.8 g / cc, about 0.4 g / cc to about 0 .8g / cc, approx. 0.5g / cc ~ approx. 0.8g / cc, approx. 0.6g / cc ~ approx. 0.8g / cc, approx. 0.65g / cc ~ approx. 0.8g / cc, approx. 0.7g / cc cc ~ approx. 0.8g / cc, approx. 0.2g / cc ~ approx. 0.7g / cc, approx. 0.2g / cc ~ approx. 0.65g / cc, approx. 0.2g / cc ~ approx. 0.6g / cc, approx. 0.2g / cc~approx. 0.5g / cc, approx. 0.2g / cc~approx. 0.4g / cc, approx. 0.2g / cc~approx. 0.3g / cc, approx. 0.3g / cc~approx. 0.7g / cc, about 0.3g / cc~about 0.65g / cc, about 0.3g / cc~about 0.6g / cc, about 0.3g / cc~about 0.5g / cc, about 0.3g / cc~about 0.4g / cc, approx. 0.4g / cc ~ approx. 0.7g / cc, approx. 0.4g / cc ~ approx. 0.65g / cc, approx. 0.4g / cc ~ approx. 0.6g / cc, approx. 0.4g / cc to about 0.5 g / cc, about 0.5 g / cc to about 0.7 g / cc, about 0.5 g / cc to about 0.65 g / cc, about 0.5 g / cc to about 0.6 g / cc, about 0.6 g / cc to about 0.7 g / cc, about 0.6 g / cc to about 0.65 g / cc, or about 0.65 g / cc to about 0.8 g / cc.

[0130] In certain embodiments, the pharmaceutical composition has a bulk density of about 0.2 g / cc to about 0.7 g / cc. In certain embodiments, the pharmaceutical composition has a bulk density of about 0.3 g / cc to about 0.65 g / cc. In certain embodiments, the pharmaceutical composition has a bulk density of about 0.4 g / cc to about 0.7 g / cc. In certain embodiments, the pharmaceutical composition has a bulk density of about 0.5 g / cc to about 0.65 g / cc.

[0131] In certain embodiments, the pharmaceutical composition has a density of from about 0.3 g / cc to about 1.1 g / cc, from about 0.35 g / cc to about 1.1 g / cc, from about 0.4 g / cc to about 1.1 g / cc, from about 0.5 g / cc to about 1.1 g / cc, from about 0.6 g / cc to about 1.1 g / cc, from about 0.7 g / cc to about 1.1 g / cc, from about 0.8 g / cc to about 1.1 g / cc, from about 0.85 g / cc to about 1.1 g / cc, from about 0.9 g / cc to about 1.1 g / cc, from about 1.0 g / cc to about 1.1 g / cc, from about 0.3 g / cc to about 1.0 g / cc, from about 0.3 g / cc to about 0.9 g / cc, from about 0.3 g / cc to about 0.85 g / cc, from about 0.3 g / cc to about 0.8 g / cc, from about 0.3 g / cc to about 0.7 g / cc, from about 0.3 g / cc to about 0.6 g / cc, from about 0.3 g / cc to about 0.5 g / cc, from about 0.3 g / cc to about 0.4 g / cc, from about 0.3 g / cc to about 0.35 g / cc, from about 0.35 g / cc to about 1.0 g / cc, from about 0.35 g / cc to about 0.9 g / cc, from about 0.35 g / cc to about 0.85 g / cc, from about 0.35 g / cc to about 0.8 g / cc, from about 0.35 g / cc to about 0.7 g / cc, from about 0.35 g / cc to about 0.6 g / cc, from about 0.35 g / cc to about 0.5 g / cc, from about 0.35 g / cc to about 0.4 g / cc, from about 0.4 g / cc to about 1.0 g / cc, from about 0.4 g / cc to about 0.9 g / cc, from about 0.4 g / cc to about 0.85 g / cc, from about 0.4 g / cc to about 0.8 g / cc, from about 0.4 g / cc to about 0.7 g / cc, from about 0.4 g / cc to about 0.6 g / cc, from about 0.4 g / cc to about 0.5 g / cc, from about 0.5 g / cc to about 1.0 g / cc, from about 0.5 g / cc to about 0.9 g / cc, from about 0.5 g / cc to about 0.85 g / cc, from about 0.5 g / cc to about 0.8 g / cc, from about 0.5 g / cc to about 0.7 g / cc, from about 0.5 g / cc to about 0.6 g / cc, from about 0.6 g / cc to about 0.85 g / cc, from about 0.6 g / cc to about 1.0 g / cc, from about 0.6 g / cc to about 0.9 g / cc, from about 0.6 g / cc to about 0.8 g / cc, from about 0.6 g / cc to about 0.7 g / cc, from about 0.7 g / cc to about 1.0 g / cc, from about 0.7 g / cc to about 0.9 g / cc, from about 0.7 g / cc to about 0.85 g / cc, from about 0.7 g / cc to about 0.8 g / cc, from about 0.8 g / cc to about 1.0 g / cc, from about 0.8 g / cc to about 0.9 g / cc, from about 0.8 g / cc to about 0.85 g / cc, from about 0.85 g / cc to about 1.0 g / cc, from about 0.It has a tap density of approximately 0.9 g / cc to 85 g / cc, or approximately 0.9 g / cc to 1.0 g / cc.

[0132] In certain embodiments, the pharmaceutical composition has a tap density of about 0.3 g / cc to about 0.9 g / cc. In certain embodiments, the pharmaceutical composition has a tap density of about 0.35 g / cc to about 0.85 g / cc. In certain embodiments, the pharmaceutical composition has a tap density of about 0.6 g / cc to about 0.85 g / cc. In certain embodiments, the pharmaceutical composition has a tap density of about 0.7 g / cc to about 0.8 g / cc.

[0133] In a particular embodiment, when the pharmaceutical composition is passed through a 710 / 25 (micron / mesh) sieve, approximately 0.2% to approximately 90%, approximately 0.5% to approximately 90%, approximately 1% to approximately 90%, approximately 2% to approximately 90%, approximately 5% to approximately 90%, approximately 10% to approximately 90%, approximately 15% to approximately 90%, approximately 20% to approximately 90%, approximately 30% to approximately 90%, approximately 40% to approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% Approximately 90%, approximately 75% to approximately 90%, approximately 80% to approximately 90%, approximately 85% to approximately 90%, approximately 0.5% to approximately 85%, approximately 0.5% to approximately 80%, approximately 0.5% to approximately 75%, approximately 0.5% to approximately 70%, approximately 0.5% to approximately 60%, approximately 0.5% to approximately 50%, approximately 0.5% to approximately 40%, approximately 0.5% to approximately 30%, approximately 0.5% to approximately 20%, approximately 0.5% to approximately 15%, approximately 0.5% to approximately 10%, approximately 0.5% to approximately 5%, approximately 0.5% to approximately 2%, approximately 0.5% to approximately 1%, approximately 1% to approximately 85%, approximately 1% to approximately 80%, approximately 1% to approximately 75%, approximately 1% to approximately 70%, approximately 1% to approximately 60%, approximately 1% to approximately 50%, approximately 1% to approximately 40%, approximately 1% to approximately 30%, approximately 1% to approximately 20%, approximately 1% to approximately 15%, approximately 1% to approximately 10%, approximately 1% to approximately 5%, approximately 1% to approximately 2%, approximately 2% to approximately 85%, approximately 2% to approximately 80%, approximately 2% to approximately 75%, approximately 2% to approximately 70%, approximately 2% to approximately 60%, approximately 2% to approximately 50%, approximately 2% to approximately 40%, approximately 2% to approximately 30%, approximately 2% to approximately 20%, approximately 2% to approximately 15%, approximately 2% to approximately 10%, approximately 2% ~5%, 5%~85%, 5%~80%, 5%~80%, 5%~75%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~15%, 5%~10%, 10%~85%, 10%~80%, 10%~75%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 10%~15%, 15%~85%, approx. 15%~approx. 80%, approx. 15%~approx. 75%, approx. 15%~approx. 70%, approx. 15%~approx. 60%, approx. 15%~approx. 50%, approx. 15%~approx. 40%, approx. 15%~approx. 30%, approx. 15%~approx. 20%, approx. 20%~approx. 85%, approx. 20%~approx. 80%, approx. 20%~approx. 75%, approx. 20%~approx. 70%, approx. 20%~approx. 60%, approx. 20%~approx. 50%, approx. 20%~approx. 40%, approx. 20%~approx. 30%, approx. 30%~approx. 85%, approx. 30%~approx. 80%, approx. 30%~approx. 75%, approx. 30%~approx. 70%, approx. 30%~approx. 60%, approx. 30%~approx. 50%, approx. 30%~ Approximately 40%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 60%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 75%, 60% to 70%, 60% to 75%, 60% to 70%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 85%, 75% to 80%, or 80% to 85% are retained.

[0134] In a particular embodiment, when the pharmaceutical composition is passed through a 710 / 25 (micron / mesh) sieve, approximately 0.5% to approximately 75% of the pharmaceutical composition is retained. In a particular embodiment, when the pharmaceutical composition is passed through a 710 / 25 (micron / mesh) sieve, approximately 0.5% to approximately 60% of the pharmaceutical composition is retained.

[0135] In a particular embodiment, when the pharmaceutical composition is passed through a 425 / 40 (micron / mesh) sieve, the material is divided into approximately 0.2% to approximately 75%, approximately 0.5% to approximately 75%, approximately 1% to approximately 75%, approximately 2% to approximately 75%, approximately 5% to approximately 75%, approximately 15% to approximately 75%, approximately 25% to approximately 75%, approximately 35% to approximately 75%, approximately 50% to approximately 75%, approximately 0.2% to approximately 50%, approximately 0.2% to approximately 35%, approximately 0.2% to approximately 25%, approximately 0.2% to approximately 15%, approximately 0.2% to approximately 5%, approximately 0.2% to approximately 2%, approximately 0.2% to approximately 0.5%, approximately 0.5% to approximately 50%, approximately 0.5% to approximately 35%, and approximately 0.5% to approximately 25%, approximately 0.5% to 15%, approximately 0.5% to 5%, approximately 0.5% to 2%, approximately 0.5% to 1%, approximately 1% to 50%, approximately 1% to 35%, approximately 1% to 25%, approximately 1% to 15%, approximately 1% to 5%, approximately 1% to 2%, approximately 2% to 50%, approximately 2% to 35%, approximately 2% to 25%, approximately 2% to 15%, approximately 2% to 5%, approximately 5% to 50%, approximately 5% to 35%, approximately 5% to 25%, approximately 5% to 15%, approximately 15% to 50%, approximately 15% to 35%, approximately 15% to 25%, approximately 25% to 50%, approximately 25% to 35%, or approximately 35% to 50%.

[0136] In a particular embodiment, when the pharmaceutical composition is passed through a 425 / 40 (micron / mesh) sieve, approximately 2% to approximately 50% of the material is retained. In a particular embodiment, when the pharmaceutical composition is passed through a 425 / 40 (micron / mesh) sieve, approximately 5% to approximately 35% of the material is retained.

[0137] In a particular embodiment, when the pharmaceutical composition is passed through a 63 / 230 (micron / mesh) sieve, approximately 0.1% to approximately 55%, approximately 0.5% to approximately 55%, approximately 1% to approximately 55%, approximately 5% to approximately 55%, approximately 10% to approximately 55%, approximately 15% to approximately 55%, approximately 20% to approximately 55%, approximately 25% to approximately 55%, approximately 30% to approximately 55%, and approximately 40% to approximately 55% of the pharmaceutical composition. %, approximately 0.1% to 40%, approximately 0.1% to 30%, approximately 0.1% to 25%, approximately 0.1% to 20%, approximately 0.1% to 15%, approximately 0.1% to 10%, approximately 0.1% to 5%, approximately 0.1% to 1%, approximately 0.1% to 0.5%, approximately 0.5% to 40%, approximately 0.5% to 30%, approximately 0.5% to 25%, approximately 0.5% to 20%, approximately 0.5% to 15% Approximately 0.5% to 10%, approximately 0.5% to 5%, approximately 0.5% to 1%, approximately 1% to 40%, approximately 1% to 30%, approximately 1% to 25%, approximately 1% to 20%, approximately 1% to 15%, approximately 1% to 10%, approximately 1% to 5%, approximately 5% to 40%, approximately 5% to 30%, approximately 5% to 25%, approximately 5% to 20%, approximately 5% to 15%, approximately 5% to 10%, approximately 10% Approximately 40%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 40%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 40%, 20% to 30%, 20% to 25%, 25% to 40%, 25% to 30%, or 30% to 40% are retained.

[0138] In a particular embodiment, when the pharmaceutical composition is passed through a 63 / 230 (micron / mesh) sieve, approximately 0.5% to approximately 30% of the pharmaceutical composition is retained. In a particular embodiment, when the pharmaceutical composition is passed through a 63 / 230 (micron / mesh) sieve, approximately 1% to approximately 25% of the pharmaceutical composition is retained.

[0139] In a particular embodiment, the pharmaceutical composition is approximately 0.5 to approximately 0.95, approximately 0.55 to approximately 0.95, approximately 0.6 to approximately 0.95, approximately 0.7 to approximately 0.95, approximately 0.8 to approximately 0.95, approximately 0.85 to approximately 0.95, approximately 0.9 to approximately 0.95, approximately 0.5 to approximately 0.9, approximately 0.5 to approximately 0.85, approximately 0.5 to approximately 0.8, approximately 0.5 to approximately 0.7, approximately 0.5 to approximately 0.6, approximately 0.5 to approximately 0.55, and approximately 0.55. The solids content is approximately 0.9, approximately 0.55 to approximately 0.85, approximately 0.55 to approximately 0.8, approximately 0.55 to approximately 0.7, approximately 0.55 to approximately 0.6, approximately 0.6 to approximately 0.9, approximately 0.6 to approximately 0.85, approximately 0.6 to approximately 0.8, approximately 0.6 to approximately 0.7, approximately 0.7 to approximately 0.9, approximately 0.7 to approximately 0.85, approximately 0.7 to approximately 0.8, approximately 0.8 to approximately 0.9, approximately 0.8 to approximately 0.85, or approximately 0.85 to approximately 0.9. In certain embodiments, the pharmaceutical composition has a solids content of approximately 0.55 to approximately 0.9. In certain embodiments, the pharmaceutical composition has a solids content of approximately 0.6 to approximately 0.85.

[0140] In a particular embodiment, the pharmaceutical composition is measured at approximately 0.05 kg / sec to approximately 4 kg / sec, approximately 0.1 kg / sec to approximately 4 kg / sec, approximately 0.5 kg / sec to approximately 4 kg / sec, approximately 1 kg / sec to approximately 4 kg / sec, approximately 2 kg / sec to approximately 4 kg / sec, approximately 3 kg / sec to approximately 4 kg / sec, approximately 0.05 kg / sec to approximately 3 kg / sec, approximately 0.05 kg / sec to approximately 2 kg / sec, approximately 0.05 kg / sec to approximately 1 kg / sec, approximately 0.05 kg / sec to approximately 0.5 kg / sec, and approximately 0.05 kg / sec ~ approx. 0.1 kg / sec, approx. 0.1 kg / sec ~ approx. 3 kg / sec, approx. 0.1 kg / sec ~ approx. 2 kg / sec, approx. 0.1 kg / sec ~ approx. 1 kg / sec, approx. 0.1 kg / sec ~ approx. 0.5 kg / sec, approx. 0.5 kg / sec ~ approx. 3 kg per second, about 0.5 kg / sec to about 2 kg / sec, about 0.5 kg / sec to about 1 kg / sec, about 1 kg / sec to about 3 kg / sec, about 1 kg / sec to about 2 kg / sec, or about 2 kg / sec to about 3 kg / sec.

[0141] In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the compound of formula (I) after about 20 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 55% of the compound of formula (I) after about 20 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 20 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 65% of the compound of formula (I) after about 20 minutes. In certain embodiments, the pharmaceutical compositions described herein release at least about 70% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 75% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 80% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 85% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 90% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus. In a particular embodiment, the pharmaceutical compositions described herein release at least about 95% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus.

[0142] In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the compound of formula (I) after about 30 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 55% of the compound of formula (I) after about 30 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 30 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 65% of the compound of formula (I) after about 30 minutes. In certain embodiments, the pharmaceutical compositions described herein release at least about 70% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 75% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 80% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 85% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 90% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus. In a particular embodiment, the pharmaceutical compositions described herein release at least about 95% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus.

[0143] In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the compound of formula (I) after about 45 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 55% of the compound of formula (I) after about 45 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 45 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 65% of the compound of formula (I) after about 45 minutes. In certain embodiments, the pharmaceutical composition described herein releases at least about 70% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical composition described herein releases at least about 75% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical composition described herein releases at least about 80% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical composition described herein releases at least about 85% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical composition described herein releases at least about 90% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus. In a particular embodiment, the pharmaceutical compositions described herein release at least about 95% of the compound of formula (I) after about 45 minutes when tested using a USP1 or USP2 apparatus.

[0144] In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the compound of formula (I) after about 60 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 55% of the compound of formula (I) after about 60 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 60 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 60 minutes. In certain embodiments, the pharmaceutical compositions described herein release at least about 70% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 75% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 80% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 85% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 90% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus. In a particular embodiment, the pharmaceutical compositions described herein release at least about 95% of the compound of formula (I) after about 60 minutes when tested using a USP1 or USP2 apparatus.

[0145] In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the compound of formula (I) after about 75 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 55% of the compound of formula (I) after about 75 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 60% of the compound of formula (I) after about 75 minutes. In certain embodiments, when tested using a USP1 or USP2 apparatus, the pharmaceutical compositions described herein release at least about 65% of the compound of formula (I) after about 75 minutes. In certain embodiments, the pharmaceutical compositions described herein release at least about 70% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 75% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 80% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 85% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus. In certain embodiments, the pharmaceutical compositions described herein release at least about 90% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus. In a particular embodiment, the pharmaceutical compositions described herein release at least about 95% of the compound of formula (I) after about 75 minutes when tested using a USP1 or USP2 apparatus.

[0146] In certain embodiments, the release profile of the pharmaceutical composition described herein is tested using a USP1 instrument. In certain embodiments, the release profile of the pharmaceutical composition described herein is tested using a USP2 instrument.

[0147] In various embodiments, the pharmaceutical composition is (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) Lubricants and (iv) Contains a fluidizing agent. In certain embodiments, the filler includes a brittle filler, a ductile filler, or a combination thereof. In certain embodiments, the filler includes a brittle filler and a ductile filler.

[0148] In certain embodiments, the mass ratio of the brittle filler to the ductile filler is approximately 1:9 to 9:1, approximately 1:8 to 8:1, approximately 1:7 to 7:1, approximately 1:6 to 6:1, approximately 1:5 to 5:1, approximately 1:4 to 4:1, approximately 1:3 to 3:1, or approximately 1:2 to 2:1. In certain embodiments, the mass ratio of the brittle filler to the ductile filler is approximately 1:9 to 9:1. In certain embodiments, the mass ratio of the brittle filler to the ductile filler is approximately 1:5 to 5:1. In certain embodiments, the mass ratio of the brittle filler to the ductile filler is approximately 1:4 to 4:1.

[0149] In certain embodiments, the mass ratio of brittle filler to ductile filler is about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, or about 9:1.

[0150] In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 0.4% (w / w) to approximately 60% (w / w).

[0151] In a particular embodiment, the amount of brittle filler in the pharmaceutical composition is approximately 0% (w / w) to approximately 90% (w / w).

[0152] In a particular embodiment, the amount of ductile filler in the pharmaceutical composition is approximately 0% (w / w) to approximately 90% (w / w).

[0153] In a particular embodiment, the amount of disintegrant in the pharmaceutical composition is approximately 0% (w / w) to approximately 10% (w / w).

[0154] In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 0.1% (w / w) to approximately 5% (w / w).

[0155] In a particular embodiment, the amount of fluidizing agent in the pharmaceutical composition is approximately 0.1% (w / w) to approximately 3% (w / w).

[0156] In certain embodiments, the pharmaceutical composition further comprises a binder. In certain embodiments, the amount of binder in the pharmaceutical composition is about 0% (w / w) to about 10% (w / w).

[0157] In certain embodiments, the pharmaceutical composition further includes a wetting agent. In certain embodiments, the amount of wetting agent in the pharmaceutical composition is about 0% (w / w) to about 3% (w / w).

[0158] In a particular embodiment, the pharmaceutical composition is (i) The crystalline form of the compound of formula (I), [ka] (ii) Brittle filler and (iii) A ductile filler and (iv) Lubricants and, (v) Contains a fluidizing agent.

[0159] In a particular embodiment, the pharmaceutical composition is (i) Crystal morphology of compounds of formula (I) in concentrations of approximately 0.4% (w / w) to approximately 60% (w / w), [ka] (ii) Brittle filler and (iii) A ductile filler and (iv) A lubricant in an amount of approximately 0.1% (w / w) to approximately 5% (w / w), (v) Contains approximately 0.1% (w / w) to approximately 3% (w / w) of a fluidizing agent.

[0160] In various embodiments, the pharmaceutical composition is (i) Crystal morphology of compounds of formula (I) in concentrations of approximately 0.4% (w / w) to approximately 60% (w / w), [ka] (ii) A brittle filler of approximately 0% (w / w) to approximately 90% (w / w), (iii) A ductile filler of approximately 0% (w / w) to approximately 90% (w / w), (iv) Approximately 0% (w / w) to approximately 15% (w / w) of disintegrant, (v) A lubricant in an amount of approximately 0.1% (w / w) to approximately 5% (w / w), (vi) Contains approximately 0.1% (w / w) to approximately 5% (w / w) of a fluidizing agent.

[0161] In a particular mechanism, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 0.4% (w / w) to 60% (w / w), approximately 5% (w / w) to 60% (w / w), approximately 10% (w / w) to 60% (w / w), approximately 15% (w / w) to 60% (w / w), approximately 20% (w / w) to 60% (w / w), approximately 30% (w / w) to 60% (w / w), approximately 40% (w / w) to 60% (w / w), and approximately 50% (w / w) to 60% (w / w). %(w / w), approximately 0.4%(w / w) to approximately 50%(w / w), approximately 0.4%(w / w) to approximately 40%(w / w), approximately 0.4%(w / w) to approximately 30%(w / w), approximately 0.4%(w / w) to approximately 20%(w / w), approximately 0.4%(w / w) to approximately 15%(w / w), approximately 0.4%(w / w) to approximately 10%(w / w), approximately 0.4%(w / w) to approximately 5%(w / w), approximately 5%(w / w) to approximately 50%(w / w), approximately 5%(w / w) to approximately 40%(w / w), Approximately 5% (w / w) to approximately 30% (w / w), approximately 5% (w / w) to approximately 20% (w / w), approximately 5% (w / w) to approximately 15% (w / w), approximately 5% (w / w) to approximately 10% (w / w), approximately 10% (w / w) to approximately 50% (w / w), approximately 10% (w / w) to approximately 40% (w / w), approximately 10% (w / w) to approximately 30% (w / w), approximately 10% (w / w) to approximately 20% (w / w), approximately 10% (w / w) to approximately 15% (w / w), approximately 15% (w / w) to approximately 50% ( The amounts are approximately 0.4%(w / w) to 40%(w / w), approximately 15%(w / w) to 30%(w / w), approximately 15%(w / w) to 20%(w / w), approximately 20%(w / w) to 50%(w / w), approximately 20%(w / w) to 40%(w / w), approximately 20%(w / w) to 30%(w / w), approximately 30%(w / w) to 50%(w / w), approximately 30%(w / w) to 40%(w / w), or approximately 40%(w / w) to 50%(w / w). In a particular mechanism, the amount of the compound of formula (I) in the pharmaceutical composition is approximately 0.4%(w / w) to 40%(w / w). In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is about 10% (w / w) to about 40% (w / w). In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is about 10% (w / w) to about 15% (w / w).

[0162] In a particular mechanism, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 0.4% (w / w), approximately 0.5% (w / w), approximately 0.6% (w / w), approximately 0.7% (w / w), approximately 0.8% (w / w), approximately 0.9% (w / w), approximately 1% (w / w), approximately 2% (w / w), approximately 3% (w / w), approximately 4% (w / w), approximately 5% (w / w), approximately 6% (w / w), approximately 7% (w / w), and approximately 8% (w / w). Approximately 9% (w / w), approximately 10% (w / w), approximately 11% (w / w), approximately 12% (w / w), approximately 13% (w / w), approximately 14% (w / w), approximately 15% (w / w), approximately 16% (w / w), approximately 17% (w / w), approximately 18% (w / w), approximately 19% (w / w), approximately 20% (w / w), approximately 21% (w / w), approximately 22% (w / w), approximately 23% (w / w), approximately 24% (w / w), approximately 25% (w / w), approximately 26% ( w / w), approximately 27% (w / w), approximately 28% (w / w), approximately 29% (w / w), approximately 30% (w / w), approximately 31% (w / w), approximately 32% (w / w), approximately 33% (w / w), approximately 34% (w / w), approximately 35% (w / w), approximately 36% (w / w), approximately 37% (w / w), approximately 38% (w / w), approximately 39% (w / w), approximately 40% (w / w), approximately 41% (w / w), approximately 42% (w / w), approximately 43% (w / w), The amounts are approximately 44% (w / w), 45% (w / w), 46% (w / w), 47% (w / w), 48% (w / w), 49% (w / w), 50% (w / w), 51% (w / w), 52% (w / w), 53% (w / w), 54% (w / w), 55% (w / w), 56% (w / w), 57% (w / w), 58% (w / w), 59% (w / w), or 60% (w / w). In a particular embodiment, the amount of the compound of formula (I) in the pharmaceutical composition is approximately 12% (w / w). In a particular embodiment, the amount of the compound of formula (I) in the pharmaceutical composition is approximately 24% (w / w). In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 36% (w / w).

[0163] In a particular application, the amount of the crystalline form of the compound of formula (I) in the pharmaceutical composition is approximately 0.1 mg to 100 mg, approximately 1 mg to 100 mg, approximately 5 mg to 100 mg, approximately 10 mg to 100 mg, approximately 15 mg to 100 mg, approximately 20 mg to 100 mg, approximately 30 mg to 100 mg, approximately 40 mg to 100 mg, approximately 50 mg to 100 mg, approximately 60 mg to 100 mg, and approximately 70 mg to 1 00mg, about 80mg to about 100mg, about 90mg to about 100mg, about 0.1mg to about 90mg, about 0.1mg to about 80mg, about 0.1mg to about 70mg, about 0.1mg to about 60mg, about 0.1m g ~ about 50mg, about 0.1mg - about 40mg, about 0.1mg - about 30mg, about 0.1mg - about 20mg, about 0.1mg - about 15mg, about 0.1mg - about 10mg, about 0.1mg - about 5mg, about 0.1mg to about 1mg, about 1mg to about 90mg, about 1mg to about 80mg, about 1mg to about 70mg, about 1mg to about 60mg, about 1mg to about 50mg, about 1mg to about 40mg, about 1mg to about 30mg, about 1mg to about 20mg, about 1 mg~15mg, 1mg~10mg, 1mg~5mg, 5mg~90mg, 5mg~80mg, 5mg~70mg, 5mg~60mg, 5mg~50mg, 5mg~40mg, 5mg ~30mg, 5mg~20mg, 5mg~15mg, 5mg~10mg, 10mg~90mg, 10mg~80mg, 10mg~70mg, 10mg~60mg, 10mg~50mg , about 10 mg to about 40 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 90 mg, about 15 mg to about 80 mg, about 15 mg to about 70 mg, about 15 mg ~ approx. 60 mg, approx. 15 mg ~ approx. 50 mg, approx. 15 mg ~ approx. 40 mg, approx. 15 mg ~ approx. 30 mg, approx. 15 mg ~ approx. 20 mg, approx. Approximately 60mg, approximately 20mg to approximately 50mg, approximately 20mg to approximately 40mg, approximately 20mg to approximately 30mg, approximately 30mg to approximately 90mg, approximately 30mg to approximately 80mg, approximately 30mg to approximately 70mg, approximately 30mg to approximately 60mg, approximately 30mg to approximately 50m g corresponds to approximately 30mg-40mg, 40mg-90mg, 40mg-80mg, 40mg-70mg, 40mg-60mg, 40mg-50mg, 50mg-90mg, 50mg-80mg, 50mg-70mg, 50mg-60mg, 60mg-90mg, 60mg-80mg, 60mg-70mg, 70mg-90mg, 70mg-80mg, or 80mg-90mg.

[0164] In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg g, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg , about 36mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, approximately 50mg, approximately 51mg, approximately 52mg, approximately 53mg, approximately 54mg, approximately 55mg, approximately 56mg, approximately 57mg, approximately 58mg, approximately 59mg, approximately 60mg, approximately 61mg, approximately 62mg, approximately 63mg, approximately 64mg, approximately 65mg, approximately 66mg, approximately 67mg, approximately 68mg, approximately 69mg, approximately 70mg, approximately 71mg, approximately 72mg, approximately 73mg, approximately 74mg, approximately 75mg g, approximately 76 mg, approximately 77 mg, approximately 78 mg, approximately 79 mg, approximately 80 mg, approximately 81 mg, approximately 82 mg, approximately 83 mg, approximately 84 mg, approximately 85 mg, approximately 86 mg, approximately 87 mg, approximately 88 mg, approximately 89 mg, approximately 90 mg, approximately 91 mg, approximately 92 mg, approximately 93 mg, approximately 94 mg, approximately 95 mg, approximately 96 mg, approximately 97 mg, approximately 98 mg, approximately 99 mg, or approximately 100 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 20 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 25 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 30 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is approximately 40 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is about 50 mg. In a particular embodiment, the amount of the compound of formula (I) in crystalline form in the pharmaceutical composition is about 60 mg.

[0165] In a particular mechanism, the amount of brittle filler in a pharmaceutical composition is approximately 0% (w / w) to 90% (w / w), approximately 10% (w / w) to 90% (w / w), approximately 20% (w / w) to 90% (w / w), approximately 30% (w / w) to 90% (w / w), approximately 40% (w / w) to 90% (w / w), approximately 50% (w / w) to 90% (w / w), approximately 60% (w / w) to 90% (w / w), approximately 70% (w / w) to 90% (w / w), approximately 75% (w / w) to 90% (w / w), approximately 80% (w / w) to 90% (w / w), and approximately 85% (w / w) to 90% (w / w). Approximately 0% (w / w) to approximately 85% (w / w), approximately 0% (w / w) to approximately 80% (w / w), approximately 0% (w / w) to approximately 75% (w / w), approximately 0% (w / w) to approximately 70% (w / w), approximately 0% (w / w) to approximately 60% (w / w), approximately 0% (w / w) to approximately 50% (w / w), approximately 0% (w / w) to approximately 4 0% (w / w), approximately 0% (w / w) to approximately 30% (w / w), approximately 0% (w / w) to approximately 20% (w / w), approximately 0% (w / w) to approximately 10% (w / w), approximately 10% (w / w) to approximately 85% (w / w), approximately 10% (w / w) to approximately 80% (w / w), approximately 10% (w / w) to approximately 75% (w / w), Approximately 10% (w / w) to approximately 70% (w / w), approximately 10% (w / w) to approximately 60% (w / w), approximately 10% (w / w) to approximately 50% (w / w), approximately 10% (w / w) to approximately 40% (w / w), approximately 10% (w / w) to approximately 30% (w / w), approximately 10% (w / w) to approximately 20% (w / w), approximately 20% ( w / w) ~ approx. 85% (w / w), approx. 20% (w / w) ~ approx. 80% (w / w), approx. 20% (w / w) ~ approx. 75% (w / w), approx. 20% (w / w) ~ approx. 70% (w / w), approx. 20% (w / w) ~ approx. 60% (w / w), approx. 20% (w / w) ~ approx. 50% (w / w), approx. 20% (w / w) ~ Approximately 40% (w / w), approximately 20% (w / w) to approximately 30% (w / w), approximately 30% (w / w) to approximately 85% (w / w), approximately 30% (w / w) to approximately 80% (w / w), approximately 30% (w / w) to approximately 75% (w / w), approximately 30% (w / w) to approximately 70% (w / w), approximately 30% (w / w) to approximately 60% ( w / w), approximately 30% (w / w) to approximately 50% (w / w), approximately 30% (w / w) to approximately 40% (w / w), approximately 40% (w / w) to approximately 80% (w / w), approximately 40% (w / w) to approximately 70% (w / w), approximately 40% (w / w) to approximately 60% (w / w), approximately 40% (w / w) to approximately 50% (w / w),Approximately 50% (w / w) to approximately 85% (w / w), approximately 50% (w / w) to approximately 80% (w / w), approximately 50% (w / w) to approximately 75% (w / w), approximately 50% (w / w) to approximately 70% (w / w), approximately 50% (w / w) to approximately 60% (w / w), approximately 60% (w / w) to approximately 85% (w / w), approximately 60% (w / w) to approximately 80% (w / w), approximately 60% (w / w) to approximately 75% The amounts are approximately %(w / w), 60%(w / w) to 70%(w / w), 70%(w / w) to 85%(w / w), 70%(w / w) to 80%(w / w), 70%(w / w) to 75%(w / w), 75%(w / w) to 85%(w / w), 75%(w / w) to 80%(w / w), or 80%(w / w) to 85%(w / w). In a particular embodiment, the amount of brittle filler in the pharmaceutical composition is approximately 30%(w / w) to 75%(w / w). In a particular embodiment, the amount of brittle filler in the pharmaceutical composition is approximately 60%(w / w) to 70%(w / w).

[0166] In a particular mechanism, the amount of brittle filler in a pharmaceutical composition is approximately 35% (w / w) to 45% (w / w), approximately 37% (w / w) to 45% (w / w), approximately 39% (w / w) to 45% (w / w), approximately 41% (w / w) to 45% (w / w), approximately 43% (w / w) to 45% (w / w), approximately 35% (w / w) to 43% (w / w), and approximately 35% (w / w) to 41% (w / w). ), approximately 35%(w / w) to approximately 39%(w / w), approximately 35%(w / w) to approximately 37%(w / w), approximately 37%(w / w) to approximately 43%(w / w), approximately 37%(w / w) to approximately 41%(w / w), approximately 37%(w / w) to approximately 39%(w / w), approximately 39%(w / w) to approximately 43%(w / w), approximately 39%(w / w) to approximately 41%(w / w), or approximately 41%(w / w) to approximately 43%(w / w). In a particular embodiment, the amount of brittle filler in the pharmaceutical composition is approximately 41%(w / w) to approximately 45%(w / w).

[0167] The amount of brittle filler in a pharmaceutical composition is approximately 100mg to 400mg, approximately 125mg to 400mg, approximately 150mg to 400mg, approximately 175mg to 400mg, approximately 200mg to 400mg, approximately 225mg to 400mg, approximately 250mg to 400mg, approximately 275mg to 400mg, approximately 300mg to 400mg, approximately 325mg to 400mg, approximately 350mg to 400mg, approximately 375mg to 400mg, approximately 100mg to 375mg, approximately 100mg to 350mg, approximately 100mg to 325mg, and approximately 100mg to approximately 3... 00mg, approximately 100mg to approximately 275mg, approximately 100mg to approximately 250mg, approximately 100mg to approximately 225mg, approximately 100mg to approximately 200mg, approximately 100mg to approximately 175mg, approximately 100mg to approximately 150mg, approximately 100mg to approximately 125mg, approximately 125mg to approximately 375mg, approximately 125mg to approximately 350mg, approximately 125mg to approximately 325mg, approximately 125mg to approximately 300mg, approximately 125mg to approximately 275mg, approximately 125mg to approximately 250mg, approximately 125mg to approximately 225mg, approximately 125mg to approximately 200mg, approximately 125mg to approximately 175mg, approximately 125mg to approximately 150mg, approximately 150mg ~approx. 375mg, approx. 150mg~approx. 350mg, approx. 150mg~approx. 325mg, approx. 150mg~approx. 300mg, approx. 150mg~approx. 275mg, approx. 150mg~approx. 250mg, approx. 150mg~approx. 225mg, approx. 150mg~approx. 200mg, approx. 150mg~approx. 175mg, approx. 175mg~approx. 375mg, approx. 175mg~approx. 350mg, approx. 175mg~approx. 325mg, approx. 175mg~approx. 300mg, approx. 175mg~approx. 275mg, approx. 175mg~approx. 250mg, approx. 175mg~approx. 225mg, approx. 175mg~approx. 200mg, approx. 200mg~approx. 400mg, approx. 200mg 0mg~approx. 375mg, approx. 200mg~approx. 350mg, approx. 200mg~approx. 325mg, approx. 200mg~approx. 300mg, approx. 200mg~approx. 275mg, approx. 200mg~approx. 250mg, approx. 200mg~approx. 225mg, approx. 225mg~approx. 375mg, approx. 225mg~approx. 350mg, approx. 225mg~approx. 325mg, approx. 250mg~approx. 300mg, approx. 250mg~approx. 275mg, approx. 250mg~approx. 350mg, approx. 250mg~approx. 325mg, approx. 250mg~approx. 300mg, approx. 250mg~approx. 275mgIt is about 275 mg to about 375 mg, about 275 mg to about 350 mg, about 275 mg to about 325 mg, about 275 mg to about 300 mg, about 300 mg to about 375 mg, about 300 mg to about 350 mg, about 300 mg to about 325 mg, about 325 mg to about 375 mg, about 325 mg to about 350 mg, or about 350 mg to about 400 mg.

[0168] In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 105.9 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 132 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 159 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 212 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 265 mg. In certain embodiments, the amount of the friable filler in the pharmaceutical composition is about 317.7 mg.

[0169] In a particular mechanism, the amount of ductile filler in a pharmaceutical composition is approximately 0% (w / w) to 90% (w / w), approximately 5% (w / w) to 90% (w / w), approximately 10% (w / w) to 90% (w / w), approximately 15% (w / w) to 90% (w / w), approximately 20% (w / w) to 90% (w / w), approximately 25% (w / w) to 90% (w / w), approximately 35% (w / w) to 90% (w / w), approximately 45% (w / w) to 90% (w / w), approximately 55% (w / w) to 90% (w / w), approximately 65% ​​(w / w) to 90% (w / w), and approximately 75% (w / w) to 90% (w / w). Approximately 0% (w / w) to 75% (w / w), approximately 0% (w / w) to 65% (w / w), approximately 0% (w / w) to 55% (w / w), approximately 0% (w / w) to 45% (w / w), approximately 0% (w / w) to 35% (w / w), approximately 0% (w / w) to 25% (w / w), approximately 0% (w / w) ~20% (w / w), 0% (w / w) to 15% (w / w), 0% (w / w) to 10% (w / w), 0% (w / w) to 5% (w / w), 5% (w / w) to 75% (w / w), 5% (w / w) to 65% (w / w), 5% (w / w) to 55% (w / w), Approximately 5% (w / w) to 45% (w / w), approximately 5% (w / w) to 35% (w / w), approximately 5% (w / w) to 25% (w / w), approximately 5% (w / w) to 20% (w / w), approximately 5% (w / w) to 15% (w / w), approximately 5% (w / w) to 10% (w / w), approximately 10% (w / w) ~75% (w / w), 10% (w / w)~65% (w / w), 10% (w / w)~55% (w / w), 10% (w / w)~45% (w / w), 10% (w / w)~35% (w / w), 10% (w / w)~25% (w / w), 10% (w / w)~20% %(w / w), approximately 10%(w / w) to approximately 15%(w / w), approximately 15%(w / w) to approximately 75%(w / w), approximately 15%(w / w) to approximately 65%(w / w), approximately 15%(w / w) to approximately 55%(w / w), approximately 15%(w / w) to approximately 45%(w / w), approximately 15%(w / w) to approximately 35%(w / w), approximately 15%(w / w) to approximately 25%(w / w), approximately 15%(w / w) to approximately 20%(w / w), approximately 20%(w / w) to approximately 75%(w / w), approximately 20%(w / w) to approximately 65%(w / w), approximately 20%(w / w) to approximately 55%(w / w), approximately 20%(w / w) to approximately 45%(w / w),About 20% (w / w) to about 35% (w / w), about 20% (w / w) to about 25% (w / w), about 25% (w / w) to about 75% (w / w), about 25% (w / w) to about 65% (w / w), about 25% (w / w) to about 55% (w / w), about 25% (w / w) to about 45% (w / w), about 25% (w / w) to about 35% (w / w), about 35% (w / w) to about 75% (w / w), about 35% (w / w) to about 65% (w / w), about 35% (w / w) to about 55% (w / w), about 35% (w / w) to about 45% (w / w), about 45% (w / w) to about 75% (w / w), about 45% (w / w) to about 65% (w / w), about 45% (w / w) to about 55% (w / w), about 55% (w / w) to about 75% (w / w), about 55% (w / w) to about 65% (w / w), or about 65% (w / w) to about 75% (w / w). In certain embodiments, the amount of the ductile filler in the pharmaceutical composition is about 5% (w / w) to about 25% (w / w). In certain embodiments, the amount of the ductile filler in the pharmaceutical composition is about 10% (w / w) to about 20% (w / w).

[0170] In certain embodiments, the amount of the ductile filler in the pharmaceutical composition is about 35% (w / w) to about 45% (w / w), about 37% (w / w) to about 45% (w / w), about 39% (w / w) to about 45% (w / w), about 41% (w / w) to about 45% (w / w), about 43% (w / w) to about 45% (w / w), about 35% (w / w) to about 43% (w / w), about 35% (w / w) to about 41% (w / w), about 35% (w / w) to about 39% (w / w), about 35% (w / w) to about 37% (w / w), about 37% (w / w) to about 43% (w / w), about 37% (w / w) to about 41% (w / w), about 37% (w / w) to about 39% (w / w), about 39% (w / w) to about 43% (w / w), about 39% (w / w) to about 41% (w / w), or about 41% (w / w) to about 43% (w / w). In certain embodiments, the amount of the ductile filler in the pharmaceutical composition is about 41% (w / w) to about 45% (w / w).

[0171] For a certain ATP, the amount of ductile filler in a pharmaceutical composition is approximately 10mg to 100mg, approximately 20mg to 100mg, approximately 30mg to 100mg, approximately 40mg to 100mg, approximately 50mg to 100mg, approximately 60mg to 100mg, approximately 70mg to 100mg, approximately 80mg to 100mg, approximately 90mg to 100mg, approximately 10mg to 90mg, approximately 10mg to 80mg, approximately 10mg to 70mg, approximately 10mg to 60mg, approximately 10mg to 50mg, approximately 10mg to 40mg, approximately 10mg to 40mg, approximately 10mg to 30mg, approximately 10mg to 20mg, approximately 20mg to 90mg, approximately 20mg to 80mg, approximately 20mg to 70mg, approximately 20mg to 20mg 60mg, about 20mg to about 50mg, about 20mg to about 40mg, about 20mg to about 30mg, about 30mg to about 90mg, about 30mg to about 80mg, about 30mg to about 70 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 40 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 70 mg, The dosages are approximately 40mg to 60mg, 40mg to 50mg, 50mg to 90mg, 50mg to 80mg, 50mg to 70mg, 50mg to 60mg, 60mg to 90mg, 60mg to 80mg, 60mg to 70mg, 70mg to 90mg, 70mg to 80mg, or 80mg to 90mg.

[0172] In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 26.2 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 32.7 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 39.3 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 52.4 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 65.5 mg. In certain embodiments, the amount of ductile filler in the pharmaceutical composition is about 78.6 mg.

[0173] At a certain mechanism, the amount of disintegrant in the pharmaceutical composition is approximately 0% (w / w) to 15% (w / w), approximately 0.5% (w / w) to 15% (w / w), approximately 1% (w / w) to 15% (w / w), approximately 1.5% (w / w) to 15% (w / w), approximately 2% (w / w) to 15% (w / w), approximately 2.5% (w / w) to 15% (w / w), approximately 4% (w / w) to 15% (w / w), approximately 6% (w / w) to 15% (w / w), approximately 8% (w / w) to 15% (w / w), and approximately 10% (w / w) to 15% (w / w). Approximately 12% (w / w) to 15% (w / w), approximately 0% (w / w) to 12% (w / w), approximately 0% (w / w) to 10% (w / w), approximately 0% (w / w) to 8% (w / w), approximately 0% (w / w) to 6% (w / w), approximately 0% (w / w) to 4% (w / w), approximately 0% (w / w) to 2.5% (w / w), approximately 0% (w / w) to 2% (w / w), approximately 0% (w / w) to 1.5% (w / w), approximately 0% (w / w) to 1% (w / w), approximately 0% (w / w) to 0.5% (w / w), approximately 0.5% (w / w) to 12% (w / w), approximately 0.5%(w / w) to approximately 10%(w / w), approximately 0.5%(w / w) to approximately 8%(w / w), approximately 0.5%(w / w) to approximately 6%(w / w), approximately 0.5%(w / w) to approximately 4%(w / w), approximately 0.5%(w / w) to approximately 2.5%(w / w), approximately 0.5%(w / w) to approximately 2%(w / w), approximately 0.5%(w / w) to approximately 1.5%(w / w), approximately 0.5%(w / w) to approximately 1%(w / w), approximately 1%(w / w) to approximately 12%(w / w), approximately 1%(w / w) to approximately 10%(w / w), approximately 1%(w / w) to approximately 8%(w / w), approximately 1% (w / w) to approximately 6% (w / w), approximately 1% (w / w) to approximately 4% (w / w), approximately 1% (w / w) to approximately 2.5% (w / w), approximately 1% (w / w) to approximately 2% (w / w), approximately 1% (w / w) to approximately 1.5% (w / w), approximately 1.5% (w / w) to approximately 12% (w / w), approximately 1.5% (w / w) to approximately 10% (w / w), approximately 1.5% (w / w) to approximately 8% (w / w), approximately 1.5% (w / w) to approximately 6% (w / w), approximately 1.5% (w / w) to approximately 4% (w / w), approximately 1.5% (w / w) to approximately 2.5% (w / w), approximately 1.5%(w / w) to approximately 2%(w / w), approximately 2%(w / w) to approximately 12%(w / w), approximately 2%(w / w) to approximately 10%(w / w), approximately 2%(w / w) to approximately 8%(w / w), approximately 2%(w / w) to approximately 6%(w / w), approximately 2%(w / w) to approximately 4%(w / w), approximately 2%(w / w) to approximately 2.5%(w / w), approximately 2.5%(w / w) to approximately 12%(w / w), approximately 2.5%(w / w) to approximately 10%(w / w), approximately 2.5%(w / w) to approximately 8%(w / w), approximately 2.5%(w / w) to approximately 6%(w / w), approximately The amounts are approximately 2.5% (w / w) to 4% (w / w), approximately 4% (w / w) to 12% (w / w), approximately 4% (w / w) to 10% (w / w), approximately 4% (w / w) to 8% (w / w), approximately 4% (w / w) to 6% (w / w), approximately 6% (w / w) to 12% (w / w), approximately 6% (w / w) to 10% (w / w), approximately 6% (w / w) to 8% (w / w), approximately 8% (w / w) to 12% (w / w), approximately 8% (w / w) to 10% (w / w), or approximately 10% (w / w) to 12% (w / w). In a particular mechanism, the amount of disintegrant in the pharmaceutical composition is approximately 2.5% (w / w) to 10% (w / w). In certain embodiments, the amount of disintegrant in the pharmaceutical composition is approximately 4% (w / w) to approximately 8% (w / w).

[0174] In a particular embodiment, the amount of disintegrant in the pharmaceutical composition is approximately 5 mg to approximately 40 mg, approximately 10 mg to approximately 40 mg, approximately 15 mg to approximately 40 mg, approximately 20 mg to approximately 40 mg, approximately 25 mg to approximately 40 mg, approximately 30 mg to approximately 40 mg, approximately 35 mg to approximately 40 mg, approximately 5 mg to approximately 35 mg, approximately 5 mg to approximately 30 mg, approximately 5 mg to approximately 25 mg, approximately 5 mg to approximately 20 mg, approximately 5 mg to approximately 15 mg, approximately 5 mg to approximately 10 mg, approximately 10 mg to approximately 35 mg, approximately 10 mg to approximately 30 mg, and approximately 10 mg g ~ about 25 mg, about 10 mg - about 20 mg, about 10 mg - about 15 mg, about 15 mg - about 35 mg, about 15 mg - about 30 mg, about 15 mg - about 25 mg, about 15 mg - about 20 mg, about 20 mg - about 35 mg, about 15 mg - about 30 mg , about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, or about 30 mg to about 35 mg.

[0175] In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, or about 40 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 10 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 12.5 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 15 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 20 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 25 mg. In certain embodiments, the amount of disintegrant in the pharmaceutical composition is about 30 mg.

[0176] In a particular mechanism, the amount of lubricant in the pharmaceutical composition is approximately 0.1% (w / w) to 5% (w / w), approximately 0.25% (w / w) to 5% (w / w), approximately 0.5% (w / w) to 5% (w / w), approximately 1% (w / w) to 5% (w / w), approximately 2% (w / w) to 5% (w / w), approximately 3% (w / w) to 5% (w / w), and approximately 4% (w / w) ~ approximately 5% (w / w), approximately 0.1% (w / w) ~ approximately 4% (w / w), approximately 0.1% (w / w) ~ approximately 3% (w / w), approximately 0.1% (w / w) ~ approximately 2% (w / w), approximately 0.1% (w / w) ~ approximately 1% (w / w), approximately 0.1% (w / w) ~ approximately 0.5% (w / w), approximately 0.1% (w / w) ~ approximately 0.25% (w / w), approximately 0.25% ( w / w) ~ approximately 4% (w / w), approximately 0.25% (w / w) ~ approximately 3% (w / w), approximately 0.25% (w / w) ~ approximately 2% (w / w), approximately 0.25% (w / w) ~ approximately 1% (w / w), approximately 0.25% (w / w) ~ approximately 0.5% (w / w), approximately 0.5% (w / w) ~ approximately 4% (w / w), approximately 0.5% (w / w) ~ approximately 3% (w / w), approximately 0.5% (w The amounts are approximately 2% (w / w), 0.5% (w / w) to 1% (w / w), 1% (w / w) to 4% (w / w), 1% (w / w) to 3% (w / w), 1% (w / w) to 2% (w / w), 2% (w / w) to 4% (w / w), 2% (w / w) to 3% (w / w), or 3% (w / w) to 4% (w / w). In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 0.25% (w / w) to 3% (w / w). In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 1% (w / w) to 2% (w / w).

[0177] In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 1 mg to 10 mg, approximately 1.2 mg to 10 mg, approximately 1.4 mg to 10 mg, approximately 1.6 mg to 10 mg, approximately 1.8 mg to 10 mg, approximately 2 mg to 10 mg, approximately 2.5 mg to 10 mg, approximately 3 mg to 10 mg, approximately 4 mg to 10 mg, approximately 5 mg to 10 mg, approximately 6 mg to 10 mg, approximately 8 mg to 10 mg, approximately 1 mg to 8 mg, approximately 1 mg to 6 mg, approximately 1 mg to 5 mg, approximately 1 mg to 4 mg, approximately 1 mg to 3 mg, approximately 1 mg to 2.5 mg, and approximately 1 mg ~2mg, approx. 1mg~approx. 1.8mg, approx. 1mg~approx. 1.6mg, approx. 1mg~approx. 1.4mg, approx. 1mg~approx. 1.2mg, approx. 1.2mg~approx. 8mg, approx. 1.2mg~approx. 6mg, approx. 1.2mg~approx. 5mg, approx. 1.2mg~approx. 4mg, approx. 1.2mg~approx. 3mg, approx. 1.2mg~approx. 2.5mg, approx. 1.2mg~approx. 2mg, approx. 1.2mg~approx. 1.8mg, approx. 1.2mg~approx. 1.6mg, approx. 1.2mg~approx. 1.4mg, approx. 1.4mg~approx. 8mg, approx. 1.4mg~approx. 6mg, approx. 1.4mg~approx. 5mg, approx. 1.4mg~approx. 4mg, approx. 1.4mg~ Approximately 3mg, approximately 1.4mg to approximately 2.5mg, approximately 1.4mg to approximately 2mg, approximately 1.4mg to approximately 1.8mg, approximately 1.4mg to approximately 1.6mg, approximately 1.6mg to approximately 8mg, approximately 1.6mg to approximately 6mg, approximately 1.6mg to approximately 5mg, approximately 1.6mg to approximately 4mg, approximately 1.6mg to approximately 3mg, approximately 1.6mg to approximately 2.5mg, approximately 1.6mg to approximately 2mg, approximately 1.6mg to approximately 1.8mg, approximately 1.8mg to approximately 8mg, approximately 1.8mg to approximately 6mg, approximately 1.8mg to approximately 5mg, approximately 1.8mg to approximately 4mg, approximately 1.8mg to approximately 3mg, approximately 1.8mg to approximately 2.5mg, approximately 1. The dosages are approximately 8mg to 2mg, 2mg to 8mg, 2mg to 6mg, 2mg to 5mg, 2mg to 4mg, 2mg to 3mg, 2mg to 2.5mg, 2.5mg to 8mg, 2.5mg to 6mg, 2.5mg to 5mg, 2.5mg to 4mg, 2.5mg to 3mg, 3mg to 8mg, 3mg to 6mg, 3mg to 5mg, 3mg to 4mg, 4mg to 8mg, 4mg to 6mg, 4mg to 5mg, 5mg to 8mg, 5mg to 6mg, or 6mg to 8mg.

[0178] In a particular embodiment, the amount of lubricant in the pharmaceutical composition is about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, 1.8 mg, about 1.9 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is about 1.7 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is about 2.1 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is about 2.5 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is about 3.3 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 4.2 mg. In a particular embodiment, the amount of lubricant in the pharmaceutical composition is approximately 5 mg.

[0179] In a particular mechanism, the amount of fluidizer in the pharmaceutical composition is approximately 0.1% (w / w) to 5% (w / w), approximately 0.25% (w / w) to 5% (w / w), approximately 0.5% (w / w) to 5% (w / w), approximately 1% (w / w) to 5% (w / w), approximately 1.5% (w / w) to 5% (w / w), approximately 2% (w / w) to 5% (w / w), approximately 2.5% (w / w) to 5% (w / w), approximately 3% (w / w) to 5% (w / w), approximately 4% (w / w) to 5% (w / w), approximately 0.1% (w / w) to 4% (w / w), and approximately 0.1% (w / w) to 3%. (w / w), approximately 0.1%(w / w) to approximately 2.5%(w / w), approximately 0.1%(w / w) to approximately 2%(w / w), approximately 0.1%(w / w) to approximately 1.5%(w / w), approximately 0.1%(w / w) to approximately 1%(w / w), approximately 0.1%(w / w) to approximately 0.5%(w / w), approximately 0.1%(w / w) to approximately 0.25%(w / w), approximately 0.25%(w / w) to approximately 4%(w / w), approximately 0.25%(w / w) to approximately 3%(w / w), approximately 0.25%(w / w) to approximately 2.5%(w / w), approximately 0.25%(w / w) to approximately 2%(w / w), approximately 0.25%(w / w) to approximately 1. 5% (w / w), approximately 0.25% (w / w) to approximately 1% (w / w), approximately 0.25% (w / w) to approximately 0.5% (w / w), approximately 0.5% (w / w) to approximately 4% (w / w), approximately 0.5% (w / w) to approximately 3% (w / w), approximately 0.5% (w / w) to approximately 2.5% (w / w), approximately 0.5% (w / w) to approximately 2% (w / w), approximately 0.5% (w / w) to approximately 1.5% (w / w), approximately 0.5% (w / w) to approximately 1% (w / w), approximately 1% (w / w) to approximately 4% (w / w), approximately 1% (w / w) to approximately 3% (w / w), approximately 1% (w / w) to approximately 2.5% (w / w), approximately 1% The percentages are approximately 2% (w / w) from 1% (w / w) to 1.5% (w / w), 4% (w / w) from 1.5% (w / w) to 3% (w / w), 2.5% (w / w) from 1.5% (w / w) to 2% (w / w), 4% (w / w) from 2% (w / w) to 3% (w / w), 2% (w / w) to 3% (w / w), 2% (w / w) to 2.5% (w / w), 4% (w / w) from 2.5% (w / w) to 3% (w / w), or 4% (w / w) from 3% (w / w). In a particular embodiment, the amount of fluidizer in the pharmaceutical composition is approximately 0.25% (w / w) to approximately 2.5% (w / w).In a particular embodiment, the amount of fluidizing agent in the pharmaceutical composition is approximately 0.5% (w / w) to approximately 2% (w / w).

[0180] In a particular embodiment, the amount of fluidizer in the pharmaceutical composition is approximately 1 mg to 10 mg, approximately 1.2 mg to 10 mg, approximately 1.4 mg to 10 mg, approximately 1.6 mg to 10 mg, approximately 1.8 mg to 10 mg, approximately 2 mg to 10 mg, approximately 2.5 mg to 10 mg, approximately 3 mg to 10 mg, approximately 3.5 mg to 10 mg, approximately 4 mg to 10 mg, approximately 4.5 mg to 10 mg, approximately 5 mg to 10 mg, approximately 6 mg to 10 mg, approximately 8 mg to 10 mg, approximately 1 mg to 8 mg, approximately 1 mg to 6 mg, approximately 1 mg to 5 mg, approximately 1 mg to 4.5 mg, and approximately 1 mg to 4 mg. , about 1 mg to about 3.5 mg, about 1 mg to about 3 mg, about 1 mg to about 2.5 mg, about 1 mg to about 2 mg, about 1 mg to about 1.8 mg, about 1 mg to about 1.6 mg, about 1 mg to about 1.4 mg, about 1 mg to about 1.2 mg, about 1.2 mg to about 8 mg, about 1.2 mg to about 6 mg, about 1.2 mg Approximately 5 mg, approximately 1.2 mg to approximately 4.5 mg, approximately 1.2 mg to approximately 4 mg, approximately 1.2 mg to approximately 3.5 mg, approximately 1.2 mg to approximately 3 mg, approximately 1.2 mg to approximately 2.5 mg, approximately 1.2 mg to approximately 2 mg, approximately 1.2 mg to approximately 1.8 mg, approximately 1.2 mg to approximately 1.6 mg, approximately 1.2 mg to approximately 1.4 mg Approximately 1.4mg to 8mg, approximately 1.4mg to 6mg, approximately 1.4mg to 5mg, approximately 1.4mg to 4.5mg, approximately 1.4mg to 4mg, approximately 1.4mg to 3.5mg, approximately 1.4mg to 3mg, approximately 1.4mg to 2.5mg, approximately 1.4mg to 2mg, approximately 1.4mg to 1.8mg, approximately 1.4mg to 1.6mg, approximately 1.6mg to 8mg, approximately 1.6mg to 6mg, approximately 1.6mg to 5mg, approximately 1.6mg to 4.5mg, approximately 1.6mg to 4mg, approximately 1.6mg to 3.5mg, approximately 1.6mg to 3mg, approximately 1.6mg to 2.5mg, approximately 1. 6mg to approximately 2mg, approximately 1.6mg to approximately 1.8mg, approximately 1.8mg to approximately 8mg, approximately 1.8mg to approximately 6mg, approximately 1.8mg to approximately 5mg, approximately 1.8mg to approximately 4.5mg, approximately 1.8mg to approximately 4mg, approximately 1.8mg to approximately 3.5mg, approximately 1.8mg to approximately 3mg, approximately 1.8mg to approximately 2.5mg, approximately 1.8mg to approximately 2mg, approximately 2mg to approximately 8mg, approximately 2mg to approximately 6mg, approximately 2mg to approximately 5mg, approximately 2mg to approximately 4mg, approximately 2mg to approximately 4mg, approximately 2mg to approximately 3.5mg, approximately 2mg to approximately 3mg, approximately 2mg to approximately 2.5mg, approximately 2.5mg to approximately 8mg, approximately 2.5mg to approximately 6mg, approximately 2.The dosages are approximately 5mg to 5mg, approximately 2.5mg to 4.5mg, approximately 2.5mg to 4mg, approximately 2.5mg to 3.5mg, approximately 2.5mg to 3mg, approximately 3mg to 8mg, approximately 3mg to 6mg, approximately 3mg to 5mg, approximately 3mg to 4.5mg, approximately 3mg to 4mg, approximately 3mg to 3.5mg, approximately 3.5mg to 8mg, approximately 3.5mg to 6mg, approximately 3.5mg to 5mg, approximately 3.5mg to 4.5mg, approximately 3.5mg to 4mg, approximately 4mg to 8mg, approximately 4mg to 6mg, approximately 4mg to 5mg, approximately 4mg to 4.5mg, approximately 4.5mg to 8mg, approximately 4.5mg to 6mg, approximately 4.5mg to 5mg, approximately 5mg to 8mg, approximately 5mg to 6mg, or approximately 6mg to 8mg. .

[0181] In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 2.9 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 3.6 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 4.4 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 5.8 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 7.3 mg. In certain embodiments, the amount of fluidizer in the pharmaceutical composition is about 8.8 mg.

[0182] In a certain mechanism, the amount of binder in the pharmaceutical composition is approximately 0% (w / w) to 10% (w / w), approximately 2% (w / w) to 10% (w / w), approximately 4% (w / w) to 10% (w / w), approximately 6% (w / w) to 10% (w / w), approximately 8% (w / w) to 10% (w / w), approximately 0% (w / w) to 8% (w / w), and approximately 0% (w / w) to 6% ( The percentages are approximately w / w, 0% (w / w) to 4% (w / w), 0% (w / w) to 2% (w / w), 2% (w / w) to 8% (w / w), 2% (w / w) to 6% (w / w), 2% (w / w) to 4% (w / w), 4% (w / w) to 8% (w / w), 4% (w / w) to 6% (w / w), or 6% (w / w) to 8% (w / w).

[0183] In a particular admin, the amount of binder in the pharmaceutical composition is approximately 1 mg to 20 mg, approximately 2 mg to 20 mg, approximately 4 mg to 20 mg, approximately 6 mg to 20 mg, approximately 8 mg to 20 mg, approximately 10 mg to 20 mg, approximately 12 mg to 20 mg, approximately 15 mg to 20 mg, approximately 1 mg to 15 mg, approximately 1 mg to 12 mg, approximately 1 mg to 10 mg, approximately 1 mg to 8 mg, approximately 1 mg to 6 mg, approximately 1 mg to 4 mg, approximately 1 mg to 2 mg, approximately 2 mg to 15 mg, and approximately 2 mg to 12 mg. The dosages are approximately 2mg to 10mg, 2mg to 8mg, 2mg to 6mg, 2mg to 4mg, 4mg to 15mg, 4mg to 12mg, 4mg to 10mg, 4mg to 8mg, 4mg to 6mg, 6mg to 15mg, 6mg to 12mg, 6mg to 10mg, 6mg to 8mg, 8mg to 15mg, 8mg to 12mg, 8mg to 10mg, 10mg to 15mg, 10mg to 12mg, or 12mg to 15mg.

[0184] In a particular administrative state, the amount of binder in the pharmaceutical composition is approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, or approximately 20 mg.

[0185] In a particular mechanism, the amount of humectant in the pharmaceutical composition is approximately 0% (w / w) to 3% (w / w), approximately 0.5% (w / w) to 3% (w / w), approximately 1% (w / w) to 3% (w / w), approximately 1.5% (w / w) to 3% (w / w), approximately 2% (w / w) to 3% (w / w), approximately 2.5% (w / w) to 3% (w / w), approximately 0% (w / w) to 2.5% (w / w), approximately 0% (w / w) to 2% (w / w), approximately 0% (w / w) to 1.5% (w / w), approximately 0% (w / w) to 1% (w / w), approximately 0% (w / w) w) ~ approximately 0.5% (w / w), approximately 0.5% (w / w) ~ approximately 2.5% (w / w), approximately 0.5% (w / w) ~ approximately 2% (w / w), approximately 0.5% (w / w) ~ approximately 1.5% (w / w), approximately 0.5% (w / w) ~ approximately 1% (w / w), approximately 1% (w / w) ~ approximately 2.5% (w / w), approximately 1% (w / w) ~ approximately 2% (w / w), approximately 1% (w / w) ~ approximately 1.5% (w / w), approximately 1.5% (w / w) ~ approximately 2.5% (w / w), approximately 1.5% (w / w) ~ approximately 2% (w / w), or approximately 2% (w / w) ~ approximately 2.5% (w / w).

[0186] In a particular admin, the amount of wetting agent in the pharmaceutical composition is approximately 1 mg to 20 mg, approximately 2 mg to 20 mg, approximately 4 mg to 20 mg, approximately 6 mg to 20 mg, approximately 8 mg to 20 mg, approximately 10 mg to 20 mg, approximately 12 mg to 20 mg, approximately 15 mg to 20 mg, approximately 1 mg to 15 mg, approximately 1 mg to 12 mg, approximately 1 mg to 10 mg, approximately 1 mg to 8 mg, approximately 1 mg to 6 mg, approximately 1 mg to 4 mg, approximately 1 mg to 2 mg, approximately 2 mg to 15 mg, and approximately 2 mg to 12 mg. The dosages are approximately 2mg to 10mg, 2mg to 8mg, 2mg to 6mg, 2mg to 4mg, 4mg to 15mg, 4mg to 12mg, 4mg to 10mg, 4mg to 8mg, 4mg to 6mg, 6mg to 15mg, 6mg to 12mg, 6mg to 10mg, 6mg to 8mg, 8mg to 15mg, 8mg to 12mg, 8mg to 10mg, 10mg to 15mg, 10mg to 12mg, or 12mg to 15mg.

[0187] In certain embodiments, the amount of the wetting agent in the pharmaceutical composition is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

[0188] In various embodiments, the pharmaceutical composition (i) about 0.4% (w / w) to 36% (w / w) of the crystalline form of the compound of formula (I), and

Chemical formula

[0189] In various embodiments, the pharmaceutical composition (i) about 10% (w / w) to about 15% (w / w) of the crystalline form of the compound of formula (I), and <00s00976>

Chemical formula

[0190] In certain embodiments, the brittle filler is selected from the group consisting of sugars, inorganic materials, and combinations thereof. In certain embodiments, the sugar is selected from the group consisting of mannitol, lactose, sucrose, fructose, glucose, maltose, and combinations thereof. In certain embodiments, the inorganic material is selected from the group consisting of dicalcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0191] In certain embodiments, the brittle filler is selected from the group consisting of mannitol, lactose, dicalcium phosphate, and combinations thereof. In certain embodiments, the brittle filler is mannitol. In certain embodiments, the brittle filler is lactose. In certain embodiments, the brittle filler is dicalcium phosphate.

[0192] In certain embodiments, the ductile filler is selected from the group consisting of microcrystalline cellulose, starch, polysaccharide, cellulose, polyvinylpyrrolidone, polyvinyl acrylate, and combinations thereof. In certain embodiments, the cellulose is selected from the group consisting of hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

[0193] In certain embodiments, the ductile filler is microcrystalline cellulose. In certain embodiments, the ductile filler is starch.

[0194] In certain embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, and combinations thereof. In certain embodiments, the disintegrant is croscarmellose sodium.

[0195] In certain embodiments, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, and combinations thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0196] In certain embodiments, the fluidizer is selected from the group consisting of colloidal silicon dioxide, talc, kaolin, bentonite, or a combination thereof. In certain embodiments, the fluidizer is colloidal silicon dioxide.

[0197] In certain embodiments, the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, starch, and combinations thereof.

[0198] In a particular embodiment, the wetting agent is selected from the group consisting of poloxamer, sodium dodecyl sulfate, sodium doxate, and combinations thereof.

[0199] In certain embodiments, the filler comprises mannitol and microcrystalline cellulose, and the mass ratio of mannitol to microcrystalline cellulose in the pharmaceutical composition is approximately 1:4 to approximately 4:1. In certain embodiments, the filler comprises lactose and microcrystalline cellulose, and the mass ratio of lactose to microcrystalline cellulose in the pharmaceutical composition is approximately 1:4 to approximately 4:1. In certain embodiments, the filler comprises dicalcium phosphate and microcrystalline cellulose, and the mass ratio of dicalcium phosphate to microcrystalline cellulose in the pharmaceutical composition is approximately 1:4 to approximately 4:1. In certain embodiments, the filler comprises mannitol and starch, and the mass ratio of mannitol to starch in the pharmaceutical composition is approximately 1:4 to approximately 4:1. In certain embodiments, the filler comprises dicalcium phosphate and starch, and the mass ratio of dicalcium phosphate to starch is approximately 1:4 to approximately 4:1.

[0200] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 10 mg of the compound of formula (I), [ka] (ii) Approximately 53 mg of mannitol and (iii) Approximately 13 mg of silicified microcrystalline cellulose, (iv) Approximately 5 mg of croscarmellose sodium, (v) Approximately 1 mg of colloidal silicon dioxide, (vi) Contains approximately 1 mg of stearyl sodium fumarate.

[0201] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 20 mg of the compound of formula (I), [ka] (ii) Approximately 105.9 mg of mannitol and (iii) Approximately 26.2 mg of silicified microcrystalline cellulose, (iv) Approximately 10 mg of croscarmellose sodium, (v) Approximately 1.7 mg of colloidal silicon dioxide, (vi) Contains approximately 2.9 mg of stearyl sodium fumarate.

[0202] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 25 mg of the compound of formula (I), [ka] (ii) Approximately 132 mg of mannitol and (iii) Approximately 32.7 mg of silicified microcrystalline cellulose, (iv) Approximately 12.5 mg of croscarmellose sodium, (v) Approximately 2.1 mg of colloidal silicon dioxide, (vi) Contains approximately 3.6 mg of stearyl sodium fumarate.

[0203] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 30 mg of the compound of formula (I), [ka] (ii) Approximately 159 mg of mannitol and (iii) Approximately 39.3 mg of silicified microcrystalline cellulose, (iv) Approximately 15 mg of croscarmellose sodium, (v) Approximately 2.5 mg of colloidal silicon dioxide, (vi) Contains approximately 4.4 mg of stearyl sodium fumarate.

[0204] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 40 mg of the compound of formula (I), [ka] (ii) Approximately 212 mg of mannitol and (iii) Approximately 52.4 mg of silicified microcrystalline cellulose, (iv) Approximately 20 mg of croscarmellose sodium, (v) Approximately 3.3 mg of colloidal silicon dioxide, (vi) Contains approximately 5.8 mg of stearyl sodium fumarate.

[0205] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 50 mg of the compound of formula (I), [ka] (ii) Approximately 265 mg of mannitol and (iii) Approximately 65.5 mg of silicified microcrystalline cellulose, (iv) Approximately 25 mg of croscarmellose sodium, (v) Approximately 4.2 mg of colloidal silicon dioxide, (vi) Contains approximately 7.3 mg of stearyl sodium fumarate.

[0206] In various embodiments, the pharmaceutical composition is (i) The crystalline form of approximately 60 mg of the compound of formula (I), (ii) Approximately 317.7 mg of mannitol and (iii) Approximately 78.6 mg of silicified microcrystalline cellulose, (iv) Approximately 30 mg of croscarmellose sodium, (v) Approximately 5 mg of colloidal silicon dioxide, (vi) Contains approximately 8.8 mg of stearyl sodium fumarate.

[0207] In various embodiments, the pharmaceutical composition comprises a plurality of particles in crystalline form of the compound of formula (I), [ka] The plurality of particles in the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 ranging from approximately 1 μm to approximately 100 μm.

[0208] In a particular embodiment, the multiple particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 1 μm to about 20 μm. In a particular embodiment, the multiple particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 1 μm to about 13 μm.

[0209] In various embodiments, the pharmaceutical composition is (i) Multiple particles of the crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) A pharmaceutical composition is provided comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, wherein the plurality of particles of the crystalline form of the compound of formula (I) have a particle size distribution defined by D90 of about 1 μm to about 20 μm.

[0210] In a particular embodiment, the crystalline particles of the compound of formula (I) have a particle size distribution defined by D90 ranging from about 1 μm to about 13 μm.

[0211] In a particular embodiment, the crystalline particles of the compound of formula (I) are approximately 5 μm to 10 μm, 5.5 μm to 10 μm, 6 μm to 10 μm, 6.5 μm to 10 μm, 7 μm to 10 μm, 7.5 μm to 10 μm, 8 μm to 10 μm, 8.5 μm to 10 μm, 9 μm to 10 μm, 9.5 μm to 10 μm, 5 μm to 9.5 μm, 5 μm to 9 μm, and 5 μm to about 8.5 μm, about 5 μm to about 8 μm, about 5 μm to about 7.5 μm, about 5 μm to about 7 μm, about 5 μm to about 6.5 μm, about 5 μm to about 6 μm, about 5 μm to about 5.5 μm, about 5.5 μm to about 9.5 μm, Approximately 5.5μm to approximately 9μm, approximately 5.5μm to approximately 8.5μm, approximately 5.5μm to approximately 8μm, approximately 5.5μm to approximately 7.5μm, approximately 5.5μm to approximately 7μm, approximately 5.5μm to approximately 6.5μm, approximately 5.5μm to approximately 6μm, Approximately 6μm to 9.5μm, approximately 6μm to 9μm, approximately 6μm to 8.5μm, approximately 6μm to 8μm, approximately 6μm to 7.5μm, approximately 6μm to 7μm, approximately 6μm to 6.5μm, approximately 6.5μm to 9.5μm, approximately 6.5μm to 9μm, approximately 6.5μm to 8.5μm, approximately 6.5μm to 8μm, approximately 6.5μm to 7.5μm, approximately 6.5μm to 7μm, approximately 7μm to 9.5μm, approximately 7μm to 9μm, approximately 7 The particle size distribution is defined by D90 as follows: μm to approximately 8.5 μm, approximately 7 μm to approximately 8 μm, approximately 7 μm to approximately 7.5 μm, approximately 7.5 μm to approximately 9.5 μm, approximately 7.5 μm to approximately 9 μm, approximately 7.5 μm to approximately 8.5 μm, approximately 7.5 μm to approximately 8 μm, approximately 8 μm to approximately 9.5 μm, approximately 8 μm to approximately 9 μm, approximately 8 μm to approximately 8.5 μm, approximately 8.5 μm to approximately 9.5 μm, approximately 8.5 μm to approximately 9 μm, or approximately 9 μm to approximately 9.5 μm. In various embodiments, the pharmaceutical composition is (i) The crystalline form (one or more) of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, The pharmaceutical composition has a bulk density of approximately 0.2 g / cc to approximately 0.8 g / cc and a tap density of approximately 0.3 g / cc to approximately 1.1 g / cc, with the tap density of the pharmaceutical composition being higher than the bulk density.

[0212] In certain embodiments, the pharmaceutical composition has a bulk density of about 0.3 g / cc to about 0.7 g / cc and a tap density of about 0.5 g / cc to about 0.9 g / cc, with the tap density of the pharmaceutical composition being higher than the bulk density. In certain embodiments, the pharmaceutical composition has a bulk density of about 0.4 g / cc to about 0.7 g / cc and a tap density of about 0.5 g / cc to about 0.9 g / cc, with the tap density of the pharmaceutical composition being higher than the bulk density.

[0213] In various embodiments, the pharmaceutical composition is (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof, wherein the pharmaceutical composition has an average flow index (FRI) of about 0.05 to about 3.1 kg / second.

[0214] In certain embodiments, the pharmaceutical composition has an average FRI of about 0.2 to about 1.5 kg / second. In certain embodiments, the pharmaceutical composition has an average FRI of about 0.4 to about 0.9 kg / second.

[0215] In various embodiments, the pharmaceutical composition is (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, capsules, and combinations thereof, the pharmaceutical composition releases at least about 50% of the compound of formula (I) after about 20 minutes when tested using a USP1 or USP2 apparatus.

[0216] In a particular embodiment, the pharmaceutical composition releases at least about 65% of the compound of formula (I) after about 30 minutes when tested using a USP1 or USP2 apparatus.

[0217] In various embodiments, the pharmaceutical composition is (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) comprising one or more pharmaceutically acceptable excipients selected from the group consisting of disintegrants, binders, wetting agents, lubricants, fluidizers, capsules, and combinations thereof, The pharmaceutical composition exhibits the following solubility profile: When tested in a USP2 instrument at approximately 37°C in approximately 500 mL to 900 mL of 50 mM sodium phosphate buffer with pH 6.8 and approximately 0.2% to 0.6% SDS, at least approximately 70% of the compound of formula (I) was released after approximately 20 minutes. At least about 80% of the compound of formula (I) is released after about 30 minutes.

[0218] In certain embodiments, the pharmaceutical compositions described herein further include a coating agent. In certain embodiments, the coating agent is selected from the group consisting of film-forming polymers, plasticizers, and combinations thereof. In certain embodiments, the film-forming polymer is selected from the group consisting of hypromellose, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylate, and combinations thereof. In certain embodiments, the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propylene glycol, and combinations thereof.

[0219] In certain embodiments, the pharmaceutical compositions described herein further include capsules. In certain embodiments, the capsules are gelatin capsules.

[0220] Dosage form In one embodiment, the present invention provides a dosage form comprising the pharmaceutical composition described herein.

[0221] In another embodiment, the present invention provides a dosage form intended for oral administration, comprising a pharmaceutical composition described herein.

[0222] In a particular embodiment, the dosage form is selected from the group consisting of powders, sachets, stick packs, capsules, mini-tablets, and tablets.

[0223] In a particular embodiment, the dosage form is a capsule. In a particular embodiment, the capsule size is selected from the group consisting of sizes 000, 00, 0, 1, 2, 3, 4, and 5.

[0224] In a particular admin, the total weight of the pharmaceutical composition in the capsule is approximately 25mg to 1000mg, 50mg to 1000mg, 75mg to 1000mg, 100mg to 1000mg, 150mg to 1000mg, 200mg to 1000mg, 250mg to 1000mg, 300mg to 1000mg, 400mg to 1000mg, 500mg to 1000mg, 600mg to 1000mg, 700mg to 1000mg, 800mg to 1000mg, 900mg to 1000mg, and 25mg to 900mg. g, approx. 25 mg ~ approx. 800 mg, approx. 25 mg ~ approx. 700 mg, approx. 25 mg ~ approx. 600 mg, approx. 25 mg ~ approx. 500 mg, approx. 25 mg ~ approx. 400 mg, approx. About 100mg, about 25mg to about 75mg, about 25mg to about 50mg, about 50mg to about 900mg, about 50mg to about 800mg, about 50mg to about 700mg, about 50mg to about 600mg, about 50mg to about 500mg, about 50mg to about 400mg, about 50mg to about 300mg, about 50 mg~250mg, 50mg~200mg, 50mg~150mg, 50mg~100mg, 50mg~75mg, 75mg~900mg, 75mg~800mg, 75mg~700mg, 75mg~600mg, 75mg~500mg , about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 200 mg, about 75 mg to about 100 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg 00mg to about 400mg, about 100mg to about 300mg, about 100mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 150mg to about 900mg, about 150mg to about 800mg, about 150mg to about 700mg, about 150mg to about 600mg, about 150mg to about 500mg, about 150mg to about 400mg, about 150mg to about 300mg, about 150mg to about 250mg, about 150mg to about 200mg, about 200mg to about 900mg, about 200mg to about 800mg, about 200mg to about 700mg, about 200mg to about 600mg,About 200mg to about 500mg, about 200mg to about 400mg, about 200mg to about 300mg, about 200mg to about 250mg, about 250mg to about 900mg, about 250mg to about 800mg, about 250mg to about 700mg, about 250mg to about 600mg, about 250mg to about 500mg, about 250mg to about 400mg, about 250mg to about 300mg, about 300mg to about 900mg, about 300mg to about 800mg, about 300mg to about 700mg, about 300mg to about 600mg, about 300mg to about 500mg, about 30 The dosage ranges are approximately 0mg to 400mg, 400mg to 900mg, 400mg to 800mg, 400mg to 700mg, 400mg to 600mg, 400mg to 500mg, 500mg to 900mg, 500mg to 800mg, 500mg to 700mg, 500mg to 600mg, 600mg to 900mg, 600mg to 800mg, 600mg to 700mg, 700mg to 900mg, 700mg to 800mg, or 800mg to 900mg.

[0225] In a particular embodiment, the dosage form is a tablet.

[0226] For a certain admin, the total weight of the pharmaceutical composition in the tablet is approximately 20mg to 1000mg, 50mg to 1000mg, 75mg to 1000mg, 100mg to 1000mg, 150mg to 1000mg, 200mg to 1000mg, 250mg to 1000mg, 300mg to 1000mg, 400mg to 1000mg, 500mg to 1000mg, 600mg to 1000mg, 700mg to 1000mg, 800mg to 1000mg, 900mg to 1000mg, and 20mg to 900mg. Approximately 20mg to approximately 800mg, approximately 20mg to approximately 700mg, approximately 20mg to approximately 600mg, approximately 20mg to approximately 500mg, approximately 20mg to approximately 400mg, approximately 20mg to approximately 300mg, approximately 20mg to approximately 250mg, approximately 20mg to approximately 200mg, approximately 20mg to approximately 150mg, approximately 20mg to approximately 100mg, about 20mg to about 75mg, about 20mg to about 50mg, about 50mg to about 900mg, about 50mg to about 800mg, about 50mg to about 700mg, about 50mg to about 600mg, about 50mg to about 500mg, about 50mg to about 400mg, about 50mg to about 300mg, about 50m g ~ approx. 250 mg, approx. 50 mg ~ approx. 200 mg, approx. 50 mg ~ approx. 150 mg, approx. 50 mg ~ approx. 100 mg, approx. , about 75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about 200 mg, about 75 mg to about 100 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg 00mg to about 400mg, about 100mg to about 300mg, about 100mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 150mg to about 900mg, about 150mg to about 800mg, about 150mg to about 700mg, about 150mg to about 600mg, about 150mg to about 500mg, about 150mg to about 400mg, about 150mg to about 300mg, about 150mg to about 250mg, about 150mg to about 200mg, about 200mg to about 900mg, about 200mg to about 800mg, about 200mg to about 700mg, about 200mg to about 600mg,About 200mg to about 500mg, about 200mg to about 400mg, about 200mg to about 300mg, about 200mg to about 250mg, about 250mg to about 900mg, about 250mg to about 800mg, about 250mg to about 700mg, about 250mg to about 600mg, about 250mg to about 500mg, about 250mg to about 400mg, about 250mg to about 300mg, about 300mg to about 900mg, about 300mg to about 800mg, about 300mg to about 700mg, about 300mg to about 600mg, about 300mg to about 500mg, about 30 The dosage ranges are approximately 0mg to 400mg, 400mg to 900mg, 400mg to 800mg, 400mg to 700mg, 400mg to 600mg, 400mg to 500mg, 500mg to 900mg, 500mg to 800mg, 500mg to 700mg, 500mg to 600mg, 600mg to 900mg, 600mg to 800mg, 600mg to 700mg, 700mg to 900mg, 700mg to 800mg, or 800mg to 900mg.

[0227] In certain embodiments, the tablets further contain a coating agent. In certain embodiments, the coating agent is selected from the group consisting of film-forming polymers, plasticizers, and combinations thereof. In certain embodiments, the film-forming polymer is selected from the group consisting of hypromellose, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylate, and combinations thereof. In certain embodiments, the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propylene glycol, and combinations thereof.

[0228] Manufacturing method In one embodiment, the present invention relates to a process for preparing a pharmaceutical composition described herein, for example, (a) In order to obtain a micronized crystalline form of the compound of formula (I), the crystalline form of the compound of formula (I) is micronized, [ka] The compound of formula (I) is formed into fine particles, with a particle size distribution defined by D90 ranging from approximately 1 μm to approximately 100 μm. (b) To obtain a blend, blend the particulate crystalline form of the compound of formula (I) with one or more pharmaceutically acceptable excipients, (c) To obtain granules, the blend is granulated, (d) In order to obtain the granular internal phase, the granules are crushed, (e) A process is provided which includes blending the granular inner phase with one or more extragranular pharmaceutical excipients in order to obtain a pharmaceutical composition.

[0229] In a particular embodiment, in step (a), the microparticle crystal form of the compound of formula (I) is approximately 1 μm to 100 μm, approximately 5 μm to 100 μm, approximately 10 μm to 100 μm, approximately 15 μm to 100 μm, approximately 20 μm to 100 μm, approximately 25 μm to 100 μm, approximately 30 μm to 100 μm, approximately 35 μm to 100 μm, approximately 40 μm to 100 μm, approximately 45 μm to 100 μm, approximately 50 μm to 100 μm, approximately 60 μm to 100 μm, approximately 70 μm to 100 μm, approximately 80 μm to 100 μm, approximately 90 μm to 100 μm, and approximately 1 μm to 90 μm. m, about 1 μm to about 80 μm, about 1 μm to about 70 μm, about 1 μm to about 60 μm, about 1 μm to about 50 μm, about 1 μm to about 45 μm, about 1 μm to about Approximately 40μm, approximately 1μm to approximately 35μm, approximately 1μm to approximately 30μm, approximately 1μm to approximately 25μm, approximately 1μm to approximately 20μm, approximately 1μm to approximately 15μm, approximately 1μm to about 10μm, about 1μm to about 5μm, about 5μm to about 90μm, about 5μm to about 80μm, about 5μm to about 70μm, about 5μm to about 60μ m, about 5 μm to about 50 μm, about 5 μm to about 45 μm, about 5 μm to about 40 μm, about 5 μm to about 35 μm, about 5 μm to about 30 μm, about 5 μm to Approximately 25μm, approximately 5μm to approximately 20μm, approximately 5μm to approximately 15μm, approximately 5μm to approximately 10μm, approximately 10μm to approximately 90μm, approximately 10μm to approximately 80μ m, about 10 μm to about 70 μm, about 10 μm to about 60 μm, about 10 μm to about 50 μm, about 10 μm to about 45 μm, about 10 μm to about 40 μm, Approximately 10μm to approximately 35μm, approximately 10μm to approximately 30μm, approximately 10μm to approximately 25μm, approximately 10μm to approximately 20μm, approximately 10μm to approximately 15μm, approximately 1 5μm to about 90μm, about 15μm to about 80μm, about 15μm to about 70μm, about 15μm to about 60μm, about 15μm to about 50μm, about 15μm m ~ about 45μm, about 15μm - about 40μm, about 15μm - about 35μm, about 15μm - about 30μm, about 15μm - about 25μm, about 15μm Approximately 20μm, approximately 20μm to approximately 90μm, approximately 20μm to approximately 80μm, approximately 20μm to approximately 70μm, approximately 20μm to approximately 60μm, approximately 20μm to approximately 5 0μm, about 20μm to about 45μm, about 20μm to about 40μm, about 20μm to about 35μm, about 20μm to about 30μm, about 20μm to about 25μm m, about 30 μm to about 90 μm, about 30 μm to about 80 μm, about 30 μm to about 70 μm, about 30 μm to about 60 μm, about 30 μm to about 50 μm,Approximately 30μm to approximately 45μm, approximately 30μm to approximately 40μm, approximately 30μm to approximately 35μm, approximately 35μm to approximately 90μm, approximately 35μm to approximately 80μm, approximately 35μm to approximately 70μm, approximately 35μm to approximately 60μm, approximately 35μm to approximately 50μm, Approximately 35μm to approximately 45μm, approximately 35μm to approximately 40μm, approximately 40μm to approximately 90μm, approximately 40μm to approximately 80μm, approximately 40μm to approximately 70μm, approximately 40μm to approximately 50μm, approximately 40μm to approximately 45μm, approximately 45μm to approximately 90μm, It has a particle size distribution defined by D90, which includes approximately 45 μm to 80 μm, approximately 45 μm to 70 μm, approximately 45 μm to 60 μm, approximately 45 μm to 50 μm, approximately 50 μm to 90 μm, approximately 50 μm to 80 μm, approximately 50 μm to 70 μm, approximately 50 μm to 60 μm, approximately 60 μm to 90 μm, approximately 60 μm to 80 μm, approximately 60 μm to 70 μm, approximately 70 μm to 90 μm, approximately 70 μm to 80 μm, or approximately 80 μm to 90 μm.

[0230] In a particular embodiment, in step (a), the microparticle crystal form of the compound of formula (I) is approximately 1 μm to 20 μm, 2 μm to 20 μm, 4 μm to 20 μm, 6 μm to 20 μm, 8 μm to 20 μm, 10 μm to 20 μm, 12 μm to 20 μm, 14 μm to 20 μm, 16 μm to 20 μm, 18 μm to 20 μm, and 1 μm to 18 μm. m, about 1 μm to about 16 μm, about 1 μm to about 14 μm, about 1 μm to about 12 μm, about 1 μm to about 10 μm, about 1 μm to about 8 μm, about 1 μm to about 6 μm, about 1 μm to about 4 μm, about 1 μm to about 2 μm , about 2 μm to about 18 μm, about 2 μm to about 16 μm, about 2 μm to about 14 μm, about 2 μm to about 12 μm, about 2 μm to about 10 μm, about 2 μm to about 8 μm, about 2 μm to about 6 μm, about 2 μm to about 4 μm , about 4 μm to about 18 μm, about 4 μm to about 16 μm, about 4 μm to about 14 μm, about 4 μm to about 12 μm, about 4 μm to about 10 μm, about 4 μm to about 8 μm, about 4 μm to about 6 μm, about 6 μm to about 18 μm m, about 6 μm to about 16 μm, about 6 μm to about 14 μm, about 6 μm to about 12 μm, about 6 μm to about 10 μm, about 6 μm to about 8 μm, about 8 μm to about 18 μm, about 8 μm to about 16 μm, about 8 μm to about 1 The particles have a particle size distribution defined by D90 of 4 μm, approximately 8 μm to approximately 12 μm, approximately 8 μm to approximately 10 μm, approximately 10 μm to approximately 18 μm, approximately 10 μm to approximately 16 μm, approximately 10 μm to approximately 14 μm, approximately 10 μm to approximately 12 μm, approximately 12 μm to approximately 18 μm, approximately 12 μm to approximately 16 μm, approximately 12 μm to approximately 14 μm, approximately 14 μm to approximately 18 μm, approximately 14 μm to approximately 16 μm, or approximately 16 μm to approximately 18 μm. In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 1 μm to approximately 20 μm.

[0231] In a particular embodiment, in step (a), the microparticle crystal form of the compound of formula (I) is approximately 1 μm to 15 μm, approximately 3 μm to 15 μm, approximately 5 μm to 15 μm, approximately 7 μm to 15 μm, approximately 9 μm to 15 μm, approximately 11 μm to 15 μm, approximately 13 μm to 15 μm, approximately 1 μm to 13 μm, approximately 1 μm to 11 μm, approximately 1 μm to 9 μm, approximately 1 μm to 7 μm, and approximately 1 μm It has a particle size distribution defined by D90 of approximately 1 μm to 5 μm, approximately 1 μm to 3 μm, approximately 3 μm to 13 μm, approximately 3 μm to 11 μm, approximately 3 μm to 9 μm, approximately 3 μm to 7 μm, approximately 3 μm to 5 μm, approximately 5 μm to 13 μm, approximately 5 μm to 11 μm, approximately 5 μm to 9 μm, approximately 5 μm to 7 μm, approximately 9 μm to 13 μm, approximately 9 μm to 11 μm, or approximately 11 μm to 13 μm. In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 1 μm to 13 μm.

[0232] In a particular embodiment, in step (a), the microparticle crystal form of the compound of formula (I) is approximately 5 μm to 10 μm, approximately 5.5 μm to 10 μm, approximately 6 μm to 10 μm, approximately 6.5 μm to 10 μm, approximately 7 μm to 10 μm, approximately 7.5 μm to 10 μm, approximately 8 μm to 10 μm, approximately 8.5 μm to 10 μm, approximately 9 μm to 10 μm, approximately 9.5 μm to 10 μm, approximately 5 μm to 9.5 μm, approximately 5 μm to Approximately 9 μm, approximately 5 μm to approximately 8.5 μm, approximately 5 μm to approximately 8 μm, approximately 5 μm to approximately 7.5 μm, approximately 5 μm to approximately 7 μm, approximately 5 μm to approximately 6.5 μm, approximately 5 μm to approximately 6 μm, approximately 5 μm to approximately 5.5 μm, approximately 5.5 μm to approximately 9.5 μm, approximately 5.5 μm to approximately 9 μm, approximately 5.5 μm to approximately 8.5 μm, approximately 5.5 μm to approximately 8 μm, approximately 5.5 μm to approximately 7.5 μm, approximately 5.5 μm to approximately 7 μm, approximately 5.5 μm to approximately 6.5 μm, approximately 5.5 μm Approximately 6 μm, approximately 6 μm to approximately 9.5 μm, approximately 6 μm to approximately 9 μm, approximately 6 μm to approximately 8.5 μm, approximately 6 μm to approximately 8 μm, approximately 6 μm to approximately 7.5 μm, approximately 6 μm to approximately 7 μm, approximately 6 μm to approximately 6.5 μm, approximately 6.5 μm to approximately 9.5 μm, approximately 6.5 μm to approximately 9 μm, approximately 6.5 μm to approximately 8.5 μm, approximately 6.5 μm to approximately 8 μm, approximately 6.5 μm to approximately 7.5 μm, approximately 6.5 μm to approximately 7 μm, approximately 7 μm to approximately 9.5 μm, approximately 7 μm to approximately 9 μm It has a particle size distribution defined by D90, which is approximately 7 μm to 8.5 μm, approximately 7 μm to 8 μm, approximately 7 μm to 7.5 μm, approximately 7.5 μm to 9.5 μm, approximately 7.5 μm to 9 μm, approximately 7.5 μm to 8.5 μm, approximately 7.5 μm to 8 μm, approximately 8 μm to 9.5 μm, approximately 8 μm to 9 μm, approximately 8 μm to 8.5 μm, approximately 8.5 μm to 9.5 μm, approximately 8.5 μm to 9 μm, or approximately 9 μm to 9.5 μm.

[0233] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0234] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0235] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0236] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0237] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0238] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0239] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0240] In a particular embodiment, in step (a), the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0241] In a particular embodiment, in step (b), one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, binders, wetting agents, lubricants, fluidizers, and combinations thereof. In a particular embodiment, in step (b), the particulate crystalline compound of formula (I) is blended with fillers, disintegrants, lubricants, and fluidizers.

[0242] In a particular embodiment, in step (b), the filler is selected from the group consisting of brittle fillers, ductile fillers, and combinations thereof. In a particular embodiment, in step (b), the filler includes a brittle filler and a ductile filler.

[0243] In a particular embodiment, in step (b), the brittle filler is selected from the group consisting of mannitol, lactose, dicalcium phosphate, and combinations thereof.

[0244] In a particular embodiment, in step (b), the ductile filler is selected from the group consisting of microcrystalline cellulose, starch, polysaccharide, cellulose, polyvinylpyrrolidone, polyvinyl acrylate, and combinations thereof.

[0245] In a particular embodiment, in step (b), the disintegrant is selected from the group consisting of sodium starch glycolate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, and combinations thereof.

[0246] In a particular embodiment, in step (b), the fluidizing agent is selected from colloidal silicon dioxide, talc, and combinations thereof.

[0247] In a particular embodiment, in step (b), the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, stearic acid, and combinations thereof.

[0248] In a particular embodiment, step (c) granulating the blend to obtain granules includes a dry granulation step. In a particular embodiment, step (c) granulating the blend to obtain granules includes a wet granulation step.

[0249] In a particular embodiment, in step (c), the granules are approximately 0.5 to approximately 0.95, approximately 0.55 to approximately 0.95, approximately 0.6 to approximately 0.95, approximately 0.7 to approximately 0.95, approximately 0.8 to approximately 0.95, approximately 0.85 to approximately 0.95, approximately 0.9 to approximately 0.95, approximately 0.5 to approximately 0.9, approximately 0.5 to approximately 0.85, approximately 0.5 to approximately 0.8, approximately 0.5 to approximately 0.7, approximately 0.5 to approximately 0.6, approximately 0.5 to approximately 0.55, The solids content is approximately 0.55 to 0.9, approximately 0.55 to 0.85, approximately 0.55 to 0.8, approximately 0.55 to 0.7, approximately 0.55 to 0.6, approximately 0.6 to 0.9, approximately 0.6 to 0.85, approximately 0.6 to 0.8, approximately 0.6 to 0.7, approximately 0.7 to 0.9, approximately 0.7 to 0.85, approximately 0.7 to 0.8, approximately 0.8 to 0.9, approximately 0.8 to 0.85, or approximately 0.85 to 0.9. In certain embodiments, the granules have a solids content of approximately 0.55 to 0.9. In certain embodiments, the granules have a solids content of approximately 0.6 to 0.85.

[0250] In a particular embodiment, in step (e), one or more external excipients are selected from the group consisting of disintegrants, lubricants, fluidizers, and combinations thereof. In a particular embodiment, in step (e), the internal phase of the granules is blended with disintegrants, lubricants, and fluidizers.

[0251] In a particular embodiment, in step (e), the disintegrant is selected from the group consisting of sodium starch glycolate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, and combinations thereof.

[0252] In a particular embodiment, in step (e), the fluidizing agent is selected from colloidal silicon dioxide, talc, and combinations thereof.

[0253] In a particular embodiment, in step (e), the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, stearic acid, and combinations thereof.

[0254] In a particular embodiment, the method further includes compressing the pharmaceutical composition into tablets.

[0255] In certain embodiments, the tablet comprises a coating agent. In certain embodiments, the coating agent comprises one or more film-forming polymers selected from the group consisting of hypromellose, ethylcellulose, polyvinylpyrrolidone, polyacrylate, plasticizers, and combinations thereof. In certain embodiments, the coating agent comprises a colorant selected from the group consisting of titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof.

[0256] In a particular embodiment, the method further includes filling the capsule with a pharmaceutical composition.

[0257] In certain embodiments, the capsule sizes are 000, 00, 0, 1, 2, 3, 4, and 5. In certain embodiments, the capsules contain gelatin, polysaccharides, starch, hypromellose, or a combination thereof. In certain embodiments, the capsules contain a coloring agent. In certain embodiments, the coloring agent is selected from the group consisting of titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof.

[0258] In another embodiment, the present invention provides a pharmaceutical composition described herein (for example, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the process for producing the pharmaceutical composition includes a micronization step. In a particular embodiment, the micronization step includes micronizing the crystalline form of the compound of formula (I) to obtain a micronized crystalline form of the compound of formula (I). In a particular embodiment, the micronized crystalline form of the compound of formula (I) has a particle size distribution as described herein.

[0259] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of the compound of formula (I), [ka] (ii) Filler and (iii) Lubricants and (iv) containing a fluidizing agent,

[0260] The present invention provides a pharmaceutical composition wherein the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I). In a particular embodiment, the micronized crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of about 6.1 μm to about 7.7 μm, about 6.1 μm to about 8.0 μm, about 4.1 μm to about 10.0 μm, about 5.6 μm to about 10.6 μm, about 4.9 μm to about 12.4 μm, about 3.9 μm to about 11.0 μm, or about 4.2 μm to about 11.6 μm.

[0261] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0262] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0263] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0264] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0265] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0266] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0267] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0268] In various embodiments, the present invention relates to a pharmaceutical composition, (i) Crystal morphology of compounds of formula (I) in concentrations of approximately 0.4% (w / w) to approximately 60% (w / w), [ka] (ii) A brittle filler of approximately 0% (w / w) to approximately 90% (w / w), (iii) A ductile filler of approximately 0% (w / w) to approximately 90% (w / w), (iv) Approximately 0% (w / w) to approximately 15% (w / w) of disintegrant, (v) A lubricant in an amount of approximately 0.1% (w / w) to approximately 5% (w / w), (vi) Contains approximately 0.1% (w / w) to approximately 5% (w / w) of a fluidizing agent, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0269] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0270] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0271] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0272] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0273] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0274] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0275] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0276] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0277] In various embodiments, the present invention relates to a pharmaceutical composition, (i) Crystal morphology of compounds of formula (I) in concentrations of approximately 0.4% (w / w) to approximately 36% (w / w), [ka] (ii) A brittle filler of approximately 15% (w / w) to approximately 75% (w / w), (iii) Approximately 10% (w / w) to approximately 60% (w / w) of ductile filler, (iv) Approximately 3% (w / w) to approximately 12% (w / w) of disintegrant, (v) Approximately 0.25% (w / w) to approximately 5% (w / w) of a fluidizing agent, (vi) Contains approximately 0.5% (w / w) to approximately 3% (w / w) of a lubricant, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0278] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0279] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0280] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0281] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0282] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0283] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0284] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0285] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0286] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of the compound of formula (I) at approximately 10% (w / w) to approximately 15% (w / w), [ka] (ii) A brittle filler of approximately 60% (w / w) to approximately 70% (w / w), (iii) Approximately 10% (w / w) to approximately 20% (w / w) of ductile filler, (iv) Approximately 4% (w / w) to approximately 8% (w / w) of disintegrant, (v) Approximately 0.5% (w / w) to approximately 2% (w / w) of a fluidizing agent, (vi) Contains approximately 1% (w / w) to approximately 2% (w / w) of a lubricant, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0287] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0288] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0289] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0290] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0291] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0292] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0293] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0294] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0295] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 20 mg of the compound of formula (I), [ka] (ii) Approximately 105.9 mg of mannitol and (iii) Approximately 26.2 mg of silicified microcrystalline cellulose, (iv) Approximately 10 mg of croscarmellose sodium, (v) Approximately 1.7 mg of colloidal silicon dioxide, (vi) Contains approximately 2.9 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0296] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0297] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0298] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0299] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0300] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0301] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0302] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0303] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0304] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 25 mg of the compound of formula (I), [ka] (ii) Approximately 132 mg of mannitol and (iii) Approximately 32.7 mg of silicified microcrystalline cellulose, (iv) Approximately 12.5 mg of croscarmellose sodium, (v) Approximately 2.1 mg of colloidal silicon dioxide, (vi) Contains approximately 3.6 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0305] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0306] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0307] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0308] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0309] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0310] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0311] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0312] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0313] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 30 mg of the compound of formula (I), [ka] (ii) Approximately 159 mg of mannitol and (iii) Approximately 39.3 mg of silicified microcrystalline cellulose, (iv) Approximately 15 mg of croscarmellose sodium, (v) Approximately 2.5 mg of colloidal silicon dioxide, (vi) Contains approximately 4.4 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0314] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0315] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0316] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0317] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0318] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0319] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0320] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0321] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0322] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 40 mg of the compound of formula (I), [ka] (ii) Approximately 212 mg of mannitol and (iii) Approximately 52.4 mg of silicified microcrystalline cellulose, (iv) Approximately 20 mg of croscarmellose sodium, (v) Approximately 3.3 mg of colloidal silicon dioxide, (vi) Contains approximately 5.8 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0323] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0324] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0325] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0326] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0327] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0328] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0329] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0330] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0331] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 50 mg of the compound of formula (I), [ka] (ii) Approximately 265 mg of mannitol and (iii) Approximately 65.5 mg of silicified microcrystalline cellulose, (iv) Approximately 25 mg of croscarmellose sodium, (v) Approximately 4.2 mg of colloidal silicon dioxide, (vi) Contains approximately 7.3 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0332] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0333] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0334] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0335] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0336] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0337] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0338] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0339] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0340] In various embodiments, the present invention relates to a pharmaceutical composition, (i) The crystalline form of approximately 60 mg of the compound of formula (I), [ka] (ii) Approximately 317.7 mg of mannitol and (iii) Approximately 78.6 mg of silicified microcrystalline cellulose, (iv) Approximately 30 mg of croscarmellose sodium, (v) Approximately 5 mg of colloidal silicon dioxide, (vi) Contains approximately 8.8 mg of stearyl sodium fumarate, The present invention provides a pharmaceutical composition in which the process for producing the pharmaceutical composition includes a micronization step, which involves micronizing the crystalline form of the compound of formula (I) in order to obtain a micronized crystalline form of the compound of formula (I).

[0341] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 of approximately 6.1 μm to approximately 7.7 μm, approximately 6.1 μm to approximately 8.0 μm, approximately 4.1 μm to approximately 10.0 μm, approximately 5.6 μm to approximately 10.6 μm, approximately 4.9 μm to approximately 12.4 μm, approximately 3.9 μm to approximately 11.0 μm, or approximately 4.2 μm to approximately 11.6 μm.

[0342] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 7.7 μm.

[0343] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 6.1 μm to about 8.0 μm.

[0344] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.1 μm to about 10.0 μm.

[0345] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 5.6 μm to about 10.6 μm.

[0346] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.9 μm to about 12.4 μm.

[0347] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 3.9 μm to about 11.0 μm.

[0348] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 4.2 μm to about 11.6 μm.

[0349] In a particular embodiment, the particulate crystalline form of the compound of formula (I) has a particle size distribution defined by D90 ranging from about 1 μm to about 100 μm.

[0350] In a particular embodiment, the process for preparing a pharmaceutical composition further includes one or more of the following method steps: To obtain a blend, blend the micronized crystalline form of the compound of formula (I) with one or more pharmaceutically acceptable excipients described herein, and granulate the blend to obtain granules. In order to obtain the granular inner phase, the granules are crushed, and To obtain a pharmaceutical composition, the granular inner phase is blended with one or more non-granular pharmaceutical excipients described herein.

[0351] In a particular embodiment, granulating a blend to obtain granules includes a dry granulation step. In a particular embodiment, granulating a blend to obtain granules includes a wet granulation step.

[0352] Instructions for use and treatment methods In one embodiment, the pharmaceutical compositions described herein (e.g., pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof) are intended to be useful as therapeutic compositions for treating central nervous system-related disorders (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, convulsive disorders, epileptic seizures, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary central nervous system conditions associated with GABA regulation include, but are not limited to, sleep disorders (e.g., insomnia), mood disorders (e.g., depression (e.g., major depressive disorder (MDD), treatment-resistant depression (TRD)), dysthymic disorders (e.g., mild depression), bipolar disorders (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), psychogenic disorders (e.g., obsessive-compulsive disorder (OCD), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder)), convulsive disorders (e.g., epilepsy (e.g., status epilepticus (SE)), seizures)), memory and / or cognitive impairments (e.g., attention deficit (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewy body dementia (Lewis dementia)). Examples of conditions that may be considered include: body dementia, vascular dementia, motor disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorder (ASD) (e.g., autism, monogenic causes of autism (e.g., synaptopathy), e.g., Rett syndrome, fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0353] In certain embodiments, central nervous system-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In certain embodiments, central nervous system-related disorders are depression. In certain embodiments, central nervous system-related disorders are postpartum depression. In certain embodiments, central nervous system-related disorders are major depressive disorder. In certain embodiments, major depressive disorder is moderate major depressive disorder. In certain embodiments, major depressive disorder is severe major depressive disorder.

[0354] In one embodiment, a method is provided for alleviating or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method alleviates or prevents epileptic seizures.

[0355] In another embodiment, combinations of a compound of formula (I) or a pharmaceutically acceptable salt thereof with another pharmacologically active agent are provided. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered as the sole active agent, or they may be administered in combination with other agents. The combined administration may be carried out by any technique apparent to those skilled in the art (e.g., including separate administration, sequential administration, simultaneous administration, and alternating administration).

[0356] In another embodiment, a method is provided for treating or preventing cerebral excitability in a subject who is sensitive to or suffering from a condition related to cerebral excitability, the method comprising administering to the subject a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0357] In another embodiment, a method is provided for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0358] In another embodiment, a method is provided for alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0359] In another embodiment, a method is provided for inducing sleep, substantially maintaining the level of REM sleep observed in normal sleep, and without inducing substantial rebound insomnia, comprising administering a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0360] In another embodiment, a method is provided for alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PPD) in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0361] In another embodiment, a method is provided for treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a particular embodiment, the mood disorder is depression.

[0362] In another embodiment, a method is provided for cognitive enhancement or treatment of memory impairment, which is done by administering to a subject a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a particular embodiment, the disorder is Alzheimer's disease. In a particular embodiment, the disorder is Rett syndrome.

[0363] In another embodiment, a method is provided for treating attention disorder, which is done by administering to a subject a pharmaceutical composition of the present invention comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a particular embodiment, the attention disorder is ADHD.

[0364] In certain embodiments, the administration of the pharmaceutical composition described herein to a subject is acute, chronic, or episodic. In certain embodiments, the pharmaceutical composition is administered orally to the subject.

[0365] Neuroendocrine disorders and dysfunctions This specification provides methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a range of conditions caused by an imbalance in the production of endocrine hormones directly related to the brain. Neuroendocrine disorders relate to the interaction between the nervous and endocrine systems. Because the hypothalamus and pituitary gland are two regions of the brain that regulate hormone production, damage to the hypothalamus or pituitary gland, for example due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is related to a women’s health disorder or condition (e.g., the women’s health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction related to a women’s health disorder or condition is polycystic ovary syndrome.

[0366] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive function-related symptoms, and physical symptoms, which include, but are not limited to, fatigue, memory impairment, anxiety, depression, weight gain or loss, mood swings, lack of concentration, attention deficit, decreased libido, infertility, amenorrhea, decreased muscle mass, increased abdominal fat, hypotension, decreased heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0367] Neurodegenerative diseases and disorders The methods described herein may be used to treat neurodegenerative diseases and disorders. The term “neurodegenerative disease” includes diseases and disorders that involve progressive loss of structure or function of nerve cells, or death of nerve cells. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including symptoms associated with mild, moderate, or severe cognitive impairment), amyotrophic lateral sclerosis (ALS), anoxic and ischemic injuries, ataxia and seizures (including those for the treatment and prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia), benign amnesia, cerebral edema, cerebellar ataxia (including McLeod’s neuroacanocyte syndrome (MLS)), closed head injury, coma, contusion injury (for example) (including spinal cord injury and head injury), dementia (including multiple infarct dementia and senile dementia), impaired consciousness, Down syndrome, drug-induced or drug-induced parkinsonism (e.g., neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor), epilepsy, fragile X syndrome, Gilles de la Tourette syndrome, head trauma, hearing impairment and loss, Huntington's disease, Lennox syndrome, levodopa-induced dyskinesia, intellectual disability, Movement disorders including akinesia and akinesia (rigidity) syndrome (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS complex dementia, Parkinson's disease, post-encephalopathy Parkinson's disease, and progressive supranuclear palsy), muscle spasms and disorders associated with muscle spasticity or weakness (including chorea (e.g., benign hereditary chorea, drug-induced chorea, unilateral ballism, Huntington's disease, neuroacanthoplasty, Sydenham's chorea, and symptomatic chorea)), dyskinesia (tic disorders, e.g., complex tics, simple tics) Strokes and symptomatic tics, myoclonus (including generalized myoclonus and focal myoclonus), tremors (e.g., resting tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia (e.g., blepharospasm, mangooral dystonia, and spasmodic dysphonia and torticollis)), neuronal damage (including ocular damage, retinopathy, or macular degeneration of the eye), neurotoxic injury (stroke, thromboembolic stroke,Examples of neurodegenerative diseases include hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and those resulting after cardiac arrest, Parkinson's disease, seizures, status epilepticus, stroke, tinnitus, tubular sclerosis, and viral infection-induced neurodegeneration (e.g., those resulting from acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases, though not limited to these, also include neurotoxic injuries resulting after stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Methods of treating or preventing neurodegenerative diseases include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0368] Mood disorder This specification also provides methods for treating mood disorders, such as clinical depression, postpartum depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent short-term depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-intractable depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein produce a therapeutic effect on subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to a disease or disorder described herein (e.g., neuroendocrine disorders and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0369] Clinical depression, also known as major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and relapsing depression, is a mental disorder characterized by widespread and persistent low mood, often accompanied by low self-esteem and a loss of interest or pleasure in activities that are normally enjoyable. Some individuals with clinical depression may experience sleep disturbances, weight loss, and generally feel agitated and irritable. Clinical depression can affect how an individual feels, thinks, and behaves, potentially leading to a range of emotional and physical problems. Individuals with clinical depression may find it difficult to perform daily activities and may feel that life is not worth living.

[0370] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, a feeling of disconnection from the infant and / or fetus, and loss of interest in previously enjoyed activities.

[0371] Postpartum depression (PPD) refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, PPD is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PPD is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0372] In some embodiments, subjects with PPD also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects who experience perinatal depression are at high risk of experiencing PPD.

[0373] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anemia) and positivity, marked weight gain or increased appetite. Patients with AD may also experience hypersomnia or somnolence, heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived rejection.

[0374] Melancholic depression is characterized by a loss of pleasure in almost all activities (anhedonic syndrome), unresponsiveness to pleasant stimuli, depressed mood more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0375] Psychotic major depressive disorder (PMD), or psychotic depression, refers to a major depressive episode of a particularly melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0376] Catastrophic depression refers to major depressive disorder accompanied by impaired motor skills and other symptoms. Individuals may be silent and stupor-like, immobile, or exhibit aimless or bizarre movements.

[0377] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience a seasonal pattern of depressive episodes that occur in the fall or winter.

[0378] Dysthymia is a condition related to unipolar depression, characterized by the same physical and cognitive problems. It is generally less severe and tends to last for a long period (e.g., at least two years).

[0379] Double depression refers to a condition in which a person experiences a significant feeling of depression (dysthymia) for at least two years, intermittently interspersed with periods of major depression.

[0380] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0381] Relapsing brief depression (RBD) is a condition in which an individual experiences a depressive episode approximately once a month, with each episode lasting less than two weeks, typically less than two to three days.

[0382] Minor depressive disorder, or minor depression, is a type of depression characterized by the presence of at least two symptoms for two weeks.

[0383] Bipolar disorder, or manic-depressive disorder, is characterized by extreme mood swings, including periods of heightened emotion (mania or hypomania) and depression. During manic episodes, individuals may experience or behave with unusual levels of happiness, energy, or irritability. Often, they may make hasty decisions without considering the consequences. Sleep needs are typically reduced. During depressive episodes, crying, lack of eye contact with others, and a negative outlook on life may be observed. Individuals with this disorder have a high risk of suicide (over 6% over a 20-year period), and self-harm occurs in 30-40%. Other mental health problems (e.g., anxiety disorders and substance use disorders) are also commonly associated with bipolar disorder.

[0384] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition (e.g., cancer or chronic pain, chemotherapy, chronic stress).

[0385] Treatment-resistant depression refers to a condition in which an individual is receiving treatment for depression, but their symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve their symptoms but then relapse. Treatment-resistant depression occurs in depressed patients who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, double and triple reuptake inhibitors, and / or anxiolytics), as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation, and / or transcranial magnetic stimulation).

[0386] Postoperative depression refers to a depressed mood that occurs after a surgical procedure (for example, as a result of having to confront one's own mortality). For example, an individual may experience persistent sadness or emptiness, loss of pleasure or interest in hobbies and activities that are normally enjoyed, or persistent feelings of worthlessness or despair.

[0387] Mood disorders associated with women's health conditions or disorders refer to mood disorders (e.g., depression) associated with (e.g., caused by) a woman's health condition or disorder (e.g., those described herein).

[0388] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's inclination to commit suicide. Suicidal ideation concerns thinking about or being abnormally preoccupied with suicide. The range of suicidal ideation is very diverse, for example, from momentary thoughts to extensive thoughts, detailed plans, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means of suicide, withdrawing from social contact, being preoccupied with death, feeling confined or desperate in a particular situation, increased alcohol or drug use, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if never to see them again.

[0389] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, despair, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, loss of interest in enjoyable activities or hobbies, loss of concentration, low self-esteem, absence of positive thoughts or plans, hypersomnia, overeating, loss of appetite, insomnia, self-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from person to person. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (for example, by a mental health assessment).

[0390] In some embodiments, the method includes monitoring subjects using known depression scales (e.g., the Hamilton Depression-D scale, the Clinical Global Impression-Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS)). In some embodiments, the therapeutic effect can be determined by the reduction in the total Hamilton Depression-D score shown by the subject. The reduction in the HAM-D score may occur within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours, or less. The therapeutic effect can be evaluated over a specified treatment period. For example, therapeutic effect can be determined by the reduction from baseline in the HAM-D total score after administration of a compound described herein, for example, a compound of formula (I) (for example, 12, 24, or 48 hours after administration, or 24, 48, 72, or 96 hours or more, or 1 day, 2 days, 14 days, 21 days, or 28 days, or 1 week, 2 weeks, 3 weeks, or 4 weeks, or 1 month, 2 months, 6 months, or 10 months, or 1 year, 2 years, or for a lifetime).

[0391] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with the compounds described herein, e.g., the compound of formula (I)) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18 (inclusive). In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 (inclusive). In some embodiments, the subject's HAM-D total score before treatment with the compounds described herein, e.g., the compound of formula (I)) is 23 or higher. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's total HAM-D score after treatment with a compound described herein, e.g., a compound of formula (I), is about 0 to 10 (e.g., less than 10, 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the total HAM-D score after treatment with a compound described herein, e.g., a compound of formula (I), is 10, 7, 5, or less than 3. In some embodiments, the reduction in the total HAM-D score is a reduction from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of about 0 to 10 (e.g., less than 10, 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound described herein, e.g., a compound of formula (I).In some embodiments, the reduction in the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein, e.g., a compound of formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction in the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein, e.g., a compound of formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score to the baseline HAM-D total score after treatment with a compound described herein, e.g., a compound of formula (I) (e.g., 12, 24, 48 hours after administration, or 24, 48, 72, 96 hours or more, or 1, 2, 14 days or more), and is at least 10, 15, or 20 points. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., measured by a decrease in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the total HAM-D score) within 1 or 2 days of treatment with a compound described herein, such as a compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the total HAM-D score) within 14 days or less of the start of treatment with a compound described herein, such as a compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the HAM-D total score) within 21 days or less of the initiation of treatment with a compound described herein, such as the compound of formula (I). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant decrease in the HAM-D total score) within 28 days or less of the initiation of treatment with a compound described herein, such as the compound of formula (I). In some embodiments, the therapeutic effect is the decrease from baseline in the HAM-D total score after treatment with a compound described herein, such as the compound of formula (I) (e.g., after treatment with a compound described herein, such as the compound of formula (I) once daily for 14 days). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, such as the compound of formula (I) is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, such as the compound of formula (I) is at least 18. In some embodiments, the subject's total HAM-D score before treatment with the compounds described herein, for example, the compound of formula (I), is between 14 and 18 (including both extreme values).In some embodiments, the reduction in the HAM-D total score from the baseline HAM-D total score after treating the subject with a compound described herein, for example, the compound of formula (I), is at least 10. In some embodiments, the reduction in the HAM-D total score from the baseline HAM-D total score after treating the subject with a compound described herein, for example, the compound of formula (I), is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, for example, the compound of formula (I), is less than or equal to a number in the range of 6 to 8. In some embodiments, the HAM-D total score associated with treating the subject with a compound described herein, for example, the compound of formula (I), is 7 or less.

[0392] In some embodiments, the method produces a therapeutic effect (e.g., measured by a decrease in the Clinical Global Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the central nervous system disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease from baseline in the CGI score at the end of the treatment period (e.g., 14 days after administration).

[0393] In some embodiments, the method produces a therapeutic effect (e.g., measured by a decrease in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the central nervous system disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease from baseline in the MADRS score at the end of the treatment period (e.g., 14 days after administration).

[0394] The effectiveness of treatment for major depressive disorder can be determined by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score, depending on the individual. For example, the MADRS score may be reduced by 4, 3, 2, or within 1 day, or by 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. It includes items related to apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, numbness, pessimistic thoughts, and suicidal thoughts.

[0395] In some embodiments, the method produces a therapeutic effect (e.g., measured by a decrease in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, or 1 day, 24, 20, 16, 12, 10, or 8 hours, or less. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0396] In some embodiments, the method produces a therapeutic effect (e.g., measured by a decrease in the 7-item scale for generalized anxiety disorder (GAD-7)) within 4, 3, 2, or 1 day, 24, 20, 16, 12, 10, or 8 hours, or less.

[0397] Anxiety disorder This specification provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorders are a broad term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0398] Generalized anxiety disorder (GPD) is a common chronic disorder characterized by persistent anxiety that does not focus on any single object or situation. Individuals with GPD experience unspecified, persistent fears or worries and become overly concerned with everyday matters. GPD is the most common anxiety disorder affecting older adults.

[0399] Panic disorder is characterized by short, intense episodes of fear and anxiety, often accompanied by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks, defined by the APA as "a sudden onset of fear or discomfort that peaks in less than 10 minutes," can last for several hours and may be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. A diagnosis of panic disorder requires not only recurrent, unexpected panic attacks but also the chronic consequences of these attacks—namely, worry about the potential effects of an attack, persistent fear of future attacks, or significant behavioral changes associated with the attacks. Therefore, individuals with panic disorder may experience symptoms even outside of specific panic episodes. Often, panic sufferers notice normal changes in their heart rate, leading them to believe there is something wrong with their heart or that another panic attack is imminent. In some cases, hyperarousal occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening (i.e., an extreme hypochondriacal state).

[0400] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (persistent, intrusive thoughts or images that cause distress) and compulsions (the urge to perform a specific action or ritual). The thought patterns of OCD can be likened to superstition in that they involve believing in causal relationships that do not actually exist. This process is often completely illogical; for example, a compulsion to walk in a particular pattern may be used to alleviate an obsession that harm is imminent. And in many cases, the obsession is completely inexplicable, and is simply a nervous urge to complete a ritual. In a small number of cases, OCD patients may experience only obsessions without overt compulsions, and even fewer patients experience only compulsions.

[0401] The largest single category within anxiety disorders is phobias, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from animals to places or bodily fluids.

[0402] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can stem from extreme situations (e.g., combat, rape, hostage situations, or serious accidents). It can also result from prolonged (chronic) exposure to severe stressors (e.g., a soldier who can withstand individual battles but cannot tolerate continuous combat). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0403] Women's health problems This specification provides methods for treating conditions or disorders relating to women's health. These conditions or disorders relating to women's health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and problems relating to women's general health and wellness (e.g., menopause).

[0404] Gynecological health issues affecting women include menstruation and menstrual irregularities, urinary tract health (including urinary incontinence and pelvic floor disorders), and conditions such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar pain.

[0405] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur in women one to two weeks before menstruation. Symptoms vary but may include bleeding, mood swings, breast tenderness, loss of appetite, fatigue, irritability, acne, and depression.

[0406] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased social conflict, tension and anxiety, irritability, decreased interest in normal activities, difficulty concentrating, fatigue, changes in appetite, feelings of being out of control or overwhelmed, sleep problems, and physical problems (e.g., bloating, breast tenderness, edema, headache, joint or muscle pain).

[0407] Issues related to pregnancy include preconception care and prenatal care, pregnancy loss (miscarriage and stillbirth), premature birth and early delivery, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0408] A miscarriage is defined as a pregnancy that ends spontaneously within 20 weeks of gestation.

[0409] Abortion refers to the intentional termination of a pregnancy and can be performed within 28 weeks of conception.

[0410] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian dysfunction.

[0411] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms resulting from increased levels of male hormones in women. In most women with PCOS, numerous small cysts grow in the ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy menstrual bleeding, excessive body or facial hair growth, acne, pelvic pain, difficulty conceiving, and dark, velvety skin. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0412] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0413] Issues related to women's overall health and wellness include violence against women, women with disabilities and their specific challenges, osteoporosis and bone health, and menopause.

[0414] Menopause refers to the 12-month period following a woman's last menstrual period, marking the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Physical (e.g., hot flashes) and emotional symptoms of menopause can disrupt sleep, cause low energy, and trigger feelings of anxiety, sadness, or loss. Menopause includes spontaneous menopause and surgical menopause, with surgical menopause being a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). Surgical menopause is induced when the ovaries are severely damaged, for example, by radiation, chemotherapy, or other drugs.

[0415] epilepsy Pharmaceutical compositions of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used in the treatment of the disorders described herein (e.g., epilepsy, status epilepticus, or seizures) by the methods described herein.

[0416] Epilepsy is a brain disorder characterized by recurrent seizures over time. While not limited to a specific type, epilepsy can include generalized epilepsy (e.g., childhood absence epilepsy, juvenile myoclonus (nyoclonic) epilepsy, epilepsy with grand mal seizures during wakefulness, West syndrome, Lennox-Gastaut syndrome), and partial epilepsy (e.g., temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children).

[0417] Epilepsygenic The pharmaceutical compositions and methods described herein can be used for the treatment or prevention of epileptogenicity. Epilepsy is a progressive process in which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epilepsy is caused by nerve cell damage suddenly triggered by the first seizure (e.g., status epilepticus).

[0418] Status epilepticus (SE) Examples of status epilepticus (SE) include convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus, as well as non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic-like discharges, and periodic unilateral epileptic-like discharges. Convulsive status epilepticus is characterized by the presence of convulsive epileptic seizures, and such conditions include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by epileptic seizures that persist despite first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by epileptic seizures that persist despite first-line and second-line therapies, and is generally treated with general anesthetics. Super-refractory status epilepticus is characterized by epileptic seizures that persist despite first-line therapy, second-line therapy, and treatment with general anesthetics for 24 hours or more.

[0419] Nonconvulsive status epilepticus can include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, subtle nonconvulsive status epilepticus, generalized nonconvulsive status epilepticus, such as delayed absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0420] Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof may be administered as a prophylactic agent to subjects with central nervous system disorders, such as traumatic brain injury, status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, hyperrefractory status epilepticus, non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic-like discharges, and periodic unilateral epileptic-like discharges, before the onset of a seizure.

[0421] seizure A seizure is a physical finding or behavioral change that follows an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A convulsion is when a person’s body shakes rapidly and uncontrollably. During a convulsion, a person’s muscles repeatedly contract and relax.

[0422] Based on the type of behavior and brain activity, seizures are classified into two main categories: generalized and partial (also called focal or localized). Classifying seizure types helps doctors diagnose whether or not a patient has epilepsy.

[0423] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses from a relatively small area of ​​the brain. The area of ​​the brain where a seizure occurs is sometimes called a focus.

[0424] There are six types of generalized seizures. The most common, dramatic, and therefore best known is the generalized convulsion, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and is usually collapsed. After losing consciousness, there is a generalized rigidity for 30 to 60 seconds (called the "tonic" phase of the seizure), followed by a violent convulsion for 30 to 60 seconds (the "clonic" phase), after which the patient falls into a deep sleep (the "post-onset" phase or late seizure phase). During grand mal seizures, injuries and accidents such as biting the tongue and urinary incontinence may occur.

[0425] Absence seizures cause a brief (only a few seconds) loss of consciousness and are usually asymptomatic. Patients (most often children) typically stop what they are doing and stare blankly. These seizures begin and end suddenly and may occur several times a day. Usually, patients are unaware that they are having a seizure, although in some exceptional cases they may recognize a "loss of time."

[0426] Myoclonic seizures consist of sporadic convulsions, usually occurring on both sides of the body. Patients sometimes describe these convulsions as short electric shocks. During severe seizures, patients may drop or involuntarily throw objects.

[0427] Clonic seizures are recurrent, rhythmic spasms that affect both sides of the body simultaneously.

[0428] Tonic seizures are characterized by muscle rigidity.

[0429] Atonic attacks consist of a sudden, general loss of muscle tone, particularly in the limbs, often resulting in falls.

[0430] The seizures described herein may include epileptic seizures, acute recurrent seizures, cluster seizures, serial seizures, persistent seizures, prolonged seizures, recurrent seizures, status epilepticus seizures, for example, refractory convulsive status epilepticus, nonconvulsive status epilepticus seizures, refractory seizures, myoclonic seizures, tonic seizures, tonic-clonic seizures, simple partial seizures, complex partial seizures, secondary generalized seizures, atypical absence seizures, absence seizures, atonic seizures, benign Rolandic seizures, febrile seizures, affective seizures, focal seizures, laughing seizures, generalized onset seizures, infantile spasms, Jacksonian seizures, giant bilateral myoclonic seizures, multifocal seizures, neonatal onset seizures, nocturnal seizures, occipital lobe seizures, post-traumatic seizures, microseizures, Sylvain seizures, visual reflex seizures, or withdrawal seizures. In some embodiments, seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis, Rett syndrome, or PCDH19 girl epilepsy. Movement impairment This specification also describes methods for treating motor disorders. As used herein, “motor disorder” refers to a variety of diseases and disorders involving hyperkinesia, motor dysfunction, and associated abnormalities in muscle control. Exemplary motor disorders include, but are not limited to, Parkinson’s disease and parkinsonism (defined especially by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, generalized rigidity syndrome, and gait disorders.

[0431] tremor The methods described herein can be used for the treatment of tremors, for example, pharmaceutical compositions of the compound of formula (I) or pharmaceutically acceptable salts thereof can be used for the treatment of cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor or red nuclear tremor. Tremors can be caused by hereditary, degenerative, and idiopathic disorders (e.g., Wilson's disease, Parkinson's disease, and essential tremor, respectively), metabolic disorders (e.g., thyroid-parathyroid disorders, liver disease, and hypoglycemia), peripheral neuropathy (associated with Charcot-Marie-Tooth, Lucy-Lewy, diabetes mellitus, and complex regional pain syndrome), toxins (nicotine, mercury, lead, CO, manganese, arsenic, and toluene), drug-induced tremors (narcolepsy, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, and vincristine), and psychogenic disorders. Clinical tremors can be classified into physiological tremors, amplified physiological tremors, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and work / position-specific tremors), dystonic tremors, Parkinsonian tremors, cerebellar tremors, Holmes tremor (i.e., red tremor), palatal tremors, neurological tremors, intoxication / drug-induced tremors, and psychogenic tremors.

[0432] Tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles, which may be accompanied by vibration or simple spasm of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, feet).

[0433] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremor can be caused by lesions or damage to the cerebellum resulting from, for example, tumors, stroke, or disease (e.g., multiple sclerosis, a hereditary degenerative disease).

[0434] Dystonic tremors occur in individuals with dystonia. Dystonia is a movement disorder characterized by persistent, involuntary muscle contractions that result in twisting and repetitive movements, and / or painful abnormal postures or positions. Dystonic tremors can affect any muscle in the body. They occur irregularly and are often relieved by complete rest.

[0435] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, but it can also progress slowly, starting on one side of the body and becoming bilateral within three years. It most commonly affects the hands, but can also affect the head, voice, tongue, feet, and trunk. The frequency of tremors may decrease with age, but their severity may increase. Tremors can be triggered and / or worsened by emotional outbursts, stress, fever, physical fatigue, or hypoglycemia. Generally, symptoms progress over time and, once onset, can be visually recognizable and persistent.

[0436] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions in the feet and trunk that occur immediately after standing. Patients may experience spasms in the thighs and feet, and may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0437] Parkinson's tremor is caused by damage to the brain structures that control movement. Often a precursor to Parkinson's disease, it typically manifests as a "pill-rolling" motion in the hand, but can also affect the jaw, lips, feet, and trunk. The onset of Parkinson's tremor typically begins after age 60. The movement may begin on one side of the body or limbs and progress to include the opposite side.

[0438] Physiological tremors can occur in healthy individuals and have no clinical significance. They are seen in all voluntary muscle groups. Physiological tremors can be triggered by certain drugs, alcohol withdrawal, or medical conditions including thyroid hyperactivity and hypoglycemia. Classically, tremors have a frequency of approximately 10 Hz.

[0439] Psychogenic tremor or hysterical tremor can occur at rest or during postural movements or exercise. Patients with psychogenic tremor may have conversion disorder or another mental disorder.

[0440] Red tremor is characterized by a coarse, slow tremor that can be present at rest, in any posture, and during intentional movements. This tremor is associated with a condition affecting the red nucleus of the midbrain and is linked to classic rare strokes.

[0441] Parkinson's disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia (slowness of movement), rigidity, and postural instability. While parkinsonism shares symptoms with Parkinson's disease, it is not a progressive neurodegenerative disease but rather a complex of symptoms.

[0442] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive, movements or postures. Dystonic movements can be patterned and twisted, and may also be tremors. Dystonia is often initiated or aggravated by spontaneous activity and is associated with overflow muscle activation.

[0443] Chorea is a neurological disorder typically characterized by spasmodic, involuntary movements affecting the shoulders, hips, and face. Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0444] Ataxia refers to a complete loss of control over bodily movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0445] Myoclonus and startle are responses to sudden, unexpected stimuli (which may be acoustic, tactile, visual, or vestibular).

[0446] Tics are involuntary movements that typically occur suddenly, briefly, repeatedly, but non-rhythmically, usually mimicking normal behavior and often occurring in the background of normal activity. Tics are classified into motor tics and vocal tics; motor tics are related to movement, and vocal tics are related to speech. Tics can be characterized as simple or complex. For example, simple motor tics affect only a few muscles limited to a specific body part. Tourette syndrome is a hereditary neuropsychiatric disorder that develops in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0447] Lower limb restlessness syndrome is a neurogenic sensorimotor disorder characterized by an overwhelming urge to move the legs while at rest.

[0448] Generalized rigidity syndrome is a progressive motor disorder characterized by involuntary, painful muscle spasms and rigidity, usually affecting the lower back and legs. A typical symptom is a rigid gait accompanied by excessive lumbar lordosis. Electromyography (EMG) typically reveals characteristic abnormalities involving continuous motor unit activity in the paraspinal axial muscles. A variant is "hand-foot rigidity syndrome," which results in localized rigidity and typically affects the distal limbs.

[0449] Gait disorders refer to abnormalities in the method or style of walking caused by neuromuscular, joint, or other bodily changes. Gaits are classified according to the system causing the abnormal walking movement and include hemiplegic gait, diplegic gait, neurogenic gait, myopathic gait, Parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0450] Anesthesia / Sedation Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects may be obtained from a single drug that alone produces the correct combination of effects, or in some cases from a combination of drugs (e.g., hypnotics, sedatives, paralyzing agents, analgesics) to achieve a highly specialized combination of results. Anesthesia allows a patient to undergo surgery and other procedures without the pain and discomfort they would otherwise experience.

[0451] Sedation generally involves reducing irritability or agitation through the administration of pharmacological agents to facilitate medical or diagnostic procedures.

[0452] Sedation and analgesia encompass a range of states of consciousness, from minimal sedation (anxiolytic) to general anesthesia.

[0453] Minimal sedation, also known as anxiolytic, is a drug-induced state in which the patient responds normally to verbal instructions. Cognitive function and motor coordination may be impaired. Respiratory and cardiovascular function are typically unaffected.

[0454] Moderate sedation / analgesia (conscious sedation) is a drug-induced state of reduced consciousness in which the patient responds intentionally, either independently or to verbal commands accompanied by mild tactile stimulation. Typically, no intervention is required to maintain airway patency. Spontaneous respiration is usually adequate. Cardiovascular function is usually maintained.

[0455] Deep sedation / analgesia is a drug-induced state of reduced consciousness in which the patient cannot easily awaken but will intentionally respond to repetitive or painful stimuli (not an escape reflex from painful stimuli). Independent respiratory function may be impaired, and the patient may require assistance to maintain a patency airway. Spontaneous breathing may be insufficient. Cardiovascular function is usually maintained.

[0456] General anesthesia is a drug-induced state of unconsciousness in which the patient cannot be awakened even by painful stimuli. The ability to maintain independent respiratory function is often impaired, and assistance is frequently required to maintain a patent airway. Positive pressure ventilation may be necessary due to decreased spontaneous respiration or drug-induced neuromuscular dysfunction. Cardiovascular function may be impaired.

[0457] Sedation in the intensive care unit (ICU) reduces a patient's awareness of their environment and minimizes their response to external stimuli. This can play a role in the care of critically ill patients and encompasses a wide range of symptom control, which varies greatly from patient to patient and individual to individual throughout the course of the illness. Intensive sedation in emergency care is used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.

[0458] In some embodiments, sedation (e.g., prolonged sedation, continuous sedation) is induced and maintained for extended periods (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months) in the ICU. Prolonged sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0459] Procedural sedation and analgesia (also known as conscious sedation) is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to induce a state in which the subject can tolerate an unpleasant procedure while maintaining cardiopulmonary function. [Examples]

[0460] To facilitate a better understanding of the disclosures described herein, the following examples are provided. The synthesis examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

[0461] To better understand the invention described herein, the following examples are provided. The examples described herein are provided to illustrate the crystalline solid forms provided herein and should not be construed as limiting their scope in any way. Abbreviations and Definitions API: Active pharmaceutical ingredient AUC: Area under the curve BA: Bioavailability BU: Blend uniformity C max : Observed highest plasma concentration CU: Uniformity of content DP: Pharmaceutical product DS: API DSC: Differential Scanning Calorimetry DVS: Dynamic Water Vapor Adsorption FaSSIF: Fasting artificial intestinal fluid FeSSIF: Artificial intestinal fluid for feeding FRI:Flow rate index GMP: Good Manufacturing Practice HDPE: High-density polyethylene HPLC: High-Performance Liquid Chromatography kp: kilopound (multiple kilopounds are possible) LOD: Detection Limit max: maximum value min: minimum value MCC: Microcrystalline Cellulose NA: Not applicable ND: Not detected (or area less than 0.05% by HPLC analysis) PVA: Polyvinyl alcohol RH: Relative humidity RRT: Relative Retention Time RSD: Relative Standard Deviation RT: Room temperature or real time SD: standard deviation SDS: Sodium dodecyl sulfate SLS: Sodium Lauryl Sulfate SMCC: Silicified microcrystalline cellulose SSF: Sodium stearyl fumarate TGA: Thermogravimetric analysis USP: United States Pharmacopeia w / w: weight versus weight XRPD: X-ray Powder Diffraction

[0462] Example 1. Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 1). To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL), 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[α]phenanthren-17-yl)ethane-1-one (50 mg, 0.12 mmol) were added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of H2O and extracted with ethyl acetate (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse-phase preparative HPLC to obtain compound 1 as a white solid (9 mg, yield 17.4%). 1 HNMR(500 MHZ, CDCl3)δ (ppm)7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB),4.2(1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dxt), 1.70-1.88 (6H, m),1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38(5H , m), 1.28 (3H, s), 1.06-1.17(3H, m), 0.67 (3H, s).LCMS: rt=2.24 min, m / z=410.1 [M+H] + .

[0463] Example 2. Preparation of crystalline form A of compound 1. Crude compound 1 was stirred as a slurry in ethyl acetate at a temperature below 10°C, filtered, and dried under vacuum to obtain crystalline form A. Alternatively, crude compound 1 was dissolved in dichloromethane, then re-concentrated twice with ethyl acetate under vacuum and dried to obtain crystalline form A.

[0464] Example 3. Preparation of crystalline form C of compound 1 Approximately 10-20 mg of form A was suspended in a mixture of 0.5 mL of isopropyl alcohol (IPA) and isopropyl acetate (IPAc). After stirring at room temperature or 50°C for 48 hours, the solid was isolated by centrifugation to obtain crystalline form C of compound 1. Alternatively, crude compound 1 was combined with ethyl acetate, and the mixture was heated under reflux to dissolve the solid. The solution was filtered by polishing, rinsed with ethyl acetate, and the filtrate was concentrated by atmospheric distillation. Once the desired volume was reached, the temperature was lowered to 65-75°C, and the slurry was stirred at this temperature for at least 2 hours. Then, heptane was added while maintaining the temperature at 65-75°C, and the mixture was held at this temperature for 6 hours. Then the temperature was slowly lowered to 30-35°C. The slurry was held at this temperature for 1-24 hours and filtered. The resulting cake was washed with ethyl acetate and heptane. The final filtered cake was dried under vacuum at a temperature below 50°C to obtain form C of compound 1 as a white to off-white crystalline solid.

[0465] Example 4. Characterization of crystalline forms A and C of compound 1 by XRPD. The XRPD pattern of compound 1, form A, was collected using a PANalytical Empyrean diffractometer with an incident beam of Cu radiation generated using an Optix long fine focus source. Cu Kα X-rays were collected through the specimen and into the detector using an elliptically tilted multilayer mirror. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed Si 111 peak location matched the NIST certified location. The specimen was sandwiched between two 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using a beam stop, a short scatter removal extension, and a scatter removal knife edge. Broadening from axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using Data Collector software with a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen. The instrument parameters used are shown in Table 1. [Table 1]

[0466] The XRPD pattern of compound 1, form C, was collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using an Optix long fine focus source. Cu Kα X-rays were collected through the specimen and into the detector using an elliptically tilted multilayer mirror. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed Si 111 peak location matched the NIST certified location. The specimen was sandwiched between two 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using a beam stop, a short scatter removal extension, and a scatter removal knife edge. Broadening from axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using Data Collector software with a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen. The instrument parameters used are shown in Table 2. [Table 2]

[0467] Morphology A: Morphology A was observed to be crystalline by XRPD, as shown in Figure 1A. Morphology C: Morphology C was observed to be crystalline by XRPD, as shown in Figure 2A.

[0468] Example 5. Preparation of single crystals of compound 1 in forms A and C. Form A: A single crystal suitable for structural determination was obtained by slowly cooling it from 50°C to 5°C in isopropyl alcohol.

[0469] Morphology C: Using a seed of morphology C, a single crystal suitable for structure determination was obtained by slowly cooling from 25°C to 5°C at a rate of 0.01°C / min in an isopropyl acetate / acetone (6:1, v / v) cosolvent.

[0470] Example 6. Single-crystal X-ray diffraction data for morphology A and morphology C. X-ray intensity data from prism-like crystals of compound 1 in morphology A (Table 3) and morphology C (Table 4) were collected at 290(2)K using a Bruker D8 Venture diffractometer (Mo Kct emission, λ=0.71073 Å). The crystal structures of compound 1 in morphology A and C were analyzed from the obtained data. [Table 3] [Table 4]

[0471] Example 7. Thermogravimetric analysis and differential scanning calorimetry of form A and form C of compound 1. Thermogravimetric analysis (TGA) data was collected using a TA Q500 / Q5000 TGA from TA Instruments. Differential scanning calorimetry (DSC) data was collected using a TA Q200 / Q2000 DSC from TA Instruments. The parameters of the instruments used are shown in Table 5. [Table 5]

[0472] TGA and DSC data for form A are shown in Figure 1C. TGA analysis of compound 1 in form A showed only a small weight loss up to 200°C. Endothermic onset, representing the conversion from form A to form K, was observed on the DSC curve at approximately 162°C, followed by the start of endothermic melting of form K at approximately 210°C.

[0473] Figure 2C shows the TGA and DSC for morphology C. TGA analysis of compound 1 in morphology C showed only a small weight loss below 100°C. Endothermic reactions, representing the conversion from morphology C to morphology K, began at approximately 170°C, followed by the start of endothermic reactions for melting morphology K at approximately 212°C.

[0474] Example 8. Preparation of particle crystal form A of compound 1 The non-particulate form A of compound 1 generates significant back pressure, clogging a standard jet mill (see Figure 3). Using a Sturtevant Model SDM2 Micronizer 2-inch jet mill (pancake pulverizer), form A of compound 1 was fed into the mill at approximately 250 g / hr using a vibrating feeder, with a venturi pressure of 80 psi and a mill pressure of 80 psi. Based on the mill's design, smaller particles moved towards the center of the mill and were collected in a filter bag after exiting the product outlet. The yield was 13%. Using a Food Pharma Systems (FPS) Model Pilotmill-2 2-inch cryogenic jet mill at -50°C, the non-particulate form A of compound 1 was fed into the mill at approximately 200 g / hr using a vibrating feeder, with a venturi pressure of 50-80 psi and a mill pressure of 70-140 psi. Based on the mill's design, smaller particles moved towards the center of the mill and were collected in a filter bag after exiting the product outlet. The particle size distribution of the contents of the filter bag was evaluated, and the material was passed through the mill as needed until the desired particle size distribution was achieved. The yield improved to 84%.

[0475] Example 9. Preparation of particle crystal form C of compound 1 Unexpectedly, the non-particulate form C of compound 1 was more suitable for the jet mill in terms of reducing particle size. Using a Sturtevant Model SDM4 Micronizer 4-inch jet mill (pancake pulverizer), form C of compound 1 was fed into the mill using a vibrating feeder at 4-6 kg / hr, venturi pressure of 80-120 psi, and mill pressure of...

Claims

[Claim 1] The invention described in the specification.

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