Solid form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-D]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile

Abstract

Solid forms of Compound (I) are disclosed. Pharmaceutical compositions containing same, methods of using same to treat disorders and conditions mediated by BTK activity, and methods of making Compound (I) and its solid forms are also disclosed. [Formula 1] TIFF2023507125000041.tif47107

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 951,958, filed December 20, 2019, and U.S. Provisional Application No. 63 / 122,309, filed December 7, 2020, which are incorporated by reference herein.

[0002] Disclosed herein are solid forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (Compound (I)), methods of use thereof, and methods of making Compound (I) that include the solid forms. The solid forms of Compound (I) are inhibitors of Bruton's tyrosine kinase (BTK) that have low residual solvent content. [Background technology]

[0003] The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in many hematopoietic cells, including B cells, mast cells, and macrophages. BTK contributes to the development and activation of B cells. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cell-related hematologic cancers (e.g., non-Hodgkin's lymphoma and chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjogren's syndrome, smallpox, IBD, lupus erythematosus, and asthma).

[0004] Compound (I), its pharma- ceutical acceptable salts, and any solid forms thereof, inhibit BTK and are useful for treating disorders and conditions mediated by BTK activity. Compound (I) is disclosed in Example 31 of Patent Document 1 and has the following chemical structure: [ka] (In the formula, *An alternative procedure for the preparation of compound (I) is described in Example 1 of WO 2005 / 023966.

[0005] Compound (I) obtained by the procedures described in Patent Documents 1 and 2 contains residual solvents in amounts well above the limits set forth in the International Council for Harmonisation ("ICH") guidelines. In general, manufacturing processes in which the amount of residual solvents approaches or exceeds the ICH limits are undesirable for manufacturing active pharmaceutical ingredients (APIs).

[0006] Solid forms of biologically active compounds, such as Compound (I) and its pharma- ceutically acceptable salts, are of interest in the pharmaceutical industry where certain physical, chemical or pharmaceutical properties, such as solubility, dissociation, true density, dissolution, melting point, morphology, compaction behavior, particle size, flow properties or solid state stability, are desirable or even necessary for pharmaceutical development. The solid form of a biologically active compound often dictates its ease of preparation, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and bioavailability in vivo.

[0007] It is also crucial that a solid form intended for use as an API in a therapeutic composition is substantially pure. Specifically, a substantially pure form is free of reaction impurities, starting materials, reagents, by-products, undesired solvents, and / or other processing impurities resulting from the manufacture and / or isolation and / or purification of the particular solid form. Specifically, a solid form intended for use as an API is substantially free of degradation products, including drug substance aggregates (e.g., dimers of the API).

[0008] It remains impossible to predict possible solid forms of a compound or salt, whether such forms will be suitable for commercial use in pharmaceutical compositions, or which forms will exhibit desirable properties. Because different solid forms may have different properties, reproducible methods for producing substantially pure solid forms, including large-scale manufacturing methods, are also desirable for biologically active compounds intended for pharmaceutical use. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2014 / 039899 [Patent Document 2] WO2015 / 127310 Summary of the Invention [Problem to be solved by the invention]

[0010] Thus, there is a need for novel solid forms, such as Compound (I) and pharma- ceutically acceptable salts thereof, that are useful for treating disorders and conditions mediated by BTK activity, as well as reproducible, scalable methods for producing the same. [Means for solving the problem]

[0011] Disclosed herein are novel solid forms of Compound (I), compositions comprising the same, and methods of using and preparing the same. Importantly, in some embodiments, the solid forms of Compound (I) have low amounts of residual solvent. Furthermore, in some embodiments, the solid forms of Compound (I) are substantially free of degradation products (e.g., dimers of Compound (I)). In some embodiments, the novel solid forms disclosed herein have properties useful for large-scale manufacturing, pharmaceutical formulation, pharmaceutical use, and / or storage. In some embodiments, the novel solid forms disclosed herein have no detectable residual solvent in the solid form. In some embodiments, the solid forms are substantially amorphous. Also disclosed herein are novel methods of preparing Compound (I).

[0012] Some embodiments of the present disclosure relate to solid forms of Compound (I) characterized by an average bulk density of greater than 0.3 g / cc. Some embodiments of the present disclosure relate to solid forms of Compound (I) characterized by a tapped density of greater than 0.5 g / cc.

[0013] Some embodiments of the present disclosure relate to solid forms of Compound (I) characterized by a Hausner ratio of 1.2 or less.

[0014] Some embodiments of the present disclosure provide a wet particle size distribution D greater than 70 μm. 10 Some embodiments of the present disclosure relate to a solid form of Compound (I) characterized in that it has a wet particle size distribution D value of greater than 200 μm. 50 Some embodiments of the present disclosure relate to a solid form of Compound (I) characterized in that it has a wet particle size distribution D value of greater than 400 μm. 90 The present invention relates to a solid form of compound (I) characterized in that it has a value of

[0015] Some embodiments of the present disclosure provide a wet particle size distribution of less than 10 μm D 10 Some embodiments of the present disclosure relate to a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 100 μm. 50 Some embodiments of the present disclosure relate to a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 200 μm. 90 The present invention relates to a solid form of compound (I) characterized in that it has a value of

[0016] Some embodiments of the present disclosure relate to solid forms of Compound (I) characterized by a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. ... g ) is greater than 90°C.

[0017] Some embodiments of the present disclosure relate to solid forms of Compound (I) having a total amount of residual solvent in the solid form of less than 1%. Some embodiments of the present disclosure relate to solid forms of Compound (I) having no detectable residual solvent in the solid form.

[0018] Some embodiments of the present disclosure relate to solid forms of Compound (I), wherein the solid form is substantially pure.

[0019] Some embodiments of the present disclosure relate to a solid form of Compound (I), wherein the solid form is substantially free of decomposition products. In some embodiments, the solid form of Compound (I) is substantially free of dimers of Compound (I). In some embodiments, the solid form of Compound (I) has the following chemical structure: [ka] The compound (I) is substantially free of a dimer having the formula:

[0020] Some embodiments of the present disclosure relate to solid forms of Compound (I), wherein the solid form is substantially amorphous.

[0021] Some embodiments of the present disclosure relate to a pharmaceutical composition comprising at least one solid form of Compound (I); and at least one pharma- ceutical acceptable excipient. In some embodiments, the at least one solid form of Compound (I) is a solid form described herein. In some embodiments, the pharmaceutical composition is in the form of a solid oral composition. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule.

[0022] Some embodiments of the present disclosure relate to a method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one solid form of Compound (I). In some embodiments, the solid form of at least one Compound (I) is a solid form described herein. Some embodiments of the present disclosure relate to a method of treating a disease mediated by BTK in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one solid form of Compound (I). In some embodiments, the solid form of at least one Compound (I) is a solid form described herein. In some embodiments, the disease mediated by BTK is pemphigus vulgaris. In some embodiments, the disease mediated by BTK is pemphigus foliaceus. In some embodiments, the disease mediated by BTK is immune thrombocytopenia. In some embodiments, the mammal is a human.

[0023] Also provided herein are methods for preparing at least one solid form of Compound (I).

[0024] In some embodiments, the method includes adding a base to an aqueous solution containing Compound (I). In some embodiments, the method includes washing the solution of Compound (I) with a first acidic aqueous solution to form a first solution containing a first organic layer and a first aqueous layer, where the solution of Compound (I) contains a first organic solvent, and removing the first aqueous layer. In some embodiments, the method further includes partially removing the first organic solvent from the first organic layer, adding a second organic solvent to the first organic layer, where the first organic solvent and the second organic solvent are not the same, and adding a second acidic aqueous solution to form a second solution containing a second organic layer and a second aqueous layer, where the second aqueous layer contains Compound (I). In some alternative embodiments, the method further comprises the steps of: adding a first organic acid to the first organic layer; concentrating the first organic layer to remove at least 70% of the first organic solvent; adding a third organic solvent to the first organic layer to form a third solution comprising a third organic layer and a third aqueous layer, where the third aqueous layer comprises compound (I), and the first organic solvent and the third organic solvent are not the same; and adding a first base to adjust the pH of the third aqueous layer to 2.5 to 3.5. In some embodiments, the method further comprises the steps of removing the second organic layer or the third organic layer; removing the residual organic solvent in the second aqueous layer or the third aqueous layer to form an aqueous solution of (I); and adding a second base to the aqueous solution of compound (I) to form a precipitate comprising compound (I). In some embodiments, the method further comprises the step of pulverizing the precipitate comprising compound (I).

[0025] In some embodiments, the method includes washing a solution comprising Compound (I) and an organic solvent with an aqueous solution of a weak organic acid having a pKa of less than or equal to 7 (≦7) to form a first organic layer and a first aqueous layer; and removing the first aqueous layer leaving behind the first organic layer comprising Compound (I).

[0026] In some embodiments, the method further comprises washing the first organic layer containing Compound (I) with an aqueous sodium bicarbonate solution. Washing the first organic layer containing Compound (I) removes substantially all of the weak organic acid having a pKa of 7 or less.

[0027] In some embodiments, the method further comprises adding a strong acid to the first organic layer and concentrating the first organic layer by removing the organic solvent to obtain a residue comprising Compound (I).

[0028] In some embodiments, the method further comprises cooling the residue comprising Compound (I) to a temperature of from 0° C. to 10° C. In some embodiments, the method further comprises washing the residue comprising Compound (I) with water or a salt water solution.

[0029] In some embodiments, the method further comprises adding a non-miscible organic solvent to the first aqueous layer to obtain a second organic layer, and a second aqueous layer comprising Compound (I); and removing the second organic layer.

[0030] In some embodiments, the method further comprises adjusting the pH of the first or second aqueous layer to a value between 1 and 5 by adding an aqueous base solution.

[0031] In some embodiments, the method further comprises measuring the amount of residual weak organic acid having a pKa of 7 or less in the first or second aqueous phase, and adjusting the amount of weak organic acid having a pKa of 7 or less to between 0% and 8% by weight.

[0032] In some embodiments, the method further comprises adding an aqueous base solution to the first or second aqueous layer to a pH of 8 to 11 to form a precipitate comprising Compound (I). In some embodiments, the method further comprises isolating the precipitate comprising Compound (I) by filtration and washing the isolated precipitate comprising Compound (I) with water. In some embodiments, the method further comprises drying the filtered and washed precipitate comprising Compound (I) to obtain a solid form of Compound (I). In some embodiments, the method further comprises slurrying the isolated precipitate with water and filtering to isolate a solid form of Compound (I).

[0033] In some embodiments, the method includes dissolving a crystalline form of Compound (I) in a solution comprising a non-miscible organic solvent and salt water; adding one equivalent of a strong acid to form an aqueous layer and an organic layer; removing the organic layer; concentrating the aqueous layer; adding an aqueous base solution to adjust the pH to a value between 8 and 11 to obtain a precipitate of the solid form of Compound (I); isolating the precipitate of the solid form of Compound (I) by filtration; rinsing the precipitate with water; and drying the precipitate to obtain a solid form of Compound (I).

[0034] In some embodiments, the method comprises spray drying a solution of Compound (I).

[0035] In some embodiments, the method includes washing the solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, the solution of Compound (I) comprising a first organic solvent, removing the first aqueous layer, and performing a solvent exchange from the first organic solvent to a second organic solvent. In some embodiments, the method further includes washing the first organic layer with a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, the second aqueous layer comprising Compound (I), and removing the second organic layer. In some embodiments, the method further includes adding a first base to the second aqueous layer to form a third solution comprising a third organic layer and a third aqueous layer, the third organic layer comprising Compound (I), extracting the third aqueous layer using a third organic solvent, and concentrating the third organic layer. In some embodiments, the method further comprises adding an anti-solvent to the third organic layer to form a precipitate comprising Compound (I). In some embodiments, the method further comprises dissolving the precipitate comprising Compound (I) in a fourth organic solvent to form a fourth solution, and spray drying the fourth solution to obtain a solid form of Compound (I). [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 shows an example of a combined differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plot for a solid form of Compound (I) (Comparative Control 1 herein) prepared substantially according to the methods detailed in Example 1, Step 1A of WO2015 / 127310. [Diagram 2] FIG. 1 shows an example combined DSC and TGA plot for a solid form of Compound (I) (Comparative Control 2 herein) prepared substantially according to the methods detailed in Example 31 of WO2014 / 039899. [Diagram 3]FIG. 1 shows an example TGA thermal curve for a solid form of Compound (I) (Comparative Control 3 herein) prepared substantially according to the methods detailed in Step 1 of Example 1 of WO2015 / 127310. [Figure 4] FIG. 2 shows an example TGA thermal curve for a solid form (micronized) of Compound (I) prepared by the precipitation methods described herein. [Diagram 5] FIG. 2 shows an example TGA thermal curve for a solid form (non-micronized) of Compound (I) prepared by the precipitation methods described herein. [Figure 6] FIG. 2 shows an example TGA thermal curve for a solid form of Compound (I) produced by the spray drying process described herein. [Figure 7] FIG. 1 shows an example modulated DSC (mDSC) thermogram at 0% relative humidity for a solid form of Compound (I) (Comparative Control 1 herein) prepared substantially according to the methods detailed in Step 1A of Example 1 of WO2015 / 127310. [Figure 8] FIG. 1 shows an example mDSC thermogram at 0% relative humidity for a solid form of Compound (I) (Comparative Control 2 herein) prepared substantially according to the methods detailed in Example 31 of WO2014 / 039899. [Figure 9] FIG. 1 shows an example mDSC thermogram at 0% relative humidity for a solid form of Compound (I) (Comparative Control 3 herein) prepared substantially according to the methods detailed in Step 1 of Example 1 of WO2015 / 127310. [Figure 10] FIG. 2 shows an example mDSC thermogram at 0% relative humidity for a solid form (non-micronized) of Compound (I) prepared by the precipitation methods described herein. [Figure 11] FIG. 2 shows an example mDSC thermogram at 0% relative humidity for a solid form of Compound (I) produced by the spray drying process described herein. [Figure 12]FIG. 2 is a diagram showing an example of a scanning electron micrograph (SEM) image of filtered particles of Compound (I) produced by precipitation with 0% by weight of acetic acid (scale bar: 10 μm). [Figure 13] FIG. 2 shows an example of an SEM image of filtered particles of Compound (I) produced by precipitation with 3% by weight of acetic acid. [Figure 14] FIG. 2 shows an example of an SEM image of filtered particles of Compound (I) produced by precipitation with 5% by weight of acetic acid. [Figure 15] FIG. 2 shows an example of an SEM image of filtered particles of Compound (I) produced by precipitation with 8% by weight of acetic acid. [Figure 16] FIG. 1 shows an example of a combined DSC and TGA plot for the solid forms of Compound (I) prepared by the conversion methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] As used herein, "a" or "an" item refers to one or more of that item. For example, "a compound" refers to one or more compounds, or at least one compound, unless otherwise specified. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably.

[0038] As used herein, "Compound (I)" refers to a compound having the following structure: [ka] (In the formula, *(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (E)-isomer, (Z)-isomer or mixture of (E)-isomer and (Z)-isomer; (S)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (S, S ... -d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, or a mixture of the (R) and (S) enantiomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile.

[0039] When compound (I) is represented by (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, it contains less than 1% by weight of the corresponding (S) enantiomer as an impurity. Thus, when compound (I) is represented as a mixture of the (R) and (S) optical isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, the amount of the (R) or (S) optical isomer in the mixture is greater than 1% by weight. Similarly, when compound (I) is represented as the (E) isomer, it contains the corresponding (Z) isomer as an impurity of less than 1% by weight. Thus, when compound (I) is represented by a mixture of the (E) and (Z) isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, the amount of the (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0040] Compound (I) may also be referred to herein as a "drug," "active agent," "therapeutically active agent," or "API."

[0041] As used herein, "substantially pure" with respect to a geometric isomer refers to a compound such as compound (I) in which more than 70% by weight of the compound exists as a given isomer. For example, "a solid form of compound (I) is substantially pure (E) isomer of compound (I)" refers to a solid form of compound (I) having at least 70% by weight of the solid form of compound (I) being the (E) isomer, and "a solid form of compound (I) is substantially pure (Z) isomer of compound (I)" refers to a solid form of compound (I) having at least 70% by weight of the solid form of compound (I) being the (Z) isomer. In some embodiments, at least 80% by weight of the solid form of compound (I) is the (E) form, or at least 80% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 85% by weight of the solid form of compound (I) is the (E) form, or at least 85% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 90% by weight of the solid form of compound (I) is the (E) form, or at least 90% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 95% by weight of the solid form of compound (I) is the (E) form, or at least 95% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 97% or 98% by weight of the solid form of compound (I) is the (E) form, or at least 97% or 98% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 99% by weight of the solid form of compound (I) is the (E) form, or at least 99% by weight of the solid form of compound (I) is the (Z) form. The relative amounts of the (E) and (Z) isomers in a solid mixture are measured by standard methods and techniques known in the art.

[0042] As used herein, "substantially pure" with respect to a solid form of a compound, such as Compound (I), refers to a solid form in which the solid form is greater than 70% by weight of the compound. For example, "a solid form of Compound (I) is substantially pure" refers to a solid form of Compound (I) that is at least 70% by weight of Compound (I).

[0043] As used herein, "substantially free of" with respect to a component in a solid form, such as a decomposition product (e.g., a dimer of Compound (I)), means that less than 5% by weight of the solid form contains the component. The relative amount of a component in a solid form is measured by standard methods and techniques known in the art. As used herein, the term "pharmaceutical acceptable salt" refers to a non-toxic salt form of the compound of the present disclosure. Pharmaceutically acceptable salts of Compound (I) of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. Suitable pharmaceutical acceptable salts include, for example, those disclosed in Berge, SM et al., J. Pharma. Sci. 66:1-19 (1977). Non-limiting examples of pharma- ceutically acceptable salts disclosed in the article include acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycolyl arsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; maleate. Acid salts include: acid salts; mandelate; mesylate; methyl bromide; methyl nitrate; methyl sulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate / diphosphate; polygalacturonate; salicylate; stearate; acetate; succinate; sulfate; tannate; tartrate; teosinate; triethioside; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum: calcium; lithium; magnesium; potassium; sodium; and zinc.

[0044] Non-limiting examples of pharma- ceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, or perchloric acids; salts formed with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids; and salts formed using other methods used in the art, such as ion exchange. Further non-limiting examples of pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like.

[0033] Non-limiting examples of pharma- ceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-butyl esters. + (C 1-4 Alkyl) 4The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Non-limiting examples of alkali and alkaline earth metals include sodium, lithium, potassium, calcium and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates. Other non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0045] As used herein, "a pharma- ceutically acceptable excipient" refers to a carrier or excipient that is useful in preparing a pharmaceutical composition. For example, pharma- ceutically acceptable excipients include carriers and excipients that are generally considered to be safe and acceptable for pharmaceutical use in mammals.

[0046] As used herein, the term "ambient conditions" refers to room temperature, open air and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" refers to a temperature between 15° C. and 30° C.

[0047] As used herein, the terms "inhibit," "inhibit," or "inhibiting" refer to a reduction or suppression of a significant decrease in the baseline activity of a given condition, symptom, disorder, disease, or biological activity or process.

[0048] As used herein, the terms "treat," "treating," or "treatment," when used in reference to a disorder or condition, include any effect that results in the improvement of the disorder or condition, e.g., lessening, reducing, modulating, ameliorating, or eliminating. The improvement or reduction in the severity of any symptom of the disorder or condition is readily assessed by standard methods and techniques known in the art.

[0049] As used herein, "mammal" refers to domestic animals (e.g., dogs, cats and horses) as well as humans. In some embodiments, the mammal is a human.

[0050] As used herein, "cc" or "cm 3 " refers to cubic centimeters.

[0051] As used herein, "residual solvent" refers to organic volatile chemicals that are used or generated during the manufacture of a drug substance or excipient, or during the manufacture of a drug product. Residual solvents are not completely removed during the manufacturing process.

[0052] As used herein, the term "amount" in "total amount of residual solvent" refers to the amount measured by gas chromatography.

[0053] Residual solvent types as used herein correspond to those defined in the International Council for Harmonisation ("ICH") guidelines, which classify residual solvents into three classes: Class 1, Class 2 and Class 3.

[0054] As used herein, "Class 1 solvents" refers to solvents that should be avoided according to ICH guidelines. Class 1 solvents include known human carcinogens, highly suspected human carcinogens, and environmental hazards, including, but not limited to, benzene, carbon tetrachloride, 1,2-dichloroethane, and 111-tetrachloroethane.

[0055] As used herein, "Class 2 solvents" refers to solvents that should be restricted according to ICH guidelines. Class 2 solvents include non-genotoxic animal carcinogens or possible causes of other irreversible toxicity such as neurotoxicity or teratogenesis, and other solvents suspected of strong but reversible toxicity. Class 2 solvents include, but are not limited to, the following solvents: acetonitrile; chlorobenzene; chloroform; cumene; cyclohexane; 1,2-dichloroethane; dichloromethane; 1,2-dimethoxyethane; N,N-dimethylacetamide; N,N-dimethylformamide; 1,4-dioxane; 2-ethoxyethanol; ethylene glycol; formamide; hexane; methanol; 2-methoxyethanol; methyl butyl ketone; methyl cyclohexane; methyl isobutyl ketone; and N-methylpyrrolidone.

[0056] As used herein, "Class 3 solvents" refers to solvents that, according to the ICH guidelines, have low toxicity to humans. There are no health-based exposure limits for Class 3 solvents under the ICH guidelines. The Permitted Daily Exposure (PDE) for Class 3 solvents is 50 mg per day. According to the ICH guidelines, residual Class 3 solvents are acceptable without justification if they are less than 50 mg per day (corresponding to 5000 ppm or 0.5%). Class 3 solvents include the following solvents: acetic acid; acetone; anisole; 1-butanol; 2-butanol; butyl acetate; tert-butyl methyl ether; dimethyl sulfoxide; ethanol; ethyl acetate; ethyl ether; ethyl formate; formic acid; heptane; isobutyl acetate; isopropyl acetate; methyl acetate; 3-methyl-1-butanol; methyl ethyl ketone; 2-methyl-1-propanol; pentane; 1-pentanol; 1-propanol; 2-propanol; propyl acetate; and trimethylamine.

[0057] As used herein, the term "antisolvent" refers to any liquid in which the product is insoluble or very poorly soluble (the solubility of the product is less than 0.01 mol / L).

[0058] As used herein, the term "anti-solvent precipitation" refers to a process in which an anti-solvent is added to a product solution to achieve supersaturation, thereby inducing precipitation.

[0059] As used herein, the term "organic layer" refers to a layer that contains at least one organic solvent that is water insoluble and immiscible in water.

[0060] As used herein, the term "aqueous layer" refers to a layer that contains water.

[0061] As used herein, the term "solid form" refers to a physical form of a compound that is not predominantly in a liquid or gaseous state, including amorphous and crystalline forms.

[0062] The term "amorphous" as used herein refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged randomly such that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. For example, an amorphous material is a solid material that does not show a sharp characteristic signal in its X-ray powder diffraction pattern (i.e., is not crystalline as measured by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its diffraction pattern. Broad peaks are characteristic of amorphous solids. For a comparison of the diffraction patterns of amorphous and crystalline materials, see, e.g., US2004 / 0006237.

[0063] The term "substantially amorphous" as used herein refers to a solid material that has little or no long-range order in the position of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). "Substantially amorphous" includes the description "amorphous," which refers to a material with no crystallinity (0% crystallinity).

[0064] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0065] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also called thermogravimetric) analysis.

[0066] As used herein, particle size refers to the particle size distribution (e.g., D 10 , D 50 and D. 90 The particle size distribution is expressed in terms of the hydration state of the particles. Specifically, the wet particle size distribution is different from the dry particle size distribution and has different characteristic D 10 , D 50 and D. 90 It has a value.

[0067] As will be appreciated by those skilled in the art, the particle size and particle size distribution of powders are measured using a variety of techniques known in the art, such as laser diffraction. In some embodiments, the particle size distribution of a solid form of Compound (I) is measured by laser diffraction (e.g., D 10 , D 50 and D. 90 It is expressed using the

[0068] As used herein, "D 50 " refers to the median diameter of the particle size distribution.

[0069] As used herein, "D 10 " means that 10% of the particle population is D 10 It refers to particle sizes having the following particle sizes:

[0070] As used herein, "D 90 " means that 90% of the particle population is D 90 It refers to particle sizes having the following particle sizes:

[0071] "Bulk density" as used herein refers to the mass of particles of a material divided by the total volume occupied by the particles. The total volume includes the volume of the particles, the volume of the voids between the particles, and the volume of the internal pores. Bulk density is not an intrinsic property of a material and varies depending on how the material is processed.

[0072] As used herein, "tap density" refers to the mass of particles of a material divided by the total volume the particles occupy after mechanically tapping the container containing the particles. The total volume includes the volume of the particles, the volume of the voids between the particles, and the volume of the internal pores. Tap density is not an intrinsic property of a material, but rather varies depending on how the material is processed.

[0073] "Hausner ratio" as used herein refers to a number related to the flowability of a powder or powdered material. The Hausner ratio is the ratio of the bulk density of the material to the tapped density of the material.

[0074] Embodiment Without being limited thereto, some embodiments of the present disclosure include the following.

[0075] 1. Compound (I): [ka] A solid form of the compound of claim 1, characterized in that the solid form has an average bulk density of greater than 0.3 g / cc. 2. The solid form of embodiment 1, having an average bulk density greater than 0.4 g / cc. 3. A solid form according to embodiment 1 or 2, characterized in that it has an average bulk density of greater than 0.5 g / cc. 4. A solid form according to any one of the preceding claims, characterized in that it has an average bulk density of greater than 0.6 g / cc. 5. A solid form according to any one of the preceding embodiments, characterized in that the average bulk density is between 0.6 g / cc and 0.7 g / cc. 6. A solid form according to any one of the preceding embodiments, characterized in that it has an average tap density of greater than 0.5 g / cc. 7. A solid form according to any one of the preceding embodiments, characterized in that it has an average tap density of greater than 0.7 g / cc. 8. A solid form according to any one of the preceding embodiments, characterized in that it has an average tap density of greater than 0.8 g / cc. 9. A solid form according to any one of the preceding embodiments, characterized in that the average tap density is between 0.7 g / cc and 0.9 g / cc. 10. A solid form according to any one of embodiments 1 to 9, characterized in that it has a Hausner ratio of less than or equal to 1.2. 11.Wet particle size distribution greater than 70μm D 10 11. A solid form according to any one of embodiments 1 to 10, characterized in that it has a value. 12.Wet particle size distribution greater than 200μm D 50 12. A solid form according to any one of embodiments 1 to 11, characterized in that it has a value. 13.Wet particle size distribution greater than 400μm D 90 13. A solid form according to any one of embodiments 1 to 12, characterized in that it has a value. 14. A solid form according to any one of the preceding embodiments, characterized in that it exhibits a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. 15. A solid form according to any one of the preceding embodiments, characterized in that it has a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. 16. A solid form according to any one of the preceding embodiments, characterized in that it has a mass loss of less than 2% by weight from 20° C. to 240° C. by thermogravimetric analysis. 17. A solid form according to any one of the preceding embodiments, characterized in that it has a mass loss by thermogravimetric analysis from 20° C. to 240° C. of less than 1.5% by weight. 18. The solid form of any one of the preceding embodiments, wherein the total amount of residual solvents in the solid form is less than 1%. 19. The solid form of any one of embodiments 1-18, wherein the total amount of residual solvents in the solid form is less than 0.5%. 20. Glass transition temperature (T g 20. The solid form according to any one of the preceding embodiments, wherein the temperature (°C) is greater than 90°C. 21. The residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or 21. The solid form of any one of the preceding embodiments, wherein the amount of residual heptane is less than 5000 ppm. 22. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or 22. The solid form of any one of the preceding embodiments, wherein the amount of residual heptane is less than 500 ppm. 23. The solid form of any one of embodiments 1-22, wherein the amount of residual dichloromethane is less than 1500 ppm. 24. The solid form of any one of embodiments 1-23, wherein the amount of residual dichloromethane is less than 1000 ppm. 25. The solid form of any one of embodiments 1-24, wherein the amount of residual dichloromethane is less than 500 ppm. 26. The solid form of any one of embodiments 1-25, wherein the amount of residual dichloromethane is less than 100 ppm. 27. The solid form according to any one of embodiments 1 to 23, wherein the solid form is free of detectable residual solvent. 28. The solid form according to any one of embodiments 1 to 27, wherein the solid form is substantially amorphous.

[0076] 29. Compound (I): [ka] 1. A solid form of the compound of claim 1, characterized in that the solid form has an average tap density of greater than 0.5 g / cc. 30. The solid form of embodiment 29, having an average tap density of greater than 0.6 g / cc. 31. The solid form according to embodiment 29 or 30, characterized in that it has an average tap density of greater than 0.7 g / cc. 32. A solid form according to any one of embodiments 29 to 31, characterized in that the average tap density is greater than 0.8 g / cc. 33. A solid form according to any one of embodiments 29 to 32, characterized in that the average tap density is from 0.7 g / cc to 0.9 g / cc. 34. A solid form according to any one of embodiments 29 to 33, characterized in that it has a Hausner ratio of less than or equal to 1.2. 35.Wet particle size distribution greater than 70μm D 10 35. The solid form according to any one of embodiments 29 to 34, characterized in that it has a value. 36.Wet particle size distribution greater than 200μm D 50 36. The solid form according to any one of embodiments 29 to 35, characterized in that it has a value. 37.Wet particle size distribution greater than 400μm D 90 37. The solid form according to any one of embodiments 29 to 36, characterized in that it has a value. 38. A solid form according to any one of embodiments 29 to 37, characterized in that it has a mass loss of less than 5% by weight from 20 ° C to 240 ° C by thermogravimetric analysis. 39. A solid form according to any one of embodiments 29 to 38, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 3 wt.%. 40. A solid form according to any one of embodiments 29 to 39, characterized in that it has a mass loss of less than 2% by weight from 20 ° C to 240 ° C by thermogravimetric analysis. 41. A solid form according to any one of embodiments 29 to 40, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 1.5% by weight. 42. A solid form according to any one of embodiments 29-41, wherein the total amount of residual solvents in the solid form is less than 1%. 43. A solid form according to any one of embodiments 29-42, wherein the total amount of residual solvents in the solid form is less than 0.5%. 44. Glass transition temperature (T g 44. The solid form according to any one of embodiments 29 to 43, wherein the temperature (°C) is greater than 90°C. 45. The residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of any one of embodiments 29-44, wherein the amount of residual heptane is less than 5000 ppm. 46. ​​Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of any one of embodiments 29-45, wherein the amount of residual heptane is less than 500 ppm. 47. The solid form of any one of embodiments 29-46, wherein the amount of residual dichloromethane is less than 1500 ppm. 48. The solid form of any one of embodiments 29-47, wherein the amount of residual dichloromethane is less than 1000 ppm. 49. The solid form of any one of embodiments 29-48, wherein the amount of residual dichloromethane is less than 500 ppm. 50. The solid form of any one of embodiments 29-49, wherein the amount of residual dichloromethane is less than 100 ppm. 51. A solid form according to any one of embodiments 29 to 50, wherein the solid form is free of detectable residual solvent. 52. The solid form according to any one of embodiments 29-51, wherein the solid form is substantially amorphous.

[0077] 53. Compound (I): [ka] A solid form of the compound of claim 1, characterized in that it has a Hausner ratio of 1.2 or less. 54.Wet particle size distribution greater than 70μm D 10 54. The solid form of embodiment 53, having a value of 55.Wet particle size distribution greater than 200μm D 50 55. The solid form according to embodiment 53 or 54, characterized in that it has a value. 56.Wet particle size distribution greater than 400μm D 9056. The solid form according to any one of embodiments 53 to 55, characterized in that it has a value. 57. A solid form according to any one of embodiments 53 to 56, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 5% by weight. 58. A solid form according to any one of embodiments 53 to 57, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 3 wt.%. 59. A solid form according to any one of embodiments 53 to 58, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 2 wt.%. 60. A solid form according to any one of embodiments 53 to 59, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 1.5% by weight. 61. A solid form according to any one of embodiments 53-60, wherein the total amount of residual solvents in the solid form is less than 1%. 62. A solid form according to any one of embodiments 53-61, wherein the total amount of residual solvents in the solid form is less than 0.5%. 63. Glass transition temperature at 0% relative humidity (T g 63. The solid form according to any one of embodiments 53 to 62, wherein the temperature (°C) is greater than 90°C. 64. The residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of any one of embodiments 53-63, wherein the amount of residual heptane is less than 5000 ppm. 65. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of any one of embodiments 53-64, wherein the amount of residual heptane is less than 500 ppm. 66. The solid form of any one of embodiments 53-65, wherein the amount of residual dichloromethane is less than 1500 ppm. 67. The solid form of any one of embodiments 53-66, wherein the amount of residual dichloromethane is less than 1000 ppm. 68. The solid form of any one of embodiments 53-67, wherein the amount of residual dichloromethane is less than 500 ppm. 69. The solid form of any one of embodiments 53-68, wherein the amount of residual dichloromethane is less than 100 ppm. 70. The solid form according to any one of embodiments 53-69, wherein the solid form is free of detectable residual solvent. 71. The solid form according to any one of embodiments 53-70, wherein the solid form is substantially amorphous.

[0078] 72.Compound (I): [ka] A solid form of the compound having a wet particle size distribution of greater than 70 μm. 10 A solid form characterized by having a value. 73.Wet particle size distribution greater than 200 μm D 50 73. The solid form of embodiment 72, having a value of 74.Wet particle size distribution greater than 400 μm D 90 74. The solid form according to embodiment 72 or 73, characterized in that it has a value. 75. The solid form of any one of embodiments 72-74, characterized in that it has a mass loss of less than 5% by weight from 20 ° C to 240 ° C by thermogravimetric analysis. 76. A solid form according to any one of embodiments 72 to 75, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 3 wt.%. 77. A solid form according to any one of embodiments 72 to 76, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 2 wt.%. 78. A solid form according to any one of embodiments 72 to 77, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 1.5 wt.%. 79. A solid form according to any one of embodiments 72-78, wherein the total amount of residual solvents in the solid form is less than 1%. 80. The solid form of any one of embodiments 72-79, wherein the total amount of residual solvents in the solid form is less than 0.5%. 81. Glass transition temperature (T g 81. The solid form according to any one of embodiments 72 to 80, wherein the temperature is higher than 90° C. 82. Residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of any one of embodiments 72-81, wherein the amount of residual heptane is less than 5000 ppm. 83. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of any one of embodiments 72-82, wherein the amount of residual heptane is less than 500 ppm. 84. The solid form of any one of embodiments 72-83, wherein the amount of residual dichloromethane is less than 1500 ppm. 85. The solid form of any one of embodiments 72-84, wherein the amount of residual dichloromethane is less than 1000 ppm. 86. The solid form of any one of embodiments 72-85, wherein the amount of residual dichloromethane is less than 500 ppm. 87. The solid form of any one of embodiments 72-86, wherein the amount of residual dichloromethane is less than 100 ppm. 88. The solid form according to any one of embodiments 72-87, wherein the solid form is free of detectable residual solvent. 89. The solid form according to any one of embodiments 72-88, wherein the solid form is substantially amorphous.

[0079] 90.Compound (I): [ka] A solid form of the compound having a wet particle size distribution of less than 10 μm, 10 A solid form characterized by having a value. 91. Wet particle size distribution of 5μm to 6μm D 10 value, or D from 1 to 2 μm 10 91. The solid form of embodiment 90, having a value of 92.Wet particle size distribution D less than 100μm 50 92. The solid form according to embodiment 90 or 91, characterized in that it has a value. 93.Wet particle size distribution of less than 200 μm D 90 93. The solid form according to any one of embodiments 90 to 92, characterized in that it has a value. 94. A solid form according to any one of embodiments 90 to 93, characterized in that the average bulk density is less than 0.3 g / cc. 95. A solid form according to any one of embodiments 90 to 94, characterized in that the average tap density is less than 0.3 g / cc. 96. A solid form according to any one of embodiments 90 to 95, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 5 wt.%. 97. A solid form according to any one of embodiments 90 to 96, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 3 wt.%. 98. The solid form of any one of embodiments 90 to 97, characterized in that it has a mass loss of less than 2% by weight from 20 ° C to 240 ° C by thermogravimetric analysis. 99. The solid form of any one of embodiments 90 to 98, characterized in that the mass loss from 20 ° C to 240 ° C by thermogravimetric analysis is less than 1.5 wt.%. 100. The solid form of any one of embodiments 90-99, wherein the total amount of residual solvents in the solid form is less than 1%. 101. The solid form of any one of embodiments 90-100, wherein the total amount of residual solvents in the solid form is less than 0.5%. 102. Glass transition temperature at 0% relative humidity (T g102. The solid form according to any one of embodiments 90 to 101, wherein the temperature (°C) is greater than 90°C. 103. The residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of any one of embodiments 90-102, wherein the amount of residual heptane is less than 5000 ppm. 104. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of any one of embodiments 90-103, wherein the amount of residual heptane is less than 500 ppm. 105. The solid form of any one of embodiments 90-104, wherein the amount of residual dichloromethane is less than 1500 ppm. 106. The solid form of any one of embodiments 90-105, wherein the amount of residual dichloromethane is less than 1000 ppm. 107. The solid form of any one of embodiments 90-106, wherein the amount of residual dichloromethane is less than 500 ppm. 108. The solid form of any one of embodiments 90-107, wherein the amount of residual dichloromethane is less than 100 ppm. 109. The solid form according to any one of embodiments 90 to 108, wherein the solid form is free of detectable residual solvent. 110. The solid form according to any one of embodiments 90 to 109, wherein the solid form is substantially amorphous.

[0080] 111.Compound (I): [ka] 1. A solid form of the compound of claim 1, characterized in that it exhibits a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. 112. The solid form of embodiment 111, characterized by a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. 113. The solid form according to embodiment 111 or 112, characterized in that it has a mass loss of less than 2% by weight from 20 ° C to 240 ° C by thermogravimetric analysis. 114. The solid form according to any one of embodiments 111 to 113, characterized in that it has a mass loss by thermogravimetric analysis from 20 ° C to 240 ° C of less than 1.5 wt.%. 115. The solid form according to any one of embodiments 111-114, wherein the total amount of residual solvents in the solid form is less than 1%. 116. A solid form according to any one of embodiments 111-115, wherein the total amount of residual solvents in the solid form is less than 0.5%. 117. Glass transition temperature (T g 117. The solid form according to any one of embodiments 111 to 116, wherein the temperature (°C) is greater than 90°C. 118. Residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of any one of embodiments 111-117, wherein the amount of residual heptane is less than 5000 ppm. 119. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of any one of embodiments 111-118, wherein the amount of residual heptane is less than 500 ppm. 120. The solid form of any one of embodiments 111-119, wherein the amount of residual dichloromethane is less than 1500 ppm. 121. The solid form of any one of embodiments 111-120, wherein the amount of residual dichloromethane is less than 1000 ppm. 122. The solid form of any one of embodiments 111-121, wherein the amount of residual dichloromethane is less than 500 ppm. 123. The solid form of any one of embodiments 111-122, wherein the amount of residual dichloromethane is less than 100 ppm. 124. The solid form according to any one of embodiments 111-123, wherein the solid form is free of detectable residual solvent. 125. The solid form according to any one of embodiments 111-124, wherein the solid form is substantially amorphous.

[0081] 126.Compound (I): [ka] A solid form of the compound having a glass transition temperature (T g ) is greater than 90°C. 127. Residual methanol content is less than 3000 ppm; Residual isopropyl acetate is less than 5000 ppm; and / or The solid form of embodiment 126, wherein the amount of residual heptane is less than 5000 ppm. 128. Residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or The solid form of embodiment 126 or 127, wherein the amount of residual heptane is less than 500 ppm. 129. The solid form of any one of embodiments 126-128, wherein the amount of residual dichloromethane is less than 1500 ppm. 130. The solid form of any one of embodiments 126-129, wherein the amount of residual dichloromethane is less than 1000 ppm. 131. The solid form of any one of embodiments 126-130, wherein the amount of residual dichloromethane is less than 500 ppm. 132. The solid form of any one of embodiments 126-131, wherein the amount of residual dichloromethane is less than 100 ppm. 133. The solid form according to any one of embodiments 126-132, wherein the solid form is free of detectable residual solvent. 134. The solid form according to any one of embodiments 126-133, wherein the solid form is substantially amorphous. 135. A method for preparing a solid form of compound (I), comprising adding a base to an aqueous solution containing compound (I). 136. The method of embodiment 135, wherein the base is an aqueous base. 137. The method of embodiment 135 or 136, wherein the base is an aqueous potassium hydroxide solution. 138. A method for producing a solid form of compound (I), comprising: washing the solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, the solution of Compound (I) comprising a first organic solvent; and Removing the first aqueous layer The method includes: 139. The method of embodiment 138, wherein the first acidic aqueous solution has a pH of 1 to 6. 140. The method of embodiment 138 or 139, wherein the first acidic aqueous solution has a pH of 2.5 to 3.5. 141. The method of any one of embodiments 138-140, wherein the first acidic aqueous solution is a phosphate buffer solution of pH 3. 142. The method of any one of embodiments 138-141, wherein the first organic solvent comprises at least one non-miscible organic solvent. 143. The method of embodiment 142, wherein the at least one non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate. 144. The method of any one of embodiments 138-143, wherein the first organic solvent is dichloromethane. 145. Partially removing the first organic solvent from the first organic layer; adding a second organic solvent to the first organic layer, the first organic solvent and the second organic solvent being not the same; and 145. The method of any one of embodiments 138-144, further comprising adding a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, wherein the second aqueous layer comprises Compound (I). 146. The method of embodiment 145, wherein partially removing the first organic solvent from the first organic layer comprises distillation under reduced pressure. 147. The method of embodiment 145 or 146, wherein the second organic solvent is isopropyl acetate. 148. The method of any one of embodiments 145-147, wherein the second aqueous acid solution is an aqueous sulfuric acid solution. 149. adding a first organic acid to the first organic layer; concentrating the first organic layer to remove at least 70% of the first organic solvent; adding a third organic solvent to the first organic layer to form a third solution comprising a third organic layer and a third aqueous layer, the third aqueous layer comprising Compound (I), and further wherein the first organic solvent and the third organic solvent are not identical; and adding a first base to adjust the pH of the third aqueous layer to between 2.5 and 3.5; The method of any one of embodiments 138 to 144, further comprising: 150. The method of embodiment 149, wherein the first organic acid is methanesulfonic acid. 151. The method of embodiment 149 or 150, wherein concentrating the first organic layer to remove at least 70% of the first organic solvent comprises distillation under reduced pressure. 152. The method of any one of embodiments 149-151, wherein the third organic solvent is isopropyl acetate. 153. The method of any one of embodiments 149-152, wherein the first base is an aqueous base. 154. The method of any one of embodiments 149-153, wherein the first base is an aqueous potassium hydroxide solution. 155. Removing the second organic layer or the third organic layer; removing residual organic solvent in the second aqueous layer or the third aqueous layer to form an aqueous solution of Compound (I); and adding a second base to the aqueous solution of compound (I) to form a precipitate comprising compound (I); 150. The method of embodiment 145 or 149, further comprising: 156. The method of embodiment 155, wherein removing the organic solvent in the second aqueous phase or the third aqueous phase comprises distillation under reduced pressure. 157. The method of embodiment 155 or 156, wherein the second base is an aqueous base. 158. The method of any one of embodiments 155 to 157, wherein the second base is an aqueous potassium hydroxide solution. 159. The method of any one of embodiments 155-158, further comprising filtering and drying the precipitate. 160. The method of embodiment 159, wherein the precipitate is substantially free of decomposition products. 161. The method of embodiment 159 or 160, wherein the residual solvent is less than 1% of the precipitate. 162. A method for producing a solid form of compound (I), comprising: washing the solution comprising Compound (I) and an organic solvent with an aqueous solution of a weak organic acid having a pKa of 7 or less to form a first solution comprising a first organic layer and a first aqueous layer; and removing the first aqueous layer leaving behind the first organic layer containing compound (I); The method includes: 163. The method of embodiment 162, wherein the organic solvent comprises at least one non-miscible organic solvent. 164. The method of embodiment 163, wherein the non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate. 165. The method of any one of embodiments 162-164, wherein the organic solvent is dichloromethane. 166. The method of any one of embodiments 162-165, wherein the weak organic acid having a pKa of 7 or less is selected from acetic acid, citric acid, formic acid and propanoic acid. 167. The method of any one of embodiments 162-166, wherein the weak organic acid having a pKa of 7 or less is acetic acid. 168. The method of any one of embodiments 162-167, further comprising washing the first organic layer containing compound (I) with an aqueous sodium bicarbonate solution. 169. adding a strong acid to the first organic layer; and Concentrating the first organic layer by removing the organic solvent to obtain a residue containing compound (I). The method of any one of embodiments 162 to 168, further comprising: 170. The method of embodiment 169, wherein the strong acid is selected from methanesulfonic acid, sulfuric acid, and hydrochloric acid. 171. The method of embodiment 169 or 170, wherein the strong acid is methanesulfonic acid. 172. The method of any one of embodiments 162-171, further comprising cooling the residue containing compound (I) to a temperature of 0 °C to 10 °C. 173. The method according to embodiment 172, wherein the residue containing compound (I) is cooled to a temperature of 5°C. 174. The method of any one of embodiments 162-173, further comprising washing the residue comprising compound (I) with water or a salt solution. 175. The method of embodiment 174, wherein the saline solution is an aqueous solution of sodium chloride. 176. Adding a non-miscible organic solvent to obtain a second organic layer and a second aqueous layer containing compound (I); and Removing the second organic layer. 176. The method of embodiment 174 or 175, further comprising: 177. The method according to embodiment 174, wherein washing the residue containing compound (I) with water or a salt solution is repeated 1 to 3 times. 178. The method of any one of embodiments 169-177, further comprising adjusting the pH of the first or second aqueous layer to a value from 1 to 5 by adding an aqueous base solution. 179. The method of embodiment 178, wherein the pH of the first or second aqueous layer is adjusted to 3. 180. The method of embodiment 178 or 179, wherein the aqueous base solution is an aqueous solution of sodium hydroxide, potassium hydroxide, or calcium hydroxide. 181. The method of any one of embodiments 178-180, further comprising measuring the amount of residual weak organic acid having a pKa of 7 or less in the first or second aqueous layer, and adjusting the amount of weak organic acid having a pKa of 7 or less to 0% by weight to 8% by weight. 182. The method of embodiment 181, wherein the weak organic acid having a pKa of 7 or less is acetic acid. 183. The method of embodiment 181 or 182, further comprising adding an aqueous base solution to the first or second aqueous layer to achieve a pH of 8 to 11 to form a precipitate comprising compound (I). 184. The method of embodiment 183, wherein the pH is 9.5. 185. The method of embodiment 183 or 184, wherein the aqueous base solution is an aqueous solution of potassium hydroxide. 186. The method of any one of embodiments 183-185, further comprising isolating the precipitate comprising compound (I) by filtration and washing the precipitate comprising compound (I) with water. 187. The method of embodiment 186, further comprising drying the filtered and washed precipitate containing compound (I) to obtain a solid form of compound (I). 188. The method of embodiment 186, further comprising slurrying the isolated precipitate with water and filtering to obtain a solid form of compound (I). 189. A method for producing a solid form of compound (I), comprising: dissolving a crystalline form of Compound (I) in a solution comprising a non-miscible organic solvent and salt water; adding 1 equivalent of a strong acid to form an aqueous layer and an organic layer; removing the organic layer; concentrating the aqueous layer; adding an aqueous base solution to adjust the pH to a value between 8 and 11 to obtain the precipitation of compound (I) in solid form; isolating the precipitate in solid form of Compound (I) by filtration; rinsing the deposit with water; and Drying the precipitate to obtain a solid form of compound (I) A method comprising: 190. The method of embodiment 189, wherein the non-miscible organic solvent is dichloromethane. 191. The method of embodiment 189 or 190, wherein the strong acid is methanesulfonic acid. 192. The method of any one of embodiments 189-191, wherein the pH of the aqueous layer after addition of the strong acid is from 1 to 4. 193. The method of embodiment 192, wherein the pH of the aqueous layer is 2. 194. The method of any one of embodiments 189-193, wherein the aqueous layer is concentrated at a temperature between 0 °C and 5 °C. 195. The method of any one of embodiments 189-194, wherein the aqueous base solution is an aqueous potassium hydroxide solution. 196. The method according to any one of embodiments 189-195, wherein the pH is adjusted to a value of 9 to 10 by adding an aqueous base solution. 197. The method according to any one of embodiments 189 to 196, wherein the aqueous layer containing the precipitate is warmed to room temperature before isolating the precipitate in solid form of compound (I). 198. The method of any one of embodiments 135-197, further comprising micronizing the particles of compound (I). 199. A solid form of compound (I) prepared by a method according to any one of embodiments 135 to 198. 200. The solid form according to embodiment 175, wherein the solid form is substantially amorphous. 201. A method for producing a solid form of Compound (I), comprising spray drying a solution of Compound (I). 202. A method for producing an amorphous form of compound (I), comprising: washing a solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, the solution of Compound (I) comprising a first organic solvent; removing the first aqueous layer; and Performing a solvent exchange from the first organic solvent to a second organic solvent. The method includes: 203. The method of embodiment 202, wherein the first acidic aqueous solution has a pH of 1 to 6. 204. The method of embodiment 202 or 203, wherein the first acidic aqueous solution has a pH of 2.5 to 3.5. 205. The method of any one of embodiments 202-204, wherein the first acidic aqueous solution is a phosphate buffer solution of pH 3. 206. The method of any one of embodiments 202-205, wherein the first organic solvent comprises at least one non-miscible organic solvent. 207. The method of embodiment 206, wherein the at least one non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate. 208. The method of any one of embodiments 202-207, wherein the first organic solvent comprises dichloromethane. 209. The method of any one of embodiments 202-208, wherein the second organic solvent comprises at least one of alkyl acetate, methyl tetrahydrofuran, toluene, methyl cyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and alkyl propionate. 210. The method of embodiment 209, wherein the alkyl acetate is isopropyl acetate. 211. The method of embodiment 209 or 210, wherein the second organic solvent comprises isopropyl acetate. 212. Washing the first organic layer with a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, the second aqueous layer comprising compound (I); and Removing the second organic layer. The method of any one of embodiments 202 to 211, further comprising: 213. The method of embodiment 212, wherein the second acidic aqueous solution has a pH of 1 to 6. 214. The method of embodiment 212 or 213, wherein the second acidic aqueous solution has a pH of 2.5 to 3.5. 215. The method of any one of embodiments 212-214, wherein the second acidic aqueous solution is a phosphate buffer solution of pH 3. 216. adding a first base to the second aqueous layer to form a third solution comprising a third organic layer and a third aqueous layer, the third organic layer comprising compound (I); extracting the third aqueous layer with a third organic solvent; and Concentrating the third organic layer. The method of any one of embodiments 212 to 215, further comprising: 217. The method of embodiment 216, wherein the first base is an aqueous base. 218. The method of embodiment 217, wherein the aqueous base solution has a pH of 8 to 14. 219. The method of any one of embodiments 216-218, wherein the first base is an aqueous potassium hydroxide solution. 220. The method of any one of embodiments 216-219, wherein the third organic solvent comprises at least one of an alkyl acetate, methyl tetrahydrofuran, toluene, methyl cyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and an alkyl propionate. 221. The method of embodiment 220, wherein the alkyl acetate is isopropyl acetate. 222. The method of any one of embodiments 216-221, wherein the third organic solvent comprises isopropyl acetate. 223. The method of any one of embodiments 216-222, further comprising adding an anti-solvent to the third organic layer to form a precipitate comprising compound (I). 224. The method of embodiment 223, wherein the antisolvent comprises at least one of hexane, heptane, and octane. 225. The method of embodiment 223 or 224, further comprising isolating the precipitate comprising compound (I). 226. The method of embodiment 225, wherein isolating the precipitate comprising compound (I) comprises drying the precipitate comprising compound (I). 227. The method of embodiment 226, wherein drying comprises air drying, blow drying or vacuum drying. 228. Dissolving the precipitate containing compound (I) in a fourth organic solvent to form a fourth solution; and Spray drying the fourth solution to obtain a solid form of Compound (I). The method of any one of embodiments 225 to 227, further comprising: 229. The method of embodiment 228, wherein the fourth organic solvent comprises at least one of methanol, ethanol, acetone, acetonitrile, and methyl ethyl ketone. 230. The method of embodiment 229, wherein the fourth organic solvent comprises methanol. 231. The method of any one of embodiments 228-230, wherein the solid form of compound (I) is substantially free of decomposition products. 232. The method of any one of embodiments 228-231, wherein the residual solvent is less than 1% of the solid form of Compound (I). 233. The method of any one of embodiments 228-232, further comprising micronizing the solid form of compound (I). 234. A solid form of compound (I), prepared by a method according to any one of embodiments 201 to 233. 235. The solid form according to embodiment 234, wherein the solid form is substantially amorphous. 236. A pharmaceutical composition comprising: A solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234 or 235; at least one pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising: 237. The pharmaceutical composition according to embodiment 236, wherein the pharmaceutical composition is in the form of a solid oral composition. 238. The pharmaceutical composition according to embodiment 236 or 237, wherein the pharmaceutical composition is in the form of a tablet or capsule. 239. A method of inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need of inhibition of BTK, comprising administering to the mammal a therapeutically effective amount of a solid form of compound (I) as described in any one of embodiments 1-134, 199, 200, 234 or 235. 240. A method of treating a disease mediated by Bruton's tyrosine kinase (BTK) in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a solid form of compound (I) as defined in any one of embodiments 1 to 134, 199, 200, 234 or 235. 241. A method of treating pemphigus vulgaris or pemphigus foliaceus in a mammal in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a solid form of compound (I) as defined in any one of embodiments 1-134, 199, 200, 234 or 235. 242. A method of treating immune thrombocytopenia in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a solid form of compound (I) as defined in any one of embodiments 1 to 134, 199, 200, 234 or 235. 243. The method of any one of embodiments 239 to 242, wherein the mammal is a human.

[0082] Average bulk density of solid forms Average bulk density reflects the amount of space that a given amount of material occupies. Average bulk density influences how the material behaves during processing operations (e.g., compounding and compression). In some cases, average bulk density dictates the choice of milling procedure for materials during pharmaceutical development.

[0083] In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.30 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.35 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.40 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.45 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.50 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.55 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.60 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of greater than 0.65 g / cc.

[0084] In some embodiments, the process results in a solid form of Compound (I) characterized by an average bulk density of 0.6 g / cc to 0.7 g / cc.

[0085] In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.30 g / cc to 0.70 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.30 g / cc to 0.35 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.35 g / cc to 0.40 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.40 g / cc to 0.45 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.45 g / cc to 0.50 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.50 g / cc to 0.55 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.55 g / cc to 0.60 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.60 g / cc to 0.65 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.65 g / cc to 0.70 g / cc.

[0086] In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.30 g / cc to 0.32 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.32 g / cc to 0.34 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.34 g / cc to 0.36 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.36 g / cc to 0.38 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.38 g / cc to 0.40 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.40 g / cc to 0.42 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.42 g / cc to 0.44 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.44 g / cc to 0.46 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.46 g / cc to 0.48 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.48 g / cc to 0.50 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.50 g / cc to 0.52 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.52 g / cc to 0.54 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.54 g / cc to 0.56 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.56 g / cc to 0.58 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.58 g / cc to 0.60 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.60 g / cc to 0.62 g / cc.In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.62 g / cc to 0.64 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.64 g / cc to 0.66 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.66 g / cc to 0.68 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average bulk density of 0.68 g / cc to 0.70 g / cc.

[0087] Average tap density of solid forms "Average tap density" or "tap density" refers to the bulk density measured after mechanically tapping a container containing a powder sample. Tap density influences the behavior of a pharmaceutical material during, for example, pre-compression, tableting, and capsule filling.

[0088] In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of greater than 0.50 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.55 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.60 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.65 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.70 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.75 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.80 g / cc. The solid forms of the present disclosure are characterized by an average tap density of greater than 0.85 g / cc.

[0089] In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.70 g / cc to 0.90 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.70 g / cc to 0.75 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.75 g / cc to 0.80 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.80 g / cc to 0.85 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.85 g / cc to 0.90 g / cc.

[0090] In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.70 g / cc to 0.72 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.72 g / cc to 0.74 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.74 g / cc to 0.76 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.76 g / cc to 0.78 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.78 g / cc to 0.80 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.80 g / cc to 0.82 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.82 g / cc to 0.84 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.88 g / cc to 0.86 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.86 g / cc to 0.88 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tap density of 0.88 g / cc to 0.90 g / cc.

[0091] Hausner ratio for solid forms The Hausner ratio indicates the flowability of a powder, and a Hausner ratio greater than 1.35 is often considered to indicate poor flowability. Powder flow is a key requirement for most pharmaceutical manufacturing processes. To ensure consistent content uniformity, acceptable flowability of powders with a Hausner ratio of less than 1.34 is often required.

[0092] In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.2 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.18 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.16 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.14 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.12 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.10 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.08 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.06 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.04 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.02 or less. In some embodiments, the solid form of the disclosure is characterized by a Hausner ratio of 1.00 or less.

[0093] In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1 to 1.2. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.00 to 1.05. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.05 to 1.10. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.10 to 1.15. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.15 to 1.20.

[0094] Wet particle size distribution of solid forms Particle size is related to several important properties for formulation procedures, including particle shape, surface area and porosity. The particle size distribution of an API affects bulk properties, product performance, processability and API stability. For example, particle size distribution affects the dissolution and absorption rate of the API, as well as product consistency. For some pharmaceutical applications, smaller particle sizes are desirable.

[0095] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of greater than 70 μm D 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 75 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 80 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 85 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 90 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 95 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 100 μm. 10In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 105 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 110 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 115 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 120 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 125 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 130 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 135 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 140 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 145 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 150 μm. 10 It is characterized by having a value.

[0096] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 70 μm to 150 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 80 μm and 150 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 90 μm and 150 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 100 μm and 150 μm.10 It is characterized by having a value.

[0097] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of greater than 200 μm D 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 205 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 210 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 215 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 220 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 225 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 230 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 235 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 240 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 245 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 250 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 255 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 260 μm. 50In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 265 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 270 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 275 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 280 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 285 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 290 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 295 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 300 μm. 50 It is characterized by having a value.

[0098] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 200 μm to 400 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 200 μm and 300 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 225 μm and 275 μm. 50 It is characterized by having a value.

[0099] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of greater than 400 μm D 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 425 μm. 90In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 450 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 475 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 500 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 525 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of greater than 550 μm. 90 It is characterized by having a value.

[0100] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 400 μm to 800 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 400 μm and 700 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 450 μm and 700 μm. 90 It is characterized by having a value.

[0101] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of less than 10 μm D 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 9 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 8 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 7 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 6 μm. 10In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 5 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 4 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 3 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 2 μm. 10 It is characterized by having a value.

[0102] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 5 μm to 6 μm. 10 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 1 μm and 2 μm. 10 It is characterized by having a value.

[0103] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of less than D 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 90 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 80 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 70 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 60 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 50 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 40 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 30 μm. 50In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 20 μm. 50 It is characterized by having a value.

[0104] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 40 μm to 70 μm. 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 10 μm and 20 μm. 50 It is characterized by having a value.

[0105] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 5 μm to 6 μm. 10 value and D from 10 μm to 20 μm 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 1 μm and 2 μm. 10 value and D from 40 μm to 70 μm 50 It is characterized by having a value.

[0106] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of less than 200 μm D 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 190 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 180 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 170 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 160 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 150 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 140 μm. 90In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 130 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 120 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 110 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 100 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 90 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 80 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 70 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 60 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 50 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 40 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution D value of less than 30 μm. 90 It is characterized by having a value.

[0107] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 100 μm to 150 μm. 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 10 μm and 50 μm. 90 It is characterized by having a value.

[0108] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 100 μm to 150 μm. 90 value and D from 40 μm to 70 μm 50 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 10 μm and 50 μm. 90 value and D from 10 μm to 20 μm 50 It is characterized by having a value.

[0109] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 5 μm to 6 μm. 10 value and D from 10 μm to 50 μm 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 1 μm and 2 μm. 10 value and D from 100 μm to 150 μm 90 It is characterized by having a value.

[0110] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 5 μm to 6 μm. 10 Value, D from 10 μm to 20 μm 50 value and D from 10 μm to 50 μm 90 In some embodiments, the solid form of the present disclosure is characterized by having a wet particle size distribution of D value between 1 μm and 2 μm. 10 Value, D from 40 μm to 70 μm 50 value and D from 100 μm to 150 μm 90 It is characterized by having a value.

[0111] Residual solvent content in solid form Residual solvents are volatile organic compounds that are used or formed during the manufacture of a compound. Regulations, including those promulgated by the United States Food and Drug Administration, require that compounds intended for use as active pharmaceutical ingredients be substantially free of toxicologically significant residual solvents. Headspace gas chromatography is commonly employed to measure the amount of residual solvent, but mass spectrometry is often used in conjunction to identify and quantify specific residual solvents.

[0112] In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 1%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.9%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.8%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.7%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.6%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.5%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.4%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.3%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.2%. In some embodiments, the total amount of residual solvents in the solid form of the present disclosure is less than 0.1%.

[0113] In some embodiments, the solid forms of the present disclosure are free of detectable residual solvent.

[0114] In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 3000 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 2500 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 2000 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 1500 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 1000 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 900 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 800 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 700 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 600 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 500 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 400 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 300 ppm. In some embodiments, the solid form of the present disclosure has less than 200 ppm of residual methanol. In some embodiments, the solid form of the present disclosure has less than 100 ppm of residual methanol. In some embodiments, the solid form of the present disclosure has no detectable residual methanol.

[0115] In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 5000 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 4500 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 4000 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 3500 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 3000 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 2500 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 2000 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 1500 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 1000 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 900 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 800 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 700 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 600 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 500 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 400 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 300 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 200 ppm. In some embodiments, the amount of residual isopropyl acetate in the solid form of the present disclosure is less than 100 ppm. In some embodiments, there is no detectable residual isopropyl acetate in the solid form of the present disclosure.

[0116] In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 5000 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 4500 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 4000 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 3500 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 3000 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 2500 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 2000 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 1500 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 1000 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 900 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 800 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 700 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 600 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 500 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 400 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 300 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 200 ppm. In some embodiments, the amount of residual heptane in the solid form of the present disclosure is less than 100 ppm. In some embodiments, there is no detectable residual heptane in the solid form of the present disclosure.

[0117] In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 3000 ppm, the amount of residual isopropyl acetate in the solid form is less than 5000 ppm, and the amount of residual heptane in the solid form is less than 5000 ppm.

[0118] In some embodiments, the solid form of the present disclosure has less than 500 ppm residual methanol, less than 4000 ppm residual isopropyl acetate, and less than 500 ppm residual heptane in the solid form.

[0119] In some embodiments, the solid form of the present disclosure has a residual isopropyl acetate amount of less than 5000 ppm, the solid form has a residual heptane amount of less than 5000 ppm, In some embodiments, the solid form of the present disclosure has a residual isopropyl acetate amount of less than 5000 ppm, the solid form has a residual heptane amount of less than 5000 ppm, and the solid form has no detectable residual methanol.

[0120] In some embodiments, the solid form of the present disclosure has a residual isopropyl acetate of less than 500 ppm, the solid form has a residual heptane of less than 500 ppm, in some embodiments, the solid form of the present disclosure has a residual isopropyl acetate of less than 500 ppm, the solid form has a residual heptane of less than 500 ppm, and the solid form has no detectable residual methanol.

[0121] In some embodiments, the solid forms of the present disclosure contain amounts of residual solvent that are within the limits set forth in the ICH guidelines.

[0122] In some embodiments, the solid form of the present disclosure comprises an amount of class 1 residual solvents within the limits set forth in the ICH guidelines. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 1%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.9%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.8%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.7%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.6%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.5%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.4%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.3%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.2%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.1%. In some embodiments, the total amount of class 1 residual solvents in the solid form is less than 0.05%. In some embodiments, the total amount of Class 1 residual solvents in the solid form is less than 0.0025%. In some embodiments, there are no detectable Class 1 residual solvents in the solid forms of the present disclosure.

[0123] In some embodiments, the solid form of the present disclosure comprises an amount of class 2 residual solvents within the limits set forth in the ICH guidelines. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 1%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.9%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.8%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.7%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.6%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.5%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.4%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.3%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.2%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.1%. In some embodiments, the total amount of class 2 residual solvents in the solid form is less than 0.05%. In some embodiments, the total amount of Class 2 residual solvents in the solid form is less than 0.0025%. In some embodiments, there are no detectable Class 2 residual solvents in the solid forms of the present disclosure.

[0124] Substantially pure solid form The solid forms intended for use as APIs in therapeutic compositions are substantially pure. Specifically, the substantially pure forms are free of reaction impurities, starting materials, reagents, by-products, undesired solvents, and other processing impurities that result from the manufacture, and / or isolation, and / or purification of the solid form.

[0125] In some embodiments, the solid form of the disclosure comprises more than 70% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 75% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 80% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 85% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 90% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 95% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 97% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 98% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 99% by weight of Compound (I). In some embodiments, the solid form of the disclosure comprises more than 99.5% by weight of Compound (I).

[0126] In some embodiments, the solid form of the present disclosure is substantially free of decomposition products. In some embodiments, the decomposition products are less than 5% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 4% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 3% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 2% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 1% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 0.5% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 0.25% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 0.1% by weight of the solid form of the present disclosure. In some embodiments, the decomposition products are less than 0.05% by weight of the solid form of the present disclosure.

[0127] In some embodiments, the solid form of the present disclosure is substantially free of dimers of Compound (I). In some embodiments, the dimers of Compound (I) are less than 5% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 4% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 3% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 2% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 1% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 0.5% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 0.25% by weight of the solid form of the present disclosure. In some embodiments, the dimers of Compound (I) are less than 0.1% by weight of the solid form of the present disclosure. In some embodiments, the dimer of Compound (I) is less than 0.05% by weight of the solid form of the present disclosure.

[0128] Substantially amorphous solid form In some embodiments, the solid forms of the present disclosure are substantially amorphous. When measured by XRPD, the APIs exhibit the same broad peaks and halos (i.e., appear as the same amorphous solid). However, how the amorphous solid is formed (e.g., by spray drying or by different precipitation methods) affects different material properties for the API (e.g., density, flowability, particle morphology and size distribution). These material properties dictate how the API interacts with excipients in oral dosage formulations (e.g., capsules and tablets) during processing, resulting in different dissolution and pharmacokinetic profiles. Specifically, the glass transition temperature (T g The amorphous solid forms with relatively high T g It exhibits better physical stability than the lower amorphous solid forms.

[0129] In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 15%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 14%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 13%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 12%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 11%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 10%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 9%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 8%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 7%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 6%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 5%. In some embodiments, the solid forms of the disclosure are characterized by a crystallinity of less than 4%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 3%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 2%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 1%.

[0130] Spray-drying process for producing solid forms of compound (I) In some embodiments, the present disclosure provides a method for preparing a solid form of Compound (I) described herein, comprising spray drying a solution of Compound (I).

[0131] In some embodiments, the disclosure provides a method for preparing an amorphous form of Compound (I), the method comprising: washing a solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, where the solution of Compound (I) comprises a first organic solvent; removing the first aqueous layer; and performing a solvent exchange from the first organic solvent to a second organic solvent.

[0132] In some embodiments, removing the first aqueous layer removes a basic impurity that is more soluble than Compound (I). In some embodiments, removing the first aqueous layer removes a basic impurity that is more polar than Compound (I). In some embodiments, the basic impurity has the following structure: [ka] or a pharma- ceutically acceptable salt thereof;

[0133] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanol having the formula: Pyrrolidine; and

[0134] The following structure: [ka] or a pharma- ceutical acceptable salt thereof.

[0135] In some embodiments, the first acidic aqueous solution has a pH of 1 to 6. In some embodiments, the first acidic aqueous solution has a pH of 2.5 to 3.5. In some embodiments, the first acidic aqueous solution is a phosphate buffer at pH 3.

[0136] In some embodiments, the first organic solvent comprises at least one non-miscible organic solvent. In some embodiments, the at least one non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran and isopropyl acetate. In some embodiments, the first organic solvent comprises dichloromethane.

[0137] In some embodiments, the second organic solvent comprises at least one of an alkyl acetate, methyl tetrahydrofuran, toluene, methyl cyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and an alkyl propionate. In some embodiments, the alkyl acetate is isopropyl acetate. In some embodiments, the second organic solvent comprises isopropyl acetate.

[0138] In some embodiments, performing a solvent exchange from the first organic solvent to the second organic solvent removes at least 50% of the first organic solvent. In some embodiments, performing a solvent exchange from the first organic solvent to the second organic solvent removes at least 60% of the first organic solvent. In some embodiments, performing a solvent exchange from the first organic solvent to the second organic solvent removes at least 70% of the first organic solvent.

[0139] In some embodiments, the method further comprises washing the first organic layer with a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, wherein the second aqueous layer comprises Compound (I); and removing the second organic layer.

[0140] In some embodiments, removing the second organic layer removes impurities that are less water soluble than Compound (I). In some embodiments, removing the second organic layer removes impurities that are less polar than Compound (I).

[0141] In some embodiments, the impurities removed with the second organic layer have the following structure: [ka] or a pharma- ceutical acceptable salt thereof; and hexamethyldisiloxane.

[0142] In some embodiments, the second acidic aqueous solution has a pH of 1 to 6. In some embodiments, the second acidic aqueous solution has a pH of 2.5 to 3.5. In some embodiments, the second acidic aqueous solution is a phosphate buffer at pH 3.

[0143] In some embodiments, the method further comprises adding a first base to the second aqueous layer to form a third solution comprising a third organic layer and a third aqueous layer, where the third organic layer comprises Compound (I); extracting the third aqueous layer using a third organic solvent; and concentrating the third organic layer.

[0144] In some embodiments, the first base is an aqueous base. In some embodiments, the aqueous base has a pH of 8 to 14. In some embodiments, the first base is potassium hydroxide.

[0145] In some embodiments, the third organic solvent comprises at least one of an alkyl acetate, methyl tetrahydrofuran, toluene, methyl cyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and an alkyl propionate. In some embodiments, the alkyl acetate is isopropyl acetate. In some embodiments, the third organic solvent comprises isopropyl acetate.

[0146] In some embodiments, the method further comprises adding an anti-solvent to the third organic layer to form a precipitate comprising Compound (I). In some embodiments, the anti-solvent comprises at least one of hexane, heptane and octane. In some embodiments, the anti-solvent is n-hexane. In some embodiments, the anti-solvent is n-heptane. In some embodiments, the anti-solvent is n-octane.

[0147] In some embodiments, the anti-solvent is added at a temperature of -10°C to 10°C.

[0148] In some embodiments, the method further comprises isolating the precipitate comprising Compound (I). In some embodiments, isolating the precipitate comprising Compound (I) comprises drying the precipitate comprising Compound (I). In some embodiments, drying comprises air drying, blow drying, or vacuum drying.

[0149] In some embodiments, the method further comprises dissolving the precipitate comprising Compound (I) in a fourth organic solvent to form a fourth solution; and spray drying the fourth solution to obtain a solid form of Compound (I).

[0150] In some embodiments, the fourth organic solvent comprises at least one of methanol, ethanol, acetone, acetonitrile, and methyl ethyl ketone. In some embodiments, the fourth organic solvent comprises methanol.

[0151] In some embodiments, the spray drying process utilizes at least one of the parameters set forth in Table 1 below.

[0152] [Table 1]

[0153] In some embodiments, spray drying the fourth solution comprises passing the fourth solution through a spray drying chamber having an inlet temperature of from 90° C. to 180° C. In some embodiments, the spray drying chamber has an inlet temperature of from 125° C. to 155° C.

[0154] In some embodiments, spray drying the fourth solution comprises passing the fourth solution through a spray drying chamber having an outlet temperature of from 25° C. to 80° C. In some embodiments, the spray drying chamber has an outlet temperature of from 45° C. to 60° C.

[0155] In some embodiments, the method provides a stable solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by weight from 20° C. to 240° C. by thermogravimetric analysis.

[0156] In some embodiments, the method comprises measuring the glass transition temperature (T g ) is greater than 90° C.

[0157] In some embodiments, the method provides microparticles of Compound (I). In some embodiments, the method provides microparticles having a wet particle size distribution of less than D 10 μm. 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 100 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 200 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 Value, D less than 100 μm 50 value and D less than 200 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0158] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 10 μm to 20 μm. 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 10 μm to 50 μm. 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0159] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 value and D from 10 μm to 20 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 5 μm to 6 μm. 10 value and D from 10 μm to 50 μm 90In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 10 μm to 20 μm. 50 value and D from 10 μm to 50 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0160] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D 5 μm to 6 μm. 10 Value, D from 10 μm to 20 μm 50 value and D from 10 μm to 50 μm 90 It is characterized by having a value.

[0161] In some embodiments, the method provides a solid form of Compound (I) characterized by a particle size distribution as described above and an average bulk density of less than 0.3 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by a particle size distribution as described above and an average tapped density of less than 0.3 g / cc.

[0162] In some embodiments, the method provides a solid form of Compound (I) that is substantially free of decomposition products. In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). [ka] The present invention provides a solid form of Compound (I) that is substantially free of a dimer of Compound (I) having the formula:

[0163] In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 1% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual solvent in the solid form. In some embodiments, the method provides a solid form of Compound (I) in which the amount of residual methanol is less than 3000 ppm; the amount of residual isopropyl acetate is less than 5000 ppm; and / or the amount of residual heptane is less than 5000 ppm. In some embodiments, the method provides a solid form of Compound (I) in which the amount of residual methanol is less than 500 ppm; the amount of residual isopropyl acetate is less than 4000 ppm; and / or the amount of residual heptane is less than 500 ppm.

[0164] In some embodiments, the method provides a solid form of Compound (I) having less than 1500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 1000 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 100 ppm residual dichloromethane.

[0165] In some embodiments, the method provides a substantially amorphous solid form of Compound (I).

[0166] In some embodiments, the method further comprises micronizing the solid form of Compound (I).

[0167] Precipitation Method for Producing Solid Forms of Compound (I) In some embodiments, the disclosure provides a method for preparing a solid form of Compound (I), comprising adding a base to an aqueous solution containing Compound (I). In some embodiments, the base is an aqueous base. In some embodiments, the base is an aqueous potassium hydroxide solution.

[0168] In some embodiments, the disclosure provides a method for preparing a solid form of Compound (I), the method comprising: washing a solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, where the solution of Compound (I) comprises a first organic solvent; and removing the first aqueous layer.

[0169] In some embodiments, the first acidic aqueous solution has a pH of 1 to 6. In some embodiments, the first acidic aqueous solution has a pH of 2.5 to 3.5. In some embodiments, the first acidic aqueous solution is a phosphate buffer at pH 3.

[0170] In some embodiments, the first organic solvent comprises at least one non-miscible organic solvent.In some embodiments, the at least one non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran and isopropyl acetate.In some embodiments, the first organic solvent is dichloromethane.

[0171] In some embodiments, removing the first aqueous layer removes a basic impurity that is more soluble than Compound (I). In some embodiments, removing the first aqueous layer removes a basic impurity that is more polar than Compound (I). In some embodiments, the basic impurity has the following structure: [ka] or a pharma- ceutically acceptable salt thereof;

[0172] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanol having the formula: Pyrrolidine; and

[0173] The following structure: [ka] or a pharma- ceutical acceptable salt thereof.

[0174] In some embodiments, the method further comprises: partially removing the first organic solvent from the first organic layer; adding a second organic solvent to the first organic layer, the first organic solvent and the second organic solvent being not the same; and adding a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, the second aqueous layer comprising Compound (I).In some embodiments, partially removing the first organic solvent from the first organic layer comprises distillation under reduced pressure.In some embodiments, the second organic solvent is isopropyl acetate.

[0175] In some embodiments, the method further comprises removing the second organic layer; removing the residual organic solvent in the second aqueous layer to form an aqueous solution of Compound (I); and adding a second base to the aqueous solution of Compound (I) to form a precipitate comprising Compound (I). In some embodiments, removing the residual organic solvent in the second aqueous phase comprises distillation under reduced pressure.

[0176] In some embodiments, removing the second organic layer removes impurities that are less water soluble than Compound (I). In some embodiments, removing the second organic layer removes impurities that are less polar than Compound (I).

[0177] In some embodiments, the impurities removed with the second organic layer have the following structure: [ka] or a pharma- ceutical acceptable salt thereof; and hexamethyldisiloxane.

[0178] In some embodiments, the second base is an aqueous base. In some embodiments, the second base is an aqueous potassium hydroxide solution.

[0179] In some embodiments, the method includes filtering and drying the precipitate.

[0180] In some embodiments, the method provides a solid form of Compound (I) that is substantially free of decomposition products. In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). [ka] The present invention provides a solid form of Compound (I) that is substantially free of a dimer of Compound (I) having the formula:

[0181] In some embodiments, the method provides a solid form of Compound (I), wherein the dimer of Compound (I) is less than 3.5% by weight of the solid form of Compound (I).

[0182] In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 1% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 0.5% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual solvent in the solid form. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 5000 ppm residual isopropyl acetate; and / or less than 5000 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 500 ppm residual isopropyl acetate; and / or less than 500 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual methanol in the solid form.

[0183] In some embodiments, the method provides a solid form of Compound (I) having less than 1500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 1000 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 100 ppm residual dichloromethane.

[0184] In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.3 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.4 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of 0.6 g / cc to 0.7 g / cc.

[0185] In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.7 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.8 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of 0.7 g / cc to 0.9 g / cc.

[0186] In some embodiments, the method provides a solid form of Compound (I), characterized by a Hausner ratio of 1.2 or less.

[0187] In some embodiments, the method comprises the step of: 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 400 μm. 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 200 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 Value, D greater than 200 μm 50 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50 value and D greater than 400 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0188] In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 4% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by thermogravimetric analysis from 20° C. to 240° C.

[0189] In some embodiments, the method comprises measuring the glass transition temperature (T g ) is greater than 90° C.

[0190] In some embodiments, the method provides a substantially amorphous solid form of Compound (I).

[0191] In some embodiments, the method further comprises micronizing the particles of Compound (I).

[0192] In some embodiments, the micronization process provides fine particles of Compound (I). In some embodiments, the micronization process provides a wet particle size distribution of less than D 10 μm. 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 100 μm 50 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 200 μm 90 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 Value, D less than 100 μm 50 value and D less than 200 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0193] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 100 μm to 150 μm. 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0194] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 value and D from 40 μm to 70 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 1 μm to 2 μm. 10 value and D from 100 μm to 150 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50 value and D from 100 μm to 150 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0195] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 1 μm to 2 μm. 10 Value, D from 40 μm to 70 μm 50 value and D from 100 μm to 150 μm 90 It is characterized by having a value.

[0196] In some embodiments, the micronization method provides a stable solid form of Compound (I). In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by weight from 20° C. to 240° C. by thermogravimetric analysis.

[0197] In some embodiments, the disclosure provides a method for preparing a solid form of Compound (I), the method comprising: washing a solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, where the solution of Compound (I) comprises a first organic solvent; and removing the first aqueous layer.

[0198] In some embodiments, the first acidic aqueous solution has a pH of 1 to 6. In some embodiments, the first acidic aqueous solution has a pH of 2.5 to 3.5. In some embodiments, the first acidic aqueous solution is a phosphate buffer at pH 3.

[0199] In some embodiments, the first organic solvent comprises at least one non-miscible organic solvent.In some embodiments, the at least one non-miscible organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran and isopropyl acetate.In some embodiments, the first organic solvent is dichloromethane.

[0200] In some embodiments, removing the first aqueous layer removes a basic impurity that is more soluble than Compound (I). In some embodiments, removing the first aqueous layer removes a basic impurity that is more polar than Compound (I). In some embodiments, the basic impurity has the following structure: [ka] or a pharma- ceutically acceptable salt thereof;

[0201] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanol having the formula: Pyrrolidine; and

[0202] The following structure: [ka] or a pharma- ceutical acceptable salt thereof.

[0203] In some embodiments, the method further includes adding a first organic acid to the first organic layer; concentrating the first organic layer to remove at least 70% of the first organic solvent; adding a third organic solvent to the first organic layer to form a third solution comprising a third organic layer and a third aqueous layer, forming a third solution comprising a third organic layer and a third aqueous layer, where the third aqueous layer comprises Compound (I), and the first organic solvent and the third organic solvent are not identical; and adding a first base to adjust the pH of the third aqueous layer to 2.5 to 3.5.

[0204] In some embodiments, the first organic acid is methanesulfonic acid.

[0205] In some embodiments, concentrating the first organic layer to remove at least 70% of the first organic solvent comprises distillation under reduced pressure.

[0206] In some embodiments, the third organic solvent is isopropyl acetate.

[0207] In some embodiments, the first base is an aqueous base. In some embodiments, the first base is an aqueous potassium hydroxide solution.

[0208] In some embodiments, the method further comprises removing the third organic layer; removing the residual organic solvent in the third aqueous layer to form an aqueous solution of Compound (I); and adding a second base to the aqueous solution of Compound (I) to form a precipitate comprising Compound (I). In some embodiments, removing the residual organic solvent in the third aqueous phase comprises distillation under reduced pressure.

[0209] In some embodiments, removing the third organic layer removes impurities that are less water soluble than Compound (I). In some embodiments, removing the third organic layer removes impurities that are less polar than Compound (I).

[0210] In some embodiments, the impurities removed with the third organic layer have the following structure: [ka] or a pharma- ceutical acceptable salt thereof; and hexamethyldisiloxane.

[0211] In some embodiments, the second base is an aqueous base. In some embodiments, the second base is an aqueous potassium hydroxide solution.

[0212] In some embodiments, the method further comprises filtering and drying the precipitate.

[0213] In some embodiments, the method provides a solid form of Compound (I) that is substantially free of decomposition products. In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). [ka] The present invention provides a solid form of Compound (I) that is substantially free of a dimer of Compound (I) having the formula:

[0214] In some embodiments, the method provides a solid form of Compound (I), wherein the dimer of Compound (I) is less than 3.5% by weight of the solid form of Compound (I).

[0215] In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 1% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 0.5% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual solvent in the solid form. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 5000 ppm residual isopropyl acetate; and / or less than 5000 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 500 ppm residual isopropyl acetate; and / or less than 500 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual methanol in the solid form.

[0216] In some embodiments, the method provides a solid form of Compound (I) having less than 1500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 1000 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 100 ppm residual dichloromethane.

[0217] In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.3 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.4 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of 0.6 g / cc to 0.7 g / cc.

[0218] In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.7 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.8 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of 0.7 g / cc to 0.9 g / cc.

[0219] In some embodiments, the method provides a solid form of Compound (I), characterized by a Hausner ratio of 1.2 or less.

[0220] In some embodiments, the method comprises the step of: 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 400 μm. 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 200 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 Value, D greater than 200 μm 50 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50 value and D greater than 400 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0221] In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 4% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by thermogravimetric analysis from 20° C. to 240° C.

[0222] In some embodiments, the method comprises measuring the glass transition temperature (T g ) is greater than 90° C.

[0223] In some embodiments, the method provides a substantially amorphous solid form of Compound (I).

[0224] In some embodiments, the method further comprises micronizing the particles of Compound (I).

[0225] In some embodiments, the micronization process provides fine particles of Compound (I). In some embodiments, the micronization process provides a wet particle size distribution of less than D 10 μm. 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 100 μm 50 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 200 μm 90 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 Value, D less than 100 μm 50 value and D less than 200 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0226] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 100 μm to 150 μm. 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0227] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 value and D from 40 μm to 70 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 1 μm to 2 μm. 10 value and D from 100 μm to 150 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50 value and D from 100 μm to 150 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0228] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 1 μm to 2 μm. 10 Value, D from 40 μm to 70 μm 50 value and D from 100 μm to 150 μm 90 It is characterized by having a value.

[0229] In some embodiments, the micronization method provides a stable solid form of Compound (I). In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by weight from 20° C. to 240° C. by thermogravimetric analysis.

[0230] In some embodiments, the disclosure provides a method for preparing a solid form of Compound (I), the method comprising: washing a solution comprising Compound (I) and an organic solvent with an aqueous solution of a weak organic acid having a pKa of less than or equal to 7 (≦7) to form a first organic layer and a first aqueous layer; and removing the first aqueous layer leaving behind the first organic layer comprising Compound (I).

[0231] In some embodiments, the organic solvent comprises dichloromethane, hi some embodiments, the organic solvent is dichloromethane.

[0232] In some embodiments, the weak organic acid with a pKa of 7 or less is acetic acid.

[0233] In some embodiments, removing the first aqueous layer removes a basic impurity that is less polar than Compound (I). In some embodiments, the basic impurity has the following structure: [ka] or a pharma- ceutically acceptable salt thereof;

[0234] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanol having the formula: Pyrrolidine; and

[0235] The following structure: [ka] or a pharma- ceutical acceptable salt thereof.

[0236] In some embodiments, the method further comprises washing the first organic layer comprising Compound (I) with aqueous sodium bicarbonate. In some embodiments, washing the first organic layer comprising Compound (I) removes substantially all of the weak organic acid having a pKa of 7 or less. In some embodiments, the weak organic acid having a pKa of 7 or less is acetic acid.

[0237] In some embodiments, the method further comprises adding a strong acid to the first organic layer; and concentrating the first organic layer by removing the organic solvent to obtain a residue comprising Compound (I).

[0238] In some embodiments, the strong acid comprises methanesulfonic acid, hi some embodiments, the strong acid is methanesulfonic acid.

[0239] In some embodiments, concentrating the first organic layer comprises distillation under reduced pressure.

[0240] In some embodiments, the residue comprising Compound (I) is a thin oil.

[0241] In some embodiments, the method further comprises cooling the residue comprising Compound (I) to a temperature of from 0° C. to 10° C. In some embodiments, the temperature is 5° C.

[0242] In some embodiments, the method further comprises washing the residue comprising Compound (I) with water or a salt solution. In some embodiments, the salt solution is an aqueous solution of sodium chloride.

[0243] In some embodiments, the method further comprises adding a non-miscible organic solvent to the first aqueous layer to obtain a second organic layer, and a second aqueous layer comprising Compound (I); and removing the second organic layer.

[0244] In some embodiments, the non-miscible organic solvent is dichloromethane.

[0245] In some embodiments, the method further comprises adjusting the pH of the first or second aqueous layer to a value between 1 and 5 by adding an aqueous base solution.

[0246] In some embodiments, the pH of the first or second aqueous layer is adjusted to 3.

[0247] In some embodiments, the aqueous base is an aqueous solution of an inorganic base, hi some embodiments, the aqueous base is an aqueous solution of potassium hydroxide.

[0248] In some embodiments, removing the second organic layer comprises distillation under reduced pressure.

[0249] In some embodiments, the method further comprises measuring the amount of residual weak organic acid having a pKa of 7 or less in the first or second aqueous phase, and adjusting the amount of weak organic acid having a pKa of 7 or less to between 0% and 8% by weight.

[0250] In some embodiments, the weak organic acid with a pKa of 7 or less is acetic acid.

[0251] In some embodiments, adjusting the amount comprises adding more weak organic acid, hi some embodiments, adjusting the amount comprises adding more acetic acid.

[0252] In some embodiments, the method further comprises adding an aqueous base solution to the first or second aqueous layer to achieve a pH of between 8 and 11 to form a precipitate comprising Compound (I).

[0253] In some embodiments, the pH is 9.5.

[0254] In some embodiments, the aqueous base is an aqueous solution of potassium hydroxide.

[0255] In some embodiments, the precipitate comprising Compound (I) is allowed to form at 20° C. for at least 3 hours.

[0256] In some embodiments, the method further comprises isolating the precipitate comprising Compound (I) by filtration and washing the isolated precipitate comprising Compound (I) with water.

[0257] In some embodiments, the method further comprises drying the filtered and washed precipitate comprising Compound (I) to obtain a solid form of Compound (I).

[0258] In some embodiments, drying the filtered and washed precipitate containing Compound (I) comprises drying under reduced pressure with minimal heat. In some embodiments, drying the filtered and washed precipitate containing Compound (I) comprises drying under reduced pressure with minimal heat at 25° C.

[0259] In some embodiments, the method further comprises slurrying the isolated precipitate with water and filtering to isolate a solid form of Compound (I).

[0260] In some embodiments, the isolated precipitate is slurried with water at 15° C. for at least 1 hour prior to filtration. In some embodiments, the filtration comprises drying under reduced pressure with minimal heat. In some embodiments, the filtration comprises drying under reduced pressure with minimal heat at 25° C.

[0261] In some embodiments, the method provides a solid form of Compound (I) that is substantially free of decomposition products. In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). In some embodiments, the method provides a solid form of Compound (I) that is substantially free of dimers of Compound (I). [ka] The present invention provides a solid form of Compound (I) that is substantially free of a dimer of Compound (I) having the formula:

[0262] In some embodiments, the method provides a solid form of Compound (I), wherein the dimer of Compound (I) is less than 3.5% by weight of the solid form of Compound (I).

[0263] In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 1% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which residual solvent is less than 0.5% of the solid form of Compound (I). In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual solvent in the solid form. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 5000 ppm residual isopropyl acetate; and / or less than 5000 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is less than 500 ppm residual isopropyl acetate; and / or less than 500 ppm residual heptane. In some embodiments, the method provides a solid form of Compound (I) in which there is no detectable residual methanol in the solid form.

[0264] In some embodiments, the method provides a solid form of Compound (I) having less than 1500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 1000 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 500 ppm residual dichloromethane. In some embodiments, the method provides a solid form of Compound (I) having less than 100 ppm residual dichloromethane.

[0265] In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.3 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.4 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average bulk density of 0.6 g / cc to 0.7 g / cc.

[0266] In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.5 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.6 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.7 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of greater than 0.8 g / cc. In some embodiments, the method provides a solid form of Compound (I) characterized by an average tap density of 0.7 g / cc to 0.9 g / cc.

[0267] In some embodiments, the method provides a solid form of Compound (I), characterized by a Hausner ratio of 1.2 or less.

[0268] In some embodiments, the method comprises the step of: 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 400 μm. 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 200 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 Value, D greater than 200 μm 50 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 70 μm. 10 value and D greater than 400 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of greater than 200 μm. 50 value and D greater than 400 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0269] In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 4% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by thermogravimetric analysis from 20° C. to 240° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by thermogravimetric analysis from 20° C. to 240° C.

[0270] In some embodiments, the method comprises measuring the glass transition temperature (T g ) is greater than 90° C.

[0271] In some embodiments, the method provides a substantially amorphous solid form of Compound (I).

[0272] In some embodiments, the method further comprises micronizing the particles of Compound (I).

[0273] In some embodiments, the micronization process provides fine particles of Compound (I). In some embodiments, the micronization process provides a wet particle size distribution of less than D 10 μm. 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 100 μm 50 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 value and D less than 200 μm 90 In some embodiments, the micronization method provides a solid form of Compound (I) characterized by having a wet particle size distribution D value of less than 10 μm. 10 Value, D less than 100 μm 50 value and D less than 200 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0274] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 100 μm to 150 μm. 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0275] In some embodiments, the method comprises subjecting a sample having a wet particle size distribution of D 10 value and D from 40 μm to 70 μm 50 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 1 μm to 2 μm. 10 value and D from 100 μm to 150 μm 90 In some embodiments, the method provides a solid form of Compound (I) characterized by having a wet particle size distribution of D value of 40 μm to 70 μm. 50 value and D from 100 μm to 150 μm 90 The present invention provides a solid form of Compound (I) characterized in that it has a value.

[0276] In some embodiments, the solid form of the present disclosure has a wet particle size distribution of D from 1 μm to 2 μm. 10 Value, D from 40 μm to 70 μm 50 value and D from 100 μm to 150 μm 90 It is characterized by having a value.

[0277] In some embodiments, the micronization method provides a stable solid form of Compound (I). In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by weight from 20° C. to 240° C. by thermogravimetric analysis. In some embodiments, the micronization method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by weight from 20° C. to 240° C. by thermogravimetric analysis.

[0278] Conversion process for preparing solid forms of compound (I) In some embodiments, the disclosure provides a method for preparing a solid form of Compound (I), comprising: dissolving a crystalline form of the compound in a solution comprising a non-miscible organic solvent and salt water; adding one equivalent of a strong acid to form an aqueous layer and an organic layer; removing the organic layer; concentrating the aqueous layer; adding an aqueous base solution to adjust the pH to a value between 8 and 11 to obtain a precipitate of the solid form of Compound (I); isolating the precipitate of the solid form of the compound by filtration; rinsing the precipitate with water; and drying the precipitate to obtain a solid form of Compound (I).

[0279] In some embodiments, the non-miscible organic solvent comprises dichloromethane, hi some embodiments, the non-miscible organic solvent is dichloromethane.

[0280] In some embodiments, the strong acid is methanesulfonic acid.

[0281] In some embodiments, concentrating the aqueous layer comprises distillation under reduced pressure. In some embodiments, concentrating the aqueous layer comprises distillation under reduced pressure at a temperature between 0° C. and 5° C.

[0282] In some embodiments, the aqueous layer is concentrated to remove residual organic solvent.

[0283] In some embodiments, the aqueous base is an aqueous potassium hydroxide solution. In some embodiments, the aqueous base is a 5% aqueous potassium hydroxide solution.

[0284] In some embodiments, the pH is adjusted to a value of 9 to 10.

[0285] In some embodiments, drying the precipitate comprises drying under reduced pressure with minimal heat. In some embodiments, drying the precipitate comprises drying under reduced pressure with minimal heat at 30° C.

[0286] In some embodiments, the method provides a substantially amorphous solid form of Compound (I).

[0287] In some embodiments, the method provides a substantially pure form of Compound (I).

[0288] In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 5% by thermogravimetric analysis from 20° C. to 200° C. In some embodiments, the method provides a solid form of Compound (I) characterized by a mass loss of less than 4% by thermogravimetric analysis from 20° C. to 200° C. The method provides a solid form of Compound (I) characterized by a mass loss of less than 3% by thermogravimetric analysis from 20° C. to 200° C. The method provides a solid form of Compound (I) characterized by a mass loss of less than 2% by thermogravimetric analysis from 20° C. to 200° C. The method provides a solid form of Compound (I) characterized by a mass loss of less than 1.5% by thermogravimetric analysis from 20° C. to 200° C. The method provides a solid form of Compound (I) characterized by a mass loss of less than 1% by thermogravimetric analysis from 20° C. to 200° C.

[0289] index The solid forms of Compound (I) described herein are useful for treating conditions mediated by BTK activity in mammals. In some embodiments, the solid forms of the compounds described herein are used to treat humans or non-human animals.

[0290] The solid forms of Compound (I) described herein are useful for treating pemphigus. In some embodiments, the solid forms of Compound (I) described herein are used to treat pemphigus vulgaris. In some embodiments, the solid forms of Compound (I) described herein are used to treat pemphigus foliaceus.

[0291] Pemphigus is a rare B cell-mediated autoimmune disease that causes debilitating intraepithelial rash and sores on the skin and / or mucous membranes. Pemphigus has a mortality rate of 10%, typically due to infections caused by skin lesions and side effects of treatment, and affects approximately 0.1 to 0.5 per 100,000 people annually (Scully et al., 2002; Scully et al., 1999). The characteristic intraepithelial rash seen in pemphigus patients is caused by IgG autoantibodies binding to specific keratinocyte desmosomal adhesion proteins, namely desmogleins 1 and 3 (Dsg1 and Dsg3), reducing cell adhesion (Amagai M et al., 2012; Diaz LA et al., 2000). B cells play a key role in the generation of these autoantibodies and in cellular tolerance mechanisms.

[0292] The solid forms of Compound (I) described herein are useful for treating immune thrombocytopenia.

[0293] Immune thrombocytopenia (commonly referred to as ITP) is characterized by autoantibody-mediated destruction of platelets and reduced platelet production that results in thrombocytopenia and predisposes to bleeding accompanied by morbidity and mortality. There is initial evidence supporting the role of BTK inhibition in patients with autoimmune cytopenia, where treatment with the BTK / EGFR / ITK inhibitor ibrutinib stopped the subsequent development of severe autoimmune hemolytic anemia and ITP in patients with chronic lymphocytic leukemia (CLL) (Rogers 2016, Montillo 2017).

[0294] Pharmaceutical Compositions The solid forms described herein are useful as materials for preparing pharmaceutical compositions that contain an active pharmaceutical ingredient (API) and one or more pharma- ceutical acceptable excipients and are suitable for administration to a human subject. In some embodiments, these pharmaceutical compositions are pharmaceutical products, such as solid oral dosage forms, e.g., tablets and / or capsules.

[0295] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one solid form of Compound (I). In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one solid form of Compound (I) and at least one additional pharma- ceutically acceptable excipient. Each excipient must be "pharma-ceutically acceptable" in the sense that it is compatible with the subject composition and its components are not harmful to the patient. Use of any conventional pharma-ceutically acceptable excipient is considered to be within the scope of the present disclosure, provided that it is not compatible with Compound (I), e.g., does not produce any undesirable biological effects or interact in an unfavorable manner with any other components of the pharma-ceutically acceptable composition.

[0296] Some non-limiting examples of materials which function as pharma- ceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glyceryl stearate, sorbitol ... (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other nontoxic compatible substances employed in pharmaceutical formulations.

[0297] Pharmaceutically acceptable excipients, as well as known techniques for preparing and using the same, are also disclosed in Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, Ed. D.B. Troy, Lippincott Williams & Wilkins, and Encyclopedia of Pharmaceutical Technology, Eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference.

[0298] The pharmaceutical compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the pharmaceutical compositions of the present disclosure are aqueous or oily suspensions. These suspensions are formulated by techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0299] For this purpose, any sterile fixed oil may be employed, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated form, are useful for the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are widely used for the preparation of pharma- ceutical acceptable dosage forms, including emulsions and suspensions. Other widely used surfactants, such as Tween, Spans, and other emulsifiers or bioavailability enhancers, which are widely used for the preparation of pharma- ceutical acceptable solid, liquid or other dosage forms, may also be used for formulation purposes.

[0300] The pharmaceutical composition disclosed herein can be orally administered in any orally acceptable dosage form, including but not limited to capsule, tablet, aqueous suspension or liquid.When aqueous suspension is required for oral use, active ingredient is usually combined with emulsifier and suspending agent.If desired, certain sweetener, flavor or coloring agent is added.

[0301] Alternatively, the pharmaceutical compositions disclosed herein are administered in the form of suppositories for rectal administration. Suppositories are prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts in the rectum and releases the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0302] The pharmaceutical compositions of the present disclosure may also be administered locally, particularly when the treatment target is an area or organ that is easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations for each of these areas or organs are readily prepared. Topical application for the lower intestinal tract is accomplished by rectal suppository or suitable enema. Topical transdermal patches may also be used.

[0303] For topical application, the pharmaceutical composition is formulated into a suitable ointment, which contains the active ingredient suspended or dissolved in at least one excipient.Excipients for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the pharmaceutical composition disclosed herein is formulated into a suitable lotion or cream, which contains the active ingredient suspended or dissolved in at least one pharma- ceutically acceptable excipient.Suitable excipients include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0304] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. The compositions are prepared by techniques well known in the art of pharmaceutical formulation and are prepared as a solution in saline employing benzyl alcohol or other suitable excipients, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0305] dosage In general, the solid forms of Compound (I) are administered in a therapeutically effective amount by any of the accepted modes of administration of drugs that exert similar benefits. The effective dose for any particular mammal (e.g., any particular human) depends on a wide variety of factors, including the disorder being treated and the severity of the disorder; the specific pharmaceutical composition employed; the mammal's age, weight, general health, sex, and dietary habits; the time of administration, the route of administration, and duration of treatment; and similar factors well known in the medical arts. In some embodiments, a therapeutically effective amount of at least one solid form of Compound (I) is administered to a mammal in need thereof. The therapeutically effective amount of the solid forms disclosed herein may range from 0.01 to 500 mg per kg of patient body weight per day, and may be administered in one or multiple doses. Suitable dosage levels may be 0.01 to 250 mg / kg per day, 0.05 to 100 mg / kg per day, or 0.1 to 50 mg / kg per day. Within this range, in some embodiments, the dosage can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, in some embodiments, the composition is provided in the form of a tablet containing 1.0 to 1000 milligrams of the active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient.

[0306] Generally, the solid forms of the present disclosure are administered as pharmaceutical compositions by one of the following routes: oral administration; systemic administration (e.g., transdermal, intranasal, or via suppository); topical administration; or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous). Specifically, the compositions can take the form of tablets, capsules, semisolids, powders, sustained release formulations, enteric or sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[0307] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0308] Any claim or specification passage containing "or" or "and / or" between at least one member of a group is deemed to be satisfied when one, more than one, or all of the group members are present in, employed in, or relevant to a given product or method, unless the context clearly suggests the contrary or other meaning. The present disclosure includes embodiments in which only one member is present in, employed in, or relevant to a given product or method. The present disclosure includes embodiments in which two or more, or all of the group members are present in, employed in, or relevant to a given product or method.

[0309] The disclosure also embraces all modifications, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, any claim that is dependent on another claim is modified to include at least one limitation found in any other claim that is dependent on the same base claim. When elements are presented as a list, for example in Markush group format, each subgroup of those elements is also disclosed, and any element is excluded from the group. In general, when the disclosure or aspects of the disclosure are considered to include certain elements and / or features, it is understood that an embodiment of the disclosure or aspects of the disclosure consists of or consists essentially of the elements and / or features. For the purpose of brevity, those embodiments have not been specifically described in the language of the specification. When ranges are presented, the endpoints are included. Additionally, unless otherwise suggested or made clear by the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can contemplate any specific value or subrange within the range described in different embodiments of the present disclosure down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0310] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the following claims. EXAMPLES

[0311] The following examples are intended to be illustrative and are not intended to limit the scope of the disclosure in any way.

[0312] The synthetic schemes described below are intended to provide general guidance for the preparation of the compounds and solid forms of the present disclosure. Those skilled in the art will understand that the formulations shown may be modified and / or optimized using general knowledge and techniques well known in the art.

[0313] Abbreviation: DCM = dichloromethane DMA = Dimethylacetamide DME = dimethoxyethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate EtOH = ethanol IPA = Isopropyl alcohol IPAC = Isopropyl acetate MeOH = methanol MTBE = methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine PP = Polypropylene rpm = revolutions per minute TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyran TMS = tris(trimethylsilyl) TMSCI = trimethylsilyl chloride EXAMPLES

[0314] Spray drying method A A solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was washed with a pH 3 phosphate buffer to remove basic impurities with higher solubility in the aqueous layer than compound (I). The dichloromethane solution was then washed with a pH 7 buffer to exchange the solvent for isopropyl acetate. The isopropyl acetate solution was then washed with a pH 3 phosphate buffer to take up compound (I) in the aqueous layer and remove non-basic impurities. The pH of the aqueous layer was adjusted to pH 9 with 10% sodium hydroxide and the aqueous layer was extracted with isopropyl acetate. After concentration under vacuum, compound (I) was precipitated from heptane at 0°C, filtered and dried to give wet compound (I) as a white amorphous solid as a mixture of (E) and (Z) isomers. Wet Compound (I) was dissolved in methanol and spray dried at a dryer inlet temperature of 125° C. to 155° C. and a dryer outlet temperature of 48 to 58° C. to obtain stable amorphous Compound (I) free base with isopropyl acetate and heptane levels less than 0.5% and 0.05%, respectively. EXAMPLES

[0315] Spray drying method B [ka] Intermediate A (20.2 kg) and Intermediate B (13.6 kg, 1.5 eq) were added to a jacketed reactor equipped with an overhead stirrer, condenser, nitrogen line, temperature probe, and recirculating cooler / heater. DCM (361.3 kg, 14.5 vol) was added to the reactor. The mixture was stirred and the vessel was cooled to 0° C. to 5° C. Pyrrolidine (18.3 kg, 6 eq) was added to the reactor followed by TMSCl (18.6 kg, 4 eq). Stirring was continued at 0° C. to 5° C. for 0.5 to 1 hour.

[0316] Acetic acid (2.0 eq.) was added to the reactor at 0° C. to 5° C., followed by water (5 eq.). Stirring was continued at 0° C. to 5° C. for 1 to 1.5 h. Water (10 eq.) was added to the reactor and the solution was adjusted to 20° C. to 25° C. The internal temperature was adjusted to 20° C. to 25° C. and the biphasic mixture was stirred for 15 to 20 min. Stirring was stopped and the phases were allowed to separate for at least 0.5 h. The lower aqueous layer was removed.

[0317] Water (7 volumes) was added to the reactor. The pH was adjusted to 2.8-3.3 with a 10 wt% solution of citric acid. Stirring was continued for 1-1.5 hours at 0-5°C. Stirring was stopped and the phases were allowed to separate for at least 0.5 hours. The lower aqueous layer was removed.

[0318] NaHCO was added to a jacketed reactor equipped with an overhead stirrer, condenser, nitrogen line, temperature probe, and recirculating liquid cooler / heater. 3 (1 vol) and the organic layer were added. The internal temperature was adjusted to 20° C. to 25° C. and the biphasic mixture was stirred for 15 to 20 minutes. The stirring was stopped and the phases were allowed to separate for at least 0.5 hours. The lower aqueous layer was removed. The pH of the lower aqueous layer was measured to be greater than 7.

[0319] The organic layer was added to a jacketed reactor equipped with an overhead stirrer, condenser, nitrogen line, temperature probe and recirculating cooler / heater. The organic phase was distilled under vacuum at a temperature below 25° C. to a total volume of 4 volumes. IPAC (15 volumes) was added to the reactor. The organic phase was distilled under vacuum at a temperature below 25° C. to a total volume of 10 volumes. Water (15 volumes) was added to the reactor at an internal temperature of 20° C. to 25° C., followed by pH 2.3 phosphate buffer. The pH was adjusted to 3. Agitation was stopped and the phases were allowed to separate for at least 0.5 hours. The organic phase was removed.

[0320] The following procedure was repeated twice: IPAC (5 vol) was added to the reactor containing the aqueous layer. Agitation was continued for 0.25 to 0.5 hours. Agitation was stopped and the phases were allowed to separate for at least 0.5 hours. The organic phase was removed.

[0321] IPAC (15 vol) was added to the reactor containing the aqueous layer. pH 10 phosphate buffer was added to the reactor and the pH was adjusted to 10 with 14% NaOH solution. Agitation was continued for 1.5 to 2 hours. Agitation was stopped and the phases were allowed to separate for at least 0.5 hour. The aqueous layer was discarded. The organic layer was dried over brine.

[0322] The organic solution was distilled under vacuum at a temperature below 25° C. to a total volume of 5 volumes.

[0323] n-Heptane (20 vol) was added to a jacketed reactor equipped with an overhead stirrer, condenser, nitrogen line, temperature probe and recirculating liquid cooler / heater. The internal temperature was adjusted to 0-5° C. and the IPAC solution was added.

[0324] The suspension was filtered. The filter cake was washed with n-heptane and tray dried at 35° C. Compound (I) (24.6 kg) was isolated in 86% yield.

[0325] Compound (I) was dissolved in methanol (6 kg) and spray dried to remove residual IPAC and n-heptane. EXAMPLES

[0326] Precipitation method A A solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was quenched with acetic acid and water, then washed with an aqueous solution of pH 3 to remove basic impurities that have a higher solubility in the aqueous layer than compound (I). The washing was repeated as necessary to reduce impurities. Methanesulfonic acid was added to the dichloromethane solution, and the dichloromethane solution was concentrated by distillation under reduced pressure, followed by addition of 1% aqueous NaCl and isopropyl acetate, and then the pH was adjusted to about 3 with potassium hydroxide. The isopropyl acetate layer was removed and discarded. The aqueous layer containing compound (I) was washed with isopropyl acetate to remove hydrophobic impurities. The washing was repeated as necessary to reduce related substance impurities. Residual isopropyl acetate was removed by distillation under reduced pressure. The aqueous solution containing compound (I) was cooled to 0-5°C, and then the pH was adjusted to about 9 with potassium hydroxide. The free base of compound (I) was precipitated and aged at 20°C for 20 hours. The temperature of the mixture was then adjusted to 20° C. to 25° C. to ensure that the hydrate impurity was less than 0.3% (<0.3%). The cake of compound (I) free base was filtered and washed as necessary to reduce conductivity. The cake was then dried on the filter under vacuum and purged with nitrogen to reduce the water content by Karl Fischer (KF<50%) before being transferred to an oven for drying. The wet cake of compound (I) free base was dried under vacuum at 25° C. until the water content by Karl Fischer was less than 1.5% (KF<1.5%) and then de-lumped by grinding to produce a homogeneous white amorphous solid as a mixture of (E) and (Z) isomers with no detectable amount of isopropyl acetate or heptane present. EXAMPLES

[0327] Precipitation method B A solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was quenched with acetic acid and water, then washed with an aqueous solution of pH 3 to remove basic impurities with higher solubility in the aqueous layer than compound (I). The washes were repeated as necessary to reduce residual solvent and impurities. The dichloromethane solution was then washed with saturated sodium bicarbonate (pH>7). Dichloromethane was removed by distillation under reduced pressure, followed by the addition of water and isopropyl acetate. The pH of the aqueous layer was adjusted to 0-5°C with 2M sulfuric acid (H 2 SO 4 The pH was adjusted to 2.8-3.3 with aqueous KOH, and the mixture was stirred and allowed to settle. After phase separation and removal of the organic layer, the aqueous layer was washed three times with isopropyl acetate, the residual isopropyl acetate in the aqueous layer was distilled off under vacuum at a temperature below 25°C, and the solution was basified to pH 9-10 with 5% aqueous KOH to give a slurry. The resulting suspension was stirred, warmed to 20-25°C, and aged for 20 hours. The product was filtered, washed with water, and dried to give a white solid in 86% yield. EXAMPLES

[0328] Precipitation method C A solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was quenched with acetic acid and water, followed by washing to remove basic impurities having a higher solubility in the aqueous layer than compound (I). The washing was repeated as necessary to reduce the impurities. Methanesulfonic acid was added to the dichloromethane solution, and the dichloromethane solution was concentrated under reduced pressure to obtain a thin oil. The concentrated oil was cooled to about 5 degrees, and then washed with an aqueous solution of sodium chloride. The organic phase was discarded. Washing of the aqueous layer with dichloromethane was repeated as necessary to remove low amounts of impurities. The pH of the aqueous solution was adjusted to about 3 with an aqueous solution of potassium hydroxide. Residual dichloromethane was removed under reduced pressure. The amount of residual acetic acid was measured, for example by titration. The aqueous solution containing compound (I) was cooled to a temperature of 0°C to 5°C. Acetic acid was present in an amount of 0% to 8% by weight. When the aqueous acid solution was washed with aqueous sodium bicarbonate or another aqueous inorganic base, the amount of acetic acid was 0% by weight. Optionally, additional acetic acid was added to bring the amount of acetic acid to 0% to 8% by weight. The aqueous solution was continuously added with an aqueous solution of potassium hydroxide to bring the pH to about 9.5. The free base of Compound (I) was precipitated and aged at about 20° C. for at least 3 hours. The cake (wet solid) of the free base of Compound (I) was filtered and washed with water. The wet cake was then dried under reduced pressure with minimal heat. Alternatively, instead of washing the wet cake with water, the wet cake was reslurried in water at about 15° C. for at least 1 hour and then filtered. The free base of Compound (I) in the form of a wet cake was dried under vacuum with minimal heat at 25° C.

[0329] Figures 12-15 are example SEM images showing the change in morphology of particles of Compound (I) during the filtration step of isolating Compound (I) based on the amount of acetic acid added during the initial steps in the precipitation of Compound (I) (Figure 12: 0 wt% acetic acid; Figure 13: 3 wt% acetic acid; Figure 14: 5 wt% acetic acid; Figure 15: 8 wt% acetic acid). Filtration rate was dependent on morphology and was fastest at 0 wt% acetic acid. Filtration rate decreased significantly with 1 wt% acetic acid and improved with 2 wt% to 3 wt% acetic acid. Morphologies with more open pores (e.g., more porous particles) improved filtration rate, whereas denser particles decreased filtration rate. EXAMPLES

[0330] Conversion of Compound (I) from a crystalline form to an amorphous form 9.8 grams of the crystalline form of Compound (I) was dissolved in about 20 mL of dichloromethane and about 120 mL of the salt water solution. About 1 equivalent of methanesulfonic acid was then added. The pH was about 2. The layers were separated. The aqueous layer was concentrated at a temperature of 0° C. to 5° C. to remove residual dichloromethane, and then aqueous KOH (about 5%) was added slowly to adjust the pH to a value of 9 to 10. Upon addition of the aqueous KOH solution, the amorphous form of Compound (I) precipitated. The slurry was gradually warmed to room temperature and then stirred for about 24 hours before filtering and washing the wet cake with water. The wet cake was dried under vacuum with minimal heat at about 30° C. to give 7 grams of a white or off-white solid (87% yield and 98.4% purity). XRPD showed that the product was an amorphous solid form of Compound (I). EXAMPLES

[0331] Micronization of the particles of compound (I) obtained by the precipitation method A fluid jet mill apparatus was used for the laboratory-scale jet milling tests. The fluid jet mill apparatus comprises a flat cylindrical chamber of 1.5 inches diameter fitted with four symmetrical jet nozzles arranged tangentially on the inner wall. Before feeding the material to the fluid jet mill in each test, the material was classified through a 355 μm sieve to remove any agglomerates and to avoid clogging of the nozzles during feeding of the material to the pulverization chamber. The material to be processed was drawn into the grinding chamber via a vacuum (0.5-1.0 bar higher pressure than P_vent-P_grind) generated by a venturi. The feed flow rate of solids (F_feed) was controlled by a manual valve and an infinite screw constant feeder. Compressed nitrogen was used to inject the feed material; compressed nitrogen was also used in the jet nozzles in the wall of the grinding chamber. The compressed fluid emanating from the nozzles expands from P_grind and imparts a very large rotational speed in the chamber. Thus, the material is accelerated by the rotating and expanding gas and is subjected to centrifugal forces. The particles move outwards and are influenced by the high velocity jets, which induce them radially inwards at very high velocities. The rapidly moving particles impinge on the slower moving particle paths circulating around the periphery of the chamber. Attrition occurs as the particles collide violently with one another. The reduced particle size resulting from this series of collisions is entrained in the circulating flow of gas and swept against the action of centrifugal force towards a central outlet. The larger particles in the gas stream are centrifugal forced back into the grinding zone. The fine particles are carried by the exhaust gases to the outlet and move out of the grinding chamber into a collector.

[0332] The feeder has a continuous feed rate control function, but the entire range of the feed rate was arbitrarily divided into 10 positions to control the feed rate more precisely. To calibrate F_feed, the feeder was disconnected from the grinding chamber and 10 g of powder of compound (I) was fed through the feeder operating at each feed rate position. The mass of powder flowing through the feeder over a 6 minute period was recorded. The resulting feed rate was directly proportional to the feeder position. After processing each of the four tests, the jet mill was stopped, the micronized product was removed from the vessel, and the grinding chamber was checked for powder accumulation.

[0333] [Table 2] EXAMPLES

[0334] Residual Solvent Amount Process solvent retention (i.e., residual solvent) is specific to each molecule and depends on van der Waals forces, which are an intrinsic property of each molecule. In addition, solvent retention depends on how the solid API is formed, isolated, washed, and dried (i.e., during manufacturing). Because residual solvents can pose a safety risk, formulation methods must be designed to minimize the amount of residual solvents (e.g., to ensure that the amount of residual solvents is below the limits set by ICH guidelines).

[0335] Residual solvent analysis was performed by gas chromatography / mass spectrometry. The amount of residual solvent in the solid form of Compound (I) produced by the spray drying method described herein and the precipitation method described herein is shown in Table 2. The amount of residual solvent in crude Compound (I) listed in Table 2 is comparable to the amount of residual solvent in crude Compound (I) produced according to the procedures detailed in Example 31 of WO2014 / 039899 and Example 1 of WO2015 / 127310.

[0336] [Table 3] EXAMPLES

[0337] Wet particle size distribution Table 3 shows the wet particle size distribution of several different solid forms of Compound (I). Comparative control 1 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 1, step 1A of WO2015 / 127310. Comparative control 2 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 31 of WO2014 / 039899.

[0338] Wet particle size distribution was measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer with the stirring speed set at 2200 rpm. Heptane containing 0.2% by volume of Span80 was used as the dispersant. To obtain the distribution measurements, the dispersant was filled and adjusted in a Hydro MV medium volume automatic dispersion unit. The background was then measured. 80-100 mg of sample was weighed into a 20 mL vial to which approximately 3 mL of dispersant was added. The mass was adjusted based on particle size with obscuration of 5% to 16%. The entire sample was added to the Hydro MV unit and the sample was analyzed five times after a pre-measurement delay of 160 seconds. The analysis time was 20 seconds (10 seconds for the red laser and 10 seconds for the blue laser) with no delay between measurements. The data obtained was processed using Mie theory with a refractive index of 1.69 and an absorption coefficient of 0.1 for the sample using a generic model with normal sensitivity and a non-spherical particle type. The 15 sets of raw data were averaged to obtain a global average that represents the mean value of the sample. If the sample was determined to be inconsistent, further preparations were examined to determine which results were anomalous. Any anomalous results were discarded. Samples were mixed thoroughly prior to sampling (e.g., some samples were aliquoted using a rotating refractor).

[0339] [Table 4] EXAMPLES

[0340] Measurement of average bulk density, average tapped density and Hausner ratio USP <616> The average bulk and tapped densities were measured using a modified method based on the method described in the literature. The powders were placed in clean, dry, pre-weighed 25 mL cylinders. Powder was added to the cylinders without compressing the samples to bring the total volume to 20-25 mL. The mass and initial volume (V 0) was recorded. Average bulk density was measured as the average mass relative to the initial volume of multiple samples. To measure the average tapped density, samples were tapped using a Copley JV2000 tapped density tester with the following sets of taps: 500, 750, and 1250 through 10,000 taps. The volume was recorded after each set of taps and the samples were then rehydrated to a constant volume (V f The average tap density was determined as the average mass of a given volume of multiple samples. Each sample was analyzed in duplicate. The Hausner ratio was calculated as the ratio of the initial volume to the given volume (V 0 / V f ) was calculated.

[0341] Table 4 shows the average bulk density, average tap density and Hausner ratio of several different solid forms of Compound (I). As above, Comparative Control 1 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 1, Step 1A of WO2015 / 127310. Also, as above, Comparative Control 2 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 31 of WO2014 / 039899.

[0342] [Table 5] EXAMPLES

[0343] thermogravimetric analysis Thermogravimetric analysis of the samples was performed using a TA Instruments Q5000 TGA. Example TGA thermal curves showing the mass losses noted below over similar temperature ranges are shown in Figures 1-6.

[0344] Table 5 shows thermogravimetric analysis data of several different solid forms of Compound (I), including mass loss information from multiple iterations over different temperature ranges. As above, Comparative Control 1 corresponds to a solid form of Compound (I) made substantially according to the method detailed in WO2015 / 127310, Example 1, Step 1A. As above, Comparative Control 2 corresponds to a solid form of Compound (I) made substantially according to the method detailed in WO2014 / 039899, ​​Example 31. Comparative Control 3 corresponds to a solid form of Compound (I) made substantially according to the method detailed in WO2015 / 127310, Example 1, Step 1.

[0345] [Table 6] EXAMPLES

[0346] Differential Scanning Calorimetry Thermal Analysis Modulated differential scanning calorimetry (DSC) analysis was performed on a TA Instruments Q2000 DSC. Samples were heated at 2°C / min with temperature modulation parameters of ±0.318°C (width) over a temperature range of -80°C to 200°C. Samples were analyzed using closed aluminum pans. Example DSC thermograms of the solid form of Compound (I) at 0% relative humidity ("RH") are shown in Figures 7-11.

[0347] Table 6 shows the glass transition temperature data of several different solid forms of Compound (I). As above, Comparative Control 1 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 1, Step 1A of WO2015 / 127310. As above, Comparative Control 2 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 31 of WO2014 / 039899. As above, Comparative Control 3 corresponds to a solid form of Compound (I) prepared substantially according to the method detailed in Example 1, Step 1 of WO2015 / 127310.

[0348]

Table 7

Claims

1. Compound (I): 【Chemistry 1】 and has an average bulk density of 300 kg / m 3 (0.3 g / cc).

2. Average tap density is 700 kg / m 3 (0.7g / cc) to 900kg / m 3 2. The solid of claim 1, characterized in that it has a viscosity of 0.9 g / cc.

3. 3. A solid according to claim 1, characterized in that it has a Hausner ratio of less than or equal to 1.

2.

4. A solid according to any one of claims 1 to 3, characterized in that the wet particle size distribution has a D10 value of more than 70 μm.

5. A solid according to any one of claims 1 to 4, characterized in that the wet particle size distribution has a D50 value of greater than 200 μm.

6. A solid according to any one of claims 1 to 5, characterized in that the wet particle size distribution has a D90 value of more than 400 μm.

7. A solid according to any one of claims 1 to 6, characterized in that it exhibits a mass loss by thermogravimetric analysis between 20°C and 240°C of less than 5% by weight.

8. A solid according to any one of claims 1 to 7, wherein the total amount of residual solvents in the solid is less than 1%.

9. A solid according to any one of claims 1 to 8, characterized in that it has a glass transition temperature (Tg) at 0% relative humidity of greater than 90°C.

10. Residual methanol content is less than 3000 ppm; and / or Residual isopropyl acetate is less than 5000 ppm; and / or A solid according to any one of claims 1 to 9, having a residual heptane content of less than 5000 ppm.

11. Residual methanol content is less than 500 ppm; and / or Residual isopropyl acetate is less than 4000 ppm; and / or A solid according to any one of claims 1 to 10, having a residual heptane content of less than 500 ppm.

12. A solid according to any one of claims 1 to 11, having a residual dichloromethane content of less than 1500 ppm.

13. A solid according to any one of claims 1 to 12, wherein the solid is substantially amorphous.

14. Compound (I): 【Chemistry 2】 4. A solid of claim 1, wherein the wet particle size distribution has a D10 value of less than 10 μm.

15. 15. A solid according to claim 14, characterized in that the wet particle size distribution has a D10 value of 5 μm to 6 μm or a D10 value of 1 to 2 μm.

16. 16. A solid according to claim 14 or 15, characterized in that the wet particle size distribution has a D50 value of less than 100 μm.

17. A solid according to any one of claims 14 to 16, characterized in that the wet particle size distribution has a D90 value of less than 200 μm.

18. Average bulk density is 300 kg / m 3 The solid according to any one of claims 14 to 17, characterized in that it has a molecular weight of less than (0.3 g / cc).

19. Average tap density is 300 kg / m 3 The solid according to any one of claims 14 to 18, characterized in that it has a molecular weight of less than (0.3 g / cc).

20. A solid according to any one of claims 14 to 19, characterized in that it exhibits a mass loss by thermogravimetric analysis between 20°C and 240°C of less than 5% by weight.

21. A solid according to any one of claims 14 to 20, wherein the total amount of residual solvents in the solid is less than 1%.

22. A solid according to any one of claims 14 to 21, characterized in that it has a glass transition temperature (Tg) at 0% relative humidity of greater than 90°C.

23. Residual methanol content is less than 3000 ppm; and / or Residual isopropyl acetate is less than 5000 ppm; and / or 23. The solid of any one of claims 14 to 22, having a residual heptane content of less than 5000 ppm.

24. Residual methanol content is less than 500 ppm; and / or Residual isopropyl acetate is less than 4000 ppm; and / or A solid according to any one of claims 14 to 23, having a residual heptane content of less than 500 ppm.

25. A solid according to any one of claims 14 to 24, having a residual dichloromethane content of less than 1500 ppm.

26. A solid according to any one of claims 14 to 25, wherein the solid is substantially amorphous.

27. Compound (I): 【Chemistry 3】 A method for producing a solid of the above, comprising the steps of: washing the solution comprising compound (I) and an organic solvent with an aqueous solution of a weak organic acid having a pKa of 7 or less to form a first solution comprising a first organic layer and a first aqueous layer; and removing the first aqueous layer leaving behind the first organic layer containing compound (I); The method comprising:

28. adding a strong acid to the first organic layer; and Concentrating the first organic layer by removing the organic solvent to obtain a residue containing compound (I).

28. The method of claim 27, further comprising:

29. 29. The method of claim 27 or 28, further comprising washing the residue comprising compound (I) with water or a salt solution.

30. adding a non-miscible organic solvent to obtain a second organic layer and a second aqueous layer containing compound (I); and Removing the second organic layer.

30. The method of claim 29, further comprising:

31. 30. The method of claim 29, wherein washing the residue containing compound (I) with water or a salt solution is repeated 1 to 3 times.

32. 32. The method of any one of claims 28 to 31, further comprising adjusting the pH of the first or second aqueous layer to a value from 1 to 5 by adding an aqueous base solution.

33. 33. The method of claim 32, further comprising measuring the amount of residual weak organic acid having a pKa of 7 or less in the first or second aqueous phase and adjusting the amount of weak organic acid having a pKa of 7 or less to 0% to 8% by weight.

34. 34. The method of claim 33, further comprising adding an aqueous base solution to the first or second aqueous layer to achieve a pH of 8 to 11 to form a precipitate comprising compound (I).

35. 35. The method of claim 34, further comprising isolating the precipitate comprising compound (I) by filtration and washing the precipitate comprising compound (I) with water.

36. 36. The method of claim 35, further comprising drying the filtered and washed precipitate containing compound (I) to obtain a solid of compound (I).

37. 36. The method of claim 35, further comprising slurrying the isolated precipitate with water and filtering to obtain a solid of compound (I).

38. Compound (I): 【Chemistry 4】 A method for producing a solid of the above, comprising the steps of: dissolving the crystalline form of Compound (I) in a solution comprising a non-miscible organic solvent and salt water; adding one equivalent of a strong acid to form an aqueous layer and an organic layer; removing the organic layer; concentrating the aqueous layer; The pH is adjusted to a value of 8 to 11 by adding an aqueous base solution to obtain a solid precipitate of compound (I). to obtain; isolating the solid precipitate of compound (I) by filtration; rinsing the deposit with water; and Drying the precipitate to obtain a solid of compound (I). The method comprising:

39. The method of any one of claims 27 to 38, further comprising micronizing the particles of compound (I).

40. Compound (I): 【Chemistry 5】 A method for producing an amorphous form of washing a solution of Compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, the solution of Compound (I) comprising a first organic solvent; removing the first aqueous layer; and performing a solvent exchange from the first organic solvent to a second organic solvent; The method comprising:

41. washing the first organic layer with a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, the second aqueous layer comprising compound (I); and Removing the second organic layer.

41. The method of claim 40, further comprising:

42. adding a first base to the second aqueous layer to form a third solution comprising a third organic layer and a third aqueous layer, the third organic layer comprising compound (I); extracting the third aqueous layer with a third organic solvent; and Concentrating the third organic layer.

42. The method of claim 41, further comprising:

43. 43. The method of claim 42, further comprising adding an anti-solvent to the third organic layer to form a precipitate comprising compound (I).

44. 44. The method of claim 43, further comprising isolating the precipitate comprising compound (I).

45. dissolving the precipitate comprising compound (I) in a fourth organic solvent to form a fourth solution; and Spray drying the fourth solution to obtain a solid of compound (I).

45. The method of claim 44, further comprising:

46. 46. ​​The method of claim 45, further comprising micronizing the solid of Compound (I).

47. 1. A pharmaceutical composition comprising: A solid of compound (I) according to any one of claims 1 to 26; at least one pharma- ceutically acceptable excipient; The pharmaceutical composition comprising:

48. 27. A therapeutically effective amount of a solid of compound (I) according to any one of claims 1 to 26, for use in inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need thereof.

49. A therapeutically effective amount of a solid of compound (I) according to any one of claims 1 to 26 for use in the treatment of pemphigus vulgaris or pemphigus foliaceus in a mammal in need of such treatment.

50. A therapeutically effective amount of a solid of compound (I) according to any one of claims 1 to 26 for use in the treatment of immune thrombocytopenia in a mammal in need thereof.

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