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

Abstract

To provide novel solid forms which are useful for treating disorders and conditions mediated by BTK activity, uses thereof and reproducible, scalable methods of making the same.SOLUTION: There is disclosed solid forms of Compound (I).SELECTED DRAWING: None

Description

Technical Field

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

[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 using the same, and methods of making Compound (I) comprising the solid forms thereof. The solid forms of Compound (I) are inhibitors of Bruton's tyrosine kinase (BTK) with low residual solvent content.

Background Art

[0003] The enzyme BTK is a member of the non-receptor tyrosine kinase of the Tec family. 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 development of several disorders and conditions such as B cell-related blood cancers (e.g., non-Hodgkin 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 pharmaceutically acceptable salts, and any solid forms thereof inhibit BTK and are useful for the treatment of disorders and conditions mediated by BTK activity. Compound (I) is disclosed in Example 31 of Patent Document 1 and has the following chemical structure:

Chemical Formula

[0005] Compound (I) obtained by the procedures described in Patent Document 1 and Patent Document 2 contains residual solvents in amounts well in excess of the limits described in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. Generally, manufacturing processes where the amount of residual solvent is near or exceeds the ICH limits are not desirable for the manufacture of active pharmaceutical ingredients (APIs).

[0006] The solid forms of bioactive compounds such as compound (I) and its pharmaceutically acceptable salts are of interest in the pharmaceutical industry as desirable and even required for pharmaceutical development, with specific physical, chemical, or pharmaceutical properties such as solubility, dissociation, true density, solubility, melting point, morphology, compaction behavior, particle size, flow properties, or solid stability. The solid forms of bioactive compounds often determine their ease of manufacture, isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. Also, for use as an API in a therapeutic composition, it is extremely important that the solid form be substantially pure. Specifically, a substantially pure form does not contain reaction impurities, starting materials, reagents, by-products, unwanted solvents, and / or other processing impurities resulting from the manufacture and / or isolation and / or purification of a particular solid form. Specifically, a solid form intended for use as an API is substantially free of degradation products that include drug substance aggregates (e.g., dimers of the API).

[0007] Moreover, it is still impossible to predict which possible solid forms of a compound or salt are suitable for commercial use in a pharmaceutical composition or which forms exhibit desirable properties. Since different solid forms can have different properties, for bioactive compounds intended for pharmaceutical use, a reproducible method for producing substantially pure solid forms, including large-scale manufacturing methods, is also desirable.

[0008] It is still impossible to predict whether a given solid form of a compound or salt is suitable for commercial use in a pharmaceutical composition or which form exhibits desirable properties. Since different solid forms can have different properties, for bioactive compounds intended for pharmaceutical use, a reproducible method for producing substantially pure solid forms, including large-scale manufacturing methods, is also desirable.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0010] Accordingly, there is a need for novel solid forms, such as compound (I) and pharmaceutically acceptable salts thereof, and a reproducible scalable method for producing the same, which are useful for treating disorders and conditions mediated by BTK activity.

Means for Solving the Problems

[0011] Disclosed herein are novel solid forms of compound (I), compositions containing the same, and methods for using and manufacturing the same. Importantly, in some embodiments, the solid form of compound (I) has a low amount of residual solvent. Further, in some embodiments, the solid form of compound (I) is 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 manufacture, pharmaceutical formulation, pharmaceutical use, and / or storage. In some embodiments, the novel solid forms disclosed herein do not contain detectable residual solvents in the solid form. In some embodiments, the solid form is substantially amorphous. Also disclosed herein is a novel method for producing compound (I).

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

[0013] Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the Hausner ratio is 1.2 or less.

[0014] Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 70 μm. 10 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 200 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 400 μm. 50 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 400 μm. 90 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value greater than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm.

[0015] Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm. 10 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm. 50 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm. 90 Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 10 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 100 μm. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the wet particle size distribution has a D value less than 200 μm.

[0016] Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 5% by weight. Some embodiments of the present disclosure relate to solid forms of compound (I) characterized in that the glass transition temperature (T g ) at a relative humidity of 0% is higher than 90 °C.

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

[0018] Some embodiments of the present disclosure relate to solid forms of compound (I) in which the solid form is substantially pure.

[0019] Some embodiments of the present disclosure relate to solid forms of compound (I) in which 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:

Chemical formula

[0020] Some embodiments of the present disclosure relate to solid forms of compound (I) in which 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 pharmaceutically acceptable excipient. In some embodiments, the at least one solid form of compound (I) is the solid form described herein is. 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, the method comprising administering to the mammal a solid form of at least one compound (I) in a therapeutically effective amount. In some embodiments, the solid form of at least one compound (I) is the solid form described herein. Some embodiments of the present disclosure relate to a method of treating a BTK-mediated disease in a mammal, the method comprising administering to the mammal a solid form of at least one compound (I) in a therapeutically effective amount. In some embodiments, the solid form of at least one compound (I) is the solid form described herein. In some embodiments, the BTK-mediated disease is pemphigus vulgaris. In some embodiments, the BTK-mediated disease is pemphigus foliaceus. In some embodiments, the BTK-mediated disease is immune thrombocytopenia. In some embodiments, the mammal is a human.

[0023] Also provided herein is a method of manufacturing a solid form of at least one compound (I).

[0024] In some embodiments, the method includes the step of adding a base to an aqueous solution containing compound (I). In some embodiments, the method is a step of washing a 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, wherein the solution of compound (I) contains a first organic solvent, and removing the first aqueous layer. In some embodiments, the method 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 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 containing a third organic layer and a third aqueous layer, where the third aqueous layer contains 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 from 2.5 to 3.5. In some embodiments, the method further includes removing the second organic layer or the third organic layer, removing residual organic solvents 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 containing compound (I). In some embodiments, the method further includes the step of micronizing the precipitate containing compound (I).

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

[0026] In some embodiments, the method further comprises washing the first organic layer containing compound (I) with an aqueous sodium bicarbonate solution. By washing the first organic layer containing compound (I), substantially all of the weak organic acids with a pKa of 7 or less are removed.

[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 containing compound (I) therefrom.

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

[0029] In some embodiments, the method further comprises adding a non-hydrating organic solvent to the first aqueous layer to obtain a second organic layer and a second aqueous layer containing 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 of from 1 to 5 by adding an aqueous base solution.

[0031] In some embodiments, the method further comprises measuring the amount of residual weak organic acid with a pKa of 7 or less in the first or second aqueous layer and adjusting the amount of weak organic acid with a pKa of 7 or less to from 0 wt% to 8 wt%.

[0032] In some embodiments, the method further comprises adding an aqueous base solution to the first or second aqueous layer to adjust the pH to 8 to 11 and 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, filtering, and isolating the solid form of compound (I).

[0033] In some embodiments, the method comprises dissolving the crystalline form of compound (I) in a solution comprising a non-hydrating organic solvent and brine; 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 of 8 to 11 to obtain a precipitate of the solid form of compound (I); isolating the precipitate of the solid form of compound (I) by filtration; washing the precipitate with water; and drying the precipitate to obtain the 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 comprises 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, wherein 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. 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. 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, wherein the third organic layer comprises 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 antisolvent 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

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Figure 10

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Figure 12

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Figure 14

Figure 15

Figure 16

Mode for Carrying Out the Invention

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

[0038]

Chemical Formula

Chem.

[0039] When the 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 the corresponding (S) optical isomer as an impurity of less than 1% by weight. Thus, when the compound (I) is represented by 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 the compound (I) is represented by the (E) isomer, it contains the corresponding (Z) isomer as an impurity of less than 1% by weight. Thus, when the 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] As used herein, the compound (I) may also be referred to as a "drug", "active agent", "therapeutically active agent" or "API".

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

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

[0043] As used herein, "substantially free of" with respect to a component in solid form, such as a degradation product (e.g., a dimer of compound (I)), means that less than 5% by weight of the solid form contains the component. The relative amounts of components in solid form are measured by standard methods and techniques known in the art. The term "pharmaceutically acceptable salt" as used herein refers to non-toxic salt forms of the compounds of the present disclosure. Pharmaceutically acceptable salts of the 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 pharmaceutically acceptable salts include, for example, those disclosed in Berge, S.M. et al., J. Pharma. Sci. 66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed in that article include acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylic acid; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycolylarsanilate; hexylresorcinate; hydrabamine; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methylnitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate / diphosphate; polygalacturonate; salicylate; stearate; basic acetate; succinate; sulfate; tannate; tartrate; theophyllinate; triethiodide; benzathine; chloroprocaine; choline; diethanolamine; ethylenediamine; meglumine; procaine; aluminum; calcium; lithium; magnesium; potassium; sodium; and zinc.

[0044] Non-limiting examples of pharmaceutically acceptable salts obtained from suitable acids include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art such as ion exchange. Further non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate salts, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate and valerate. Non-limiting examples of pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4Salts of (alkyl)4 are included. In the present disclosure, the quaternization of any basic nitrogen-containing group of the compounds disclosed herein is also contemplated. 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 amines formed using ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0045] As used herein, the term "pharmaceutically acceptable excipient" refers to a single entity or excipient useful in the manufacture of a pharmaceutical composition. For example, pharmaceutically acceptable excipients include entities and excipients that are generally considered to be overall safe and acceptable for pharmaceutical use in mammals.

[0046] As used herein, the term "atmospheric conditions" refers to room temperature, open atmosphere, and unregulated humidity conditions. As used herein, the term "room temperature" or "atmospheric temperature" means a temperature of 15°C to 30°C.

[0047] As used herein, the terms "inhibit", "inhibiting", or "inhibited" refer to the reduction or suppression of a significant decrease in the basic 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 with respect to a disorder or condition, include any effect that results in an improvement of the disorder or condition, such as a decrease, reduction, modulation, improvement, or elimination. An improvement or decrease in the severity of any symptom of a disorder or condition can be readily evaluated 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 legislative centimeter.

[0051] As used herein, "residual solvent" refers to an organic volatile chemical substance used or generated during the manufacture of a drug substance or excipient, or during the manufacture of a pharmaceutical product. The residual solvent is 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] The residual solvent species used herein correspond to those defined in the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The ICH guidelines classify residual solvents into three classes: Class 1, Class 2, and Class 3.

[0054] As used herein, "Class 1 solvent" refers to a solvent to be avoided according to the ICH guidelines. Class 1 solvents include known human carcinogens, strongly suspected human carcinogens, and environmental hazardous substances, including but not limited to benzene, carbon tetrachloride, 1,2-dichloroethane, and 1,1,1-trichloroethane.

[0055] As used herein, the term "Class 2 solvent" refers to solvents to be restricted according to the ICH guidelines. Class 2 solvents include non-genotoxic animal carcinogens, or suspected causative agents of other irreversible toxicities such as neurotoxicity or teratogenesis, and solvents suspected of other strong but reversible toxicities. Examples of 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; methylcyclohexane; methyl isobutyl ketone; and N-methylpyrrolidone.

[0056] As used herein, the term "Class 3 solvent" refers to solvents with low toxicity to humans according to the ICH guidelines. For Class 3 solvents, there are no health-based exposure limits based on the ICH guidelines. The permitted daily exposure (PDE) of Class 3 solvents is 50 mg per day. According to the ICH guidelines, if the amount of residual Class 3 solvent is 50 mg or less per day (an amount corresponding to 5000 ppm or 0.5%), it is acceptable without justifiable reasons. Examples of Class 3 solvents include, but are not limited to, 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 "anti-solvent" 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 "antisolvent precipitation" refers to a process in which supersaturation is achieved by adding an antisolvent to a product solution, resulting in the induction of precipitation.

[0059] As used herein, the term "organic layer" refers to a layer that is insoluble in water and contains at least one organic solvent that is immiscible with 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 the physical form of a compound in which the liquid or gaseous state is not predominant, including amorphous and crystalline forms.

[0062] As used herein, the term "amorphous" refers to a solid material that has no long-range order in the positions of its molecules. Amorphous solids are generally supercooled liquids in which there is no well-defined arrangement, such as molecular packing, and the molecules are randomly arranged so that there is no long-range order. For example, an amorphous material is a solid material that does not exhibit sharp characteristic signals in an 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. The broad peaks are characteristic of amorphous solids. For a comparison of the diffraction patterns of amorphous and crystalline materials, see, for example, US2004 / 0006237.

[0063] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the positions of its molecules. For example, a substantially amorphous material has a crystallinity of less than 15% (e.g., less than 10% or less than 5%). "Substantially amorphous" includes the description "amorphous" for materials that are non-crystalline (crystallinity 0%).

[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 thermo gravimetric (also referred to as thermal gravimetric) analysis.

[0066] The particle size used herein is expressed in terms of the particle size distribution (e.g., D 10 , D 50 and D 90 values). The particle size distribution is affected by 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 values.

[0067] As will be understood by those skilled in the art, the particle size and particle size distribution of a powder are measured using various techniques known in the art, such as laser diffraction. In some embodiments, the particle size distribution of the solid form of compound (I) is represented by values (e.g., D 10 , D 50 and D 90 values) measured by laser diffraction.

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

[0069] As used herein, "D 10 " refers to the particle size at which 10% of the population of particles has a particle size of D 10 or less.

[0070] As used herein, "D 90 " refers to the particle size at which 90% of the population of particles has a particle size of D 90 or less.

[0071] As used herein, "bulk density" refers to the mass of the 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 a characteristic inherent to the material, but rather varies depending on how the material is processed.

[0072] As used herein, "tap density" refers to the mass of the particles of a material divided by the total volume occupied by the particles after the container containing the particles has been mechanically tapped gently. 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 a characteristic inherent to the material, but rather varies depending on how the material is processed.

[0073] As used herein, the "Hausner ratio" refers to a number related to the fluidity of a powder or powdery material. The Hausner ratio is the ratio of the bulk density of the material to the tap density of the material.

[0074] Embodiments Without limitation, some embodiments of the present disclosure include the following.

[0075] 1. Compound (I):

Chemical formula

[0076] 29. Compound (I):

Chemical formula

[0077] 53. Compound (I):

Chemical formula

[0078] 72. Compound (I):

Chemical formula

[0079] It should be noted that there seems to be an incomplete number in the original text at "83. 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, the solid form according to any one of embodiments 72 to 82.", where "。。。" is shown in the translation. Please check and correct the original text for a more accurate translation.90.Compound (I): [ka] A solid form of the compound having a wet particle size distribution of less than 10 μm D 10 A solid form characterized by having a value. 91. Wet particle size distribution of 5 μm to 6 μm D 10 value, or D between 1 and 2 μm 10 91. The solid form according to embodiment 90, characterized in that it has a value. 92. Wet particle size distribution D less than 100 μm 50 92. The solid form according to embodiment 90 or 91, characterized in that it has a value. 93. Wet particle size distribution D less than 200 μm 90 93. The solid form according to any one of embodiments 90 to 92, characterized in that it has a value. 94. The solid form of any one of embodiments 90-93, characterized in that it has an average bulk density of less than 0.3 g / cc. 95. The solid form of any one of embodiments 90-94, characterized in that it has an average tap density of less than 0.3 g / cc. 96. The solid form of any one of embodiments 90-95, characterized by a mass loss of less than 5% by weight from 20°C to 240°C by thermogravimetric analysis. 97. The solid form of any one of embodiments 90-96, characterized by a mass loss of less than 3% by weight from 20°C to 240°C by thermogravimetric analysis. 98. The solid form of any one of embodiments 90-97, characterized by 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 90-98, characterized by a mass loss by thermogravimetric analysis from 20°C to 240°C of less than 1.5% by weight. 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 (T g 102. The solid form according to any one of embodiments 90 to 101, wherein the temperature is higher 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. The residual methanol content is less than 500 ppm; Residual isopropyl acetate is less than 4000 ppm; and / or Any one of embodiments 90 to 103, wherein the amount of residual heptane is less than 500 ppm. Solid form of. 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 90-108, wherein the solid form is free of detectable residual solvent. 110. The solid form according to any one of embodiments 90-109, 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 loses less than 5% by weight from 20°C to 240°C by thermogravimetric analysis. 112. The solid form according to Embodiment 111, characterized in that the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 3% by weight. 113. The solid form according to Embodiment 111 or 112, characterized in that the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 2% by weight. 114. The solid form according to any one of Embodiments 111 to 113, characterized in that the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 1.5% by weight. 115. The solid form according to any one of Embodiments 111 to 114, wherein the total amount of residual solvent in the solid form is less than 1%. 116. The solid form according to any one of Embodiments 111 to 115, wherein the total amount of residual solvent in the solid form is less than 0.5%. 117. The glass transition temperature (T g ) at a relative humidity of 0% is higher than 90 °C, and the solid form according to any one of Embodiments 111 to 116. 118. 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, and the solid form according to any one of Embodiments 111 to 117. 119. 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, and the solid form according to any one of Embodiments 111 to 118. 120. The amount of residual dichloromethane is less than 1500 ppm, and the solid form according to any one of Embodiments 111 to 119. 121. The amount of residual dichloromethane is less than 1000 ppm, and the solid form according to any one of Embodiments 111 to 120. 122. The amount of residual dichloromethane is less than 500 ppm, and the solid form according to any one of Embodiments 111 to 121. 123. The solid form according to any one of Embodiments 111 to 122, wherein the residual dichloromethane amount is less than 100 ppm. 124. The solid form according to any one of Embodiments 111 to 123, wherein no detectable residual solvent is present in the solid form. 125. The solid form according to any one of Embodiments 111 to 124, wherein the solid form is substantially amorphous.

[0081] 126. Compound (I): [Chemical formula] A solid form thereof, characterized in that the glass transition temperature (T g ) at 0% relative humidity is higher than 90 °C. 127. The residual methanol amount is less than 3000 ppm; The residual isopropyl acetate amount is less than 5000 ppm; and / or The residual heptane amount is less than 5000 ppm, the solid form according to Embodiment 126. 128. The residual methanol amount is less than 500 ppm; The residual isopropyl acetate amount is less than 4000 ppm; and / or The residual heptane amount is less than 500 ppm, the solid form according to Embodiment 126 or 127. 129. The residual dichloromethane amount is less than 1500 ppm, the solid form according to any one of Embodiments 126 to 128. 130. The residual dichloromethane amount is less than 1000 ppm, the solid form according to any one of Embodiments 126 to 129. 131. The residual dichloromethane amount is less than 500 ppm, the solid form according to any one of Embodiments 126 to 130. 132. The residual dichloromethane amount is less than 100 ppm, the solid form according to any one of Embodiments 126 to 131. 133. The solid form according to any one of Embodiments 126 to 132, wherein no detectable residual solvent is present in the solid form. 134. The solid form according to any one of embodiments 126 to 133, wherein the solid form is substantially amorphous. 135. A method for producing a solid form of compound (I), the method comprising adding a base to an aqueous solution containing compound (I). 136. The method according to embodiment 135, wherein the base is an aqueous base solution. 137. The method according to 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 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, wherein the solution of compound (I) contains a first organic solvent; and removing the first aqueous layer The method comprising. 139. The method according to embodiment 138, wherein the first acidic aqueous solution has a pH of 1 to 6. 140. The method according to embodiment 138 or 139, wherein the first acidic aqueous solution has a pH of 2.5 to 3.5. 141. The method according to any one of embodiments 138 to 140, wherein the first acidic aqueous solution is a phosphate buffer at pH 3. 142. The method according to any one of embodiments 138 to 141, wherein the first organic solvent contains at least one non-hydrated organic solvent. 143. The method according to embodiment 142, wherein the at least one non-hydrated organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran and isopropyl acetate. 144. The method according to any one of embodiments 138 to 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, wherein 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 comprising a second organic layer and a second aqueous layer, further comprising forming, wherein the second aqueous layer contains compound (I), the method according to any one of embodiments 138 to 144. 146. The method according to embodiment 145, wherein partially removing the first organic solvent from the first organic layer comprises distillation under reduced pressure. 147. The method according to embodiment 145 or 146, wherein the second organic solvent is isopropyl acetate. 148. The method according to any one of embodiments 145 to 147, wherein the second acidic aqueous 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, wherein the third aqueous layer contains compound (I), and further wherein 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 from 2.5 to 3.5 The method according to any one of embodiments 138 to 144, further comprising. 150. The method according to embodiment 149, wherein the first organic acid is methanesulfonic acid. 151. The method according to 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 according to any one of embodiments 149 to 151, wherein the third organic solvent is isopropyl acetate. 153. The method according to any one of embodiments 149 to 152, wherein the first base is an aqueous base solution. 154. The method according to any one of embodiments 149 to 153, wherein the first base is an aqueous potassium hydroxide solution. 155. 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 compound (I); and Adding a second base to the aqueous solution of compound (I) to form a precipitate containing compound (I) The method according to embodiment 145 or 149, further comprising. 156. The method according to 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 according to embodiment 155 or 156, wherein the second base is an aqueous base solution. 158. The method according to any one of embodiments 155 to 157, wherein the second base is an aqueous potassium hydroxide solution. 159. The method according to any one of embodiments 155 to 158, further comprising filtering and drying the precipitate. 160. The method according to embodiment 159, wherein the precipitate substantially does not contain decomposition products. 161. The method according to 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 a solution containing 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 containing a first organic layer and a first aqueous layer; and Removing the first aqueous layer while leaving the first organic layer containing compound (I) A method comprising. 163. The method according to embodiment 162, wherein the organic solvent comprises at least one non-hydrating organic solvent. 164. The method according to embodiment 163, wherein the non-hydrating organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyl tetrahydrofuran, and isopropyl acetate. 165. The method according to any one of embodiments 162 to 164, wherein the organic solvent is dichloromethane. 166. The method according to any one of embodiments 162 to 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 according to any one of embodiments 162 to 166, wherein the weak organic acid having a pKa of 7 or less is acetic acid. 168. The method according to any one of embodiments 162 to 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 according to any one of embodiments 162 to 168, further comprising. 170. The method according to embodiment 169, wherein the strong acid is selected from methanesulfonic acid, sulfuric acid, and hydrochloric acid. 171. The method according to embodiment 169 or 170, wherein the strong acid is methanesulfonic acid. 172. The method according to any one of embodiments 162 to 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 according to any one of embodiments 162 to 173, further comprising washing the residue containing compound (I) with water or an aqueous salt solution. 175. The method according to embodiment 174, wherein the aqueous salt solution is an aqueous sodium chloride solution. 176. Adding a non-aqueous organic solvent to obtain a second organic layer and a second aqueous layer containing compound (I); and Removing the second organic layer The method according to embodiment 174 or 175, further comprising. 177. The method according to embodiment 174, wherein washing the residue containing compound (I) with water or an aqueous salt solution is repeated 1 to 3 times. 178. By adding an aqueous base solution, the pH of the first or second aqueous layer is adjusted to a value of 1 to 5 The method according to any one of Embodiments 169 to 177, further comprising adjusting to 179. The method according to Embodiment 178, wherein the pH of the first or second aqueous layer is adjusted to 3. 180. The method according to Embodiment 178 or 179, wherein the aqueous base solution is an aqueous solution of sodium hydroxide, potassium hydroxide or calcium hydroxide. 181. The method according to any one of Embodiments 178 to 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 the weak organic acid having a pKa of 7 or less to 0 wt% to 8 wt%. 182. The method according to Embodiment 181, wherein the weak organic acid having a pKa of 7 or less is acetic acid. 183. The method according to Embodiment 181 or 182, further comprising adding an aqueous base solution to the first or second aqueous layer to adjust the pH to 8 to 11 to form a precipitate containing Compound (I). 184. The method according to Embodiment 183, wherein the pH is 9.5. 185. The method according to Embodiment 183 or 184, wherein the aqueous base solution is an aqueous solution of potassium hydroxide. 186. The method according to any one of Embodiments 183 to 185, further comprising isolating the precipitate containing Compound (I) by filtration and washing the precipitate containing Compound (I) with water. 187. The method according to Embodiment 186, further comprising drying the filtered and washed precipitate containing Compound (I) to obtain a solid form of Compound (I). 188. The method according to 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 the crystalline form of Compound (I) in a solution containing a non-hydrating organic solvent and brine; 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 a precipitate of the solid form of compound (I); Isolating the precipitate of the solid form of compound (I) by filtration; Washing the precipitate with water; and Drying the precipitate to obtain the solid form of compound (I) A method comprising. The method according to embodiment 189, wherein the non-aqueous organic solvent is dichloromethane. The method according to embodiment 189 or 190, wherein the strong acid is methanesulfonic acid. The method according to any one of embodiments 189 to 191, wherein the pH of the aqueous layer after addition of the strong acid is between 1 and 4. The method according to embodiment 192, wherein the pH of the aqueous layer is 2. The method according to any one of embodiments 189 to 193, wherein the aqueous layer is concentrated at a temperature between 0°C and 5°C. The method according to any one of embodiments 189 to 194, wherein the aqueous base solution is an aqueous potassium hydroxide solution. The method according to any one of embodiments 189 to 195, wherein an aqueous base solution is added to adjust the pH to a value between 9 and 10. 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 of the solid form of compound (I). The method according to any one of embodiments 135 to 197, further comprising micronizing the particles of compound (I). The solid form of compound (I) produced by the method according to any one of embodiments 135 to 198. The solid form according to embodiment 175, wherein the solid form is substantially amorphous. A method for producing a solid form of compound (I), comprising spray-drying a solution of compound (I). A method for producing an amorphous 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, wherein the solution of compound (I) contains a first organic solvent; Removing the first aqueous layer; and Performing a solvent exchange from the first organic solvent to a second organic solvent A method comprising. 203. The method according to embodiment 202, wherein the first acidic aqueous solution has a pH of 1 to 6. 204. The method according to embodiment 202 or 203, wherein the first acidic aqueous solution has a pH of 2.5 to 3.5. 205. The method according to any one of embodiments 202 to 204, wherein the first acidic aqueous solution is a phosphate buffer at pH 3. 206. The method according to any one of embodiments 202 to 205, wherein the first organic solvent contains at least one non-hydrating organic solvent. 207. The method according to embodiment 206, wherein the at least one non-hydrating organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyl tetrahydrofuran and isopropyl acetate. 208. The method according to any one of embodiments 202 to 207, wherein the first organic solvent contains dichloromethane. 209. The method according to any one of embodiments 202 to 208, wherein the second organic solvent contains 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 according to embodiment 209, wherein the alkyl acetate is isopropyl acetate. 211. The method according to embodiment 209 or 210, wherein the second organic solvent contains 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, wherein the second aqueous layer contains compound (I); and Removing the second organic layer The method according to any one of Embodiments 202 to 211, further comprising 213. The method according to Embodiment 212, wherein the second acidic aqueous solution has a pH of 1 to 6. 214. The method according to Embodiment 212 or 213, wherein the second acidic aqueous solution has a pH of 2.5 to 3.5. 215. The method according to any one of Embodiments 212 to 214, wherein the second acidic aqueous solution is a phosphate buffer solution with a pH of 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, wherein the third organic layer contains Compound (I); Extracting the third aqueous layer using a third organic solvent; and Concentrating the third organic layer The method according to any one of Embodiments 212 to 215, further comprising 217. The method according to Embodiment 216, wherein the first base is an aqueous base solution. 218. The method according to Embodiment 217, wherein the aqueous base solution has a pH of 8 to 14. 219. The method according to any one of Embodiments 216 to 218, wherein the first base is an aqueous potassium hydroxide solution. 220. The third organic solvent comprises at least one of alkyl acetate, methyltetrahydrofuran, toluene, methylcyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and alkyl propionate, according to any one of Embodiments 216 to 219. 221. The method according to Embodiment 220, wherein the alkyl acetate is isopropyl acetate. 222. The method according to any one of Embodiments 216 to 221, wherein the third organic solvent contains isopropyl acetate. 223. The method according to any one of Embodiments 216 to 222, further comprising adding an antisolvent to the third organic layer to form a precipitate containing Compound (I). 224. The antisolvent is the method according to embodiment 223, comprising at least one of hexane, heptane, and octane. 225. The method according to embodiment 223 or 224, further comprising isolating the precipitate containing compound (I). 226. The method according to embodiment 225, wherein isolating the precipitate containing compound (I) comprises drying the precipitate containing compound (I). 227. The method according to embodiment 226, wherein the 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 according to any one of embodiments 225 to 227, further comprising. 229. The method according to embodiment 228, wherein the fourth organic solvent comprises at least one of methanol, ethanol, acetone, acetonitrile, and methyl ethyl ketone. 230. The method according to embodiment 229, wherein the fourth organic solvent comprises methanol. 231. The method according to any one of embodiments 228 to 230, wherein the solid form of compound (I) substantially does not contain decomposition products. 232. The method according to any one of embodiments 228 to 231, wherein the residual solvent is less than 1% of the solid form of compound (I). 233. The method according to any one of embodiments 228 to 232, further comprising micronizing the solid form of compound (I). 234. A solid form of compound (I) produced by the 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, The solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234, or 235, and At least one pharmaceutically acceptable excipient A pharmaceutical composition comprising. The pharmaceutical composition according to embodiment 236, which is in the form of a solid oral composition. The pharmaceutical composition according to embodiment 236 or 237, which is in the form of a tablet or a capsule. A method for inhibiting Bruton's tyrosine kinase (BTK) in a mammal in need of inhibiting BTK, the method comprising administering to the mammal a therapeutically effective amount of a solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234 or 235. A method for treating a mammal in need of treatment for a disease mediated by Bruton's tyrosine kinase (BTK), the method comprising administering to the mammal a therapeutically effective amount of a solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234 or 235. 241. A method for treating a mammal in need of treatment for pemphigus vulgaris or pemphigus foliaceus, the method comprising administering to the mammal a therapeutically effective amount of a solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234 or 235. Method. A method for treating a mammal in need of treatment for immune thrombocytopenia, the method comprising administering to the mammal a therapeutically effective amount of a solid form of compound (I) according to any one of embodiments 1 to 134, 199, 200, 234 or 235. The method according to any one of embodiments 239 to 242, wherein the mammal is a human.

[0082] Average bulk density of the solid form The average bulk density reflects the amount of space occupied by a given amount of material. The average bulk density affects the behavior of the material during processing operations (e.g., blending and compression). In some cases, the average bulk density influences the selection of the milling procedure for the material during pharmaceutical development.

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

[0084] In some embodiments, the method results in a solid form of compound (I) having an average bulk density of from 0.6 g / cc to 0.7 g / cc.

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

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

[0087] Average tapped density of the solid form "Average tapped density" or "tapped density" refers to the bulk density measured after mechanically tapping a container containing a powder sample. Tapped density affects, for example, the behavior of pharmaceutical materials during pre-compression, tableting and capsule filling.

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

[0089] In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 0.70 g / cc to 0.90 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 0.70 g / cc to 0.75 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 0.75 g / cc to 0.80 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 0.80 g / cc to 0.85 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 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 tapped density of from 0.70 g / cc to 0.72 g / cc. In some embodiments, the solid forms of the present disclosure are characterized by an average tapped density of from 0.72 g / cc to 0.74 g / cc. It is characterized by. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.74 g / cc to 0.76 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.76 g / cc to 0.78 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.78 g / cc to 0.80 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.80 g / cc to 0.82 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.82 g / cc to 0.84 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.88 g / cc to 0.86 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.86 g / cc to 0.88 g / cc. In some embodiments, the solid form of the present disclosure is characterized in that the average tapped density is from 0.88 g / cc to 0.90 g / cc.

[0091] Hausner ratio of the solid form The Hausner ratio indicates the fluidity of the powder, and a Hausner ratio greater than 1.35 is often considered to suggest low fluidity. The flow of the powder is an important requirement for most pharmaceutical manufacturing methods. In order to ensure consistent content uniformity, powders with a Hausner ratio of less than 1.34 often require acceptable fluidity.

[0092] In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.2 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.18 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.16 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.14 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.12 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.10 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.08 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.06 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.04 or less. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of 1.02 or less. In some embodiments, the solid form of the present 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 from 1 to 1.2. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of from 1.00 to 1.05. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of from 1.05 to 1.10. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of from 1.10 to 1.15. In some embodiments, the solid form of the present disclosure is characterized by a Hausner ratio of from 1.15 to 1.20.

[0094] Wet particle size distribution of the solid form Particle size is related to several important properties of the formulation procedure, including particle shape, surface area, and porosity. The particle size distribution of the API affects bulk properties, product performance, processability, and API stability. For example, the particle size distribution affects the dissolution and absorption rates of the API, as well as product consistency. Depending on the pharmaceutical application, a smaller particle size may be desirable.

[0095] In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 70 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 75 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 80 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 85 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 90 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 95 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 100 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 105 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 110 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 115 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 120 μm ID 10 value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 125 μm ID10 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution greater than 130 μm 10 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution greater than 135 μm 10 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution greater than 140 μm 10 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution greater than 145 μm 10 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution greater than 150 μm 10 Characterized by having a value.

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

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

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

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

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

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

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

[0103] In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 100 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 90 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 80 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 70 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 60 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 50 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 40 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 30 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution less than 20 μm 50 Characterized by having a value.

[0104] In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution ranging from 40 μm to 70 μm 50 Characterized by having a value. In some embodiments, the solid form of the present disclosure has a D value of the wet particle size distribution ranging from 10 μm to 20 μm 50 Characterized by having a value.

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

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

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

[0108] In some embodiments, the solid form of the present disclosure has a D of 100 μm to 150 μm in wet particle size distribution 90 value and a D of 40 μm to 70 μm 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure has a D of 10 μm to 50 μm in wet particle size distribution 90 value and a D of 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 D of 5 μm to 6 μm in wet particle size distribution 10 value and a D of 10 μm to 50 μm 90Characterized by having a value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution with a D value of 1 μm to 2 μm and a D value of 100 μm to 150 μm. 10 value and a D value of 100 μm to 150 μm. 90 Characterized by having a value.

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

[0111] Amount of residual solvent in the solid form The residual solvent is a volatile organic compound used or formed during the manufacture of the compound. Regulations, including those published by the US Food and Drug Administration, require that compounds intended for use as active pharmaceutical ingredients be substantially free of toxicologically significant residual solvents. Generally, headspace gas chromatography is employed to measure the amount of residual solvent, although mass spectrometry is often used in combination to identify and quantify specific residual solvents.

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

[0113] In some embodiments, no detectable residual solvent is present in the solid form of the present disclosure.

[0114] In some embodiments, the amount of residual methanol in the solid form of the present disclosure is 3000 It is less than 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 amount of residual methanol in the solid form of the present disclosure is less than 200 ppm. In some embodiments, the amount of residual methanol in the solid form of the present disclosure is less than 100 ppm. In some embodiments, no detectable residual methanol is present in the solid form of the present disclosure.

[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, no detectable residual isopropyl acetate is present in the solid form of the present disclosure.

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

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

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

[0121] In some embodiments, the solid form of the present disclosure contains residual solvents in amounts within the limits specified in the ICH guidelines.

[0122] In some embodiments, the solid forms of the present disclosure contain Class 1 residual solvents in amounts within the limits defined by 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 forms of the present disclosure contain Class 2 residual solvents in amounts within the limits specified 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, no detectable Class 2 residual solvents are present 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, a substantially pure form does not contain reaction impurities, starting materials, reagents, by-products, undesirable solvents, and other processing impurities resulting from the manufacture, and / or isolation, and / or purification of the solid form.

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

[0126] In some embodiments, the solid form of the present disclosure substantially does not contain 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 forms of the present disclosure substantially do not contain the dimer of compound (I). In some embodiments, the dimer of compound (I) is less than 5% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 4% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 3% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 2% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 1% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 0.5% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 0.25% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 0.1% by weight of the solid forms of the present disclosure. In some embodiments, the dimer of compound (I) is less than 0.05% by weight of the solid forms of the present disclosure.

[0128] Substantially amorphous solid form In some embodiments, the solid forms of the present disclosure are substantially amorphous. As measured by XRPD, the API shows the same broad peaks and halos (i.e., appears as the same amorphous solid). However, depending on how the amorphous solid is formed (e.g., by spray drying or different precipitation methods), different material properties of the API (e.g., density, flowability, particle morphology, and particle size distribution) are affected. These material properties result in different dissolution profiles and pharmacokinetic profiles because they determine how the API interacts with excipients in oral dosage forms (e.g., capsules and tablets) during processing. Specifically, an amorphous solid form with a relatively high glass transition temperature (T g ) shows better physical stability than an amorphous solid form with a substantially identical XRPD halo and a lower T g .

[0129] In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 15%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 14%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 13%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 12%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 11%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 10%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 9%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 8%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 7%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 6%. In some embodiments, the solid forms of the present disclosure are characterized by a crystallinity of less than 5%. In some embodiments, the solid forms of the present 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 method for producing the solid form of compound (I) In some embodiments, the present disclosure provides a method for producing the solid form of compound (I) described herein, comprising spray drying a solution of compound (I).

[0131] In some embodiments, the present disclosure provides 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, wherein 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 basic impurities that are more soluble than compound (I). In some embodiments, removing the first aqueous layer removes basic impurities that are more polar than compound (I). In some embodiments, the basic impurities have the following structures:

Chemical formula

[0133] The following structure:

Chemical formula

[0134] The following structure:

Chemical formula

[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 solution with a pH of 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 alkyl acetate, methyl tetrahydrofuran, toluene, methyl cyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and 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, by removing the second organic layer, impurities less water-soluble than compound (I) are removed. In some embodiments, removing the second organic layer removes impurities less polar than compound (I).

[0141] In some embodiments, the impurities removed together with the second organic layer have the following structure:

Chemical formula

[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 with a pH of 3.

[0143] In some embodiments, the method 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, wherein the third organic layer contains compound (I); extracting the third aqueous layer using a third organic solvent; and further concentrating the third organic layer.

[0144] In some embodiments, the first base is an aqueous base solution. In some embodiments, the aqueous base solution 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 alkyl acetate, methyltetrahydrofuran, toluene, methylcyclopentyl ether, methyl tert-butyl ether, pentanone, acetone, acetonitrile, and 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 antisolvent to the third organic layer to form a precipitate comprising compound (I). In some embodiments, the antisolvent comprises at least one of hexane, heptane, and octane. In some embodiments, the antisolvent is n-hexane. In some embodiments, the antisolvent is n-heptane. In some embodiments, the antisolvent is n-octane.

[0147] In some embodiments, the antisolvent is added at a temperature from -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 method utilizes at least one of the parameters described in Table 1 below.

[0152] [Table 1]

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

[0154] In some embodiments, spray drying the fourth solution includes passing the fourth solution through a spray drying chamber having an outlet temperature of 25°C to 80°C. In some embodiments, the spray drying chamber has an outlet temperature of 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 in that the mass loss from 20°C to 240°C by thermogravimetric analysis is less than 5 wt%. In some embodiments, the method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 240°C by thermogravimetric analysis is less than 3 wt%. In some embodiments, the method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 240°C by thermogravimetric analysis is less than 2 wt% and provides a solid form of compound (I) characterized in that the mass loss from 20°C to 240°C by thermogravimetric analysis is less than 1.5 wt%.

[0156] In some embodiments, the method provides a stable solid form of compound (I) characterized in that the glass transition temperature (T g ) at a relative humidity of 0% is higher than 90°C.

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

[0158] In some embodiments, the method provides a solid form of compound (I) characterized by having a D 10 value of from 5 μm to 6 μm in wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized by having a D 50 value of from 10 μm to 20 μm in wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized by having a D 90 value of from 10 μm to 50 μm in wet particle size distribution.

[0159] In some embodiments, the method provides a solid form of compound (I) characterized by having a D 10 value of from 5 μm to 6 μm and a D 50 value of from 10 μm to 20 μm in wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized by having a D 10 value of from 5 μm to 6 μm and a D 90Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D value of 10 μm to 20 μm and a D value of 10 μm to 50 μm in the wet particle size distribution. 50 Provided is a solid form of compound (I) characterized by having a value and a D value of 10 μm to 50 μm. 90

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

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

[0162] In some embodiments, the method provides a solid form of compound (I) substantially free of decomposition products. In some embodiments, the method provides a solid form of compound (I) substantially free of dimers of compound (I). In some embodiments, the method has the following structure:

Chemical formula

[0163] ​In some embodiments, the method provides a solid form of compound (I) in which the 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 no detectable residual solvent is present 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) in which the amount of residual dichloromethane is less than 1500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1000 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 100 ppm.

[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 a solid form of compound (I) In some embodiments, the present disclosure provides a method for producing a solid form of compound (I), the method comprising adding a base to an aqueous solution containing compound (I). In some embodiments, the base is an aqueous base solution. In some embodiments, the base is an aqueous potassium hydroxide solution.

[0168] In some embodiments, the present disclosure provides a method for manufacturing a solid 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, wherein the solution of compound (I) comprises a first organic solvent. Forming; and removing the first aqueous layer.

[0169] In some embodiments, the first acidic aqueous solution has a pH of from 1 to 6. In some embodiments, the first acidic aqueous solution has a pH of from 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-hydrating organic solvent. In some embodiments, the at least one non-hydrating 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 basic impurities that are more soluble than compound (I). In some embodiments, removing the first aqueous layer removes basic impurities that are more polar than compound (I). In some embodiments, the basic impurity has the following structure:

Chem.

[0172] The following structure:

Chem.

[0173] The following structure: [Chemical formula] Comprising at least one of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)penta-nitrile, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the method further comprises: partially removing a first organic solvent from the first organic layer; adding a second organic solvent to the first organic layer, wherein 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 comprising a second organic layer and a second aqueous layer, wherein the second aqueous layer contains 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 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 containing Compound (I). In some embodiments, removing 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:

Chemical formula

[0178] In some embodiments, the second base is an aqueous base solution. 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 degradation 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) having the following structure:

Chemical formula

[0181] In some embodiments, the method provides a solid form of compound (I) in which 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 the 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 the 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 no detectable residual solvent is present in the solid form. In some embodiments, the method provides a solid form of compound (I) in which 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 isopropyl acetate is less than 500 ppm; and / or the amount of residual heptane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which no detectable residual methanol is present in the solid form.

[0183] In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1000 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 100 ppm.

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

[0185] In some embodiments, the method provides a solid form of compound (I) characterized in that the average tapped density is greater than 0.5 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized in that the average tapped density is greater than 0.6 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized in that the average tapped density is greater than 0.7 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized in that the average tapped density is greater than 0.8 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized in that the average tapped density is from 0.7 g / cc to 0.9 g / cc.

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

[0187] In some embodiments, the method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value greater than 70 μm. In some embodiments, the method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 50To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 400 μm D 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 200 μm 50 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value, a D greater than 200 μm 50 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 200 μm D 50 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value.

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

[0189] In some embodiments, the method provides a solid form of compound (I) characterized in that the glass transition temperature (T g ) is higher 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 method provides fine particles of compound (I). In some embodiments, the micronization method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value of less than 10 μm. In some embodiments, the method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value of less than 10 μm and a D 50 value of less than 100 μm. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value of less than 10 μm and a D 90 value of less than 200 μm. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value of less than 10 μm, a D 50 value of less than 100 μm and a D 90 value of less than 200 μm.

[0193] In some embodiments, the method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 10 value of from 1 μm to 2 μm. In some embodiments, the method provides a solid form of compound (I) characterized in that the wet particle size distribution has a D 50To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 100 μm to 150 μm 90 To provide a solid form of compound (I) characterized by having a value.

[0194] In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 40 μm to 70 μm 50 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 100 μm to 150 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 40 μm to 70 μm 50 value and a D of 100 μm to 150 μm 90 To provide a solid form of compound (I) characterized by having a value.

[0195] In some embodiments, the solid form of the present disclosure has a D of wet particle size distribution from 1 μm to 2 μm 10 value, a D of 40 μm to 70 μm 50 value and a D of 100 μm to 150 μm 90 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 thermogravimetric analysis from 20 °C to 240 °C. In some embodiments, the micronization 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 micronization 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 micronization 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.

[0197] In some embodiments, the present disclosure provides a method for producing a solid 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, wherein 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-hydrating organic solvent. In some embodiments, the at least one non-hydrating organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyl tetrahydrofuran, and isopropyl acetate. In some embodiments, the first organic solvent is dichloromethane.

[0200] In some embodiments, by removing the first aqueous layer, basic impurities more soluble than compound (I) are removed. In some embodiments, by removing the first aqueous layer, basic impurities more polar than compound (I) are removed. In some embodiments, the basic impurity has the following structure:

Chem.

[0201] The following structure:

Chem.

[0202] The following structure:

Chem.

[0203] In some embodiments, the method comprises adding a first organic acid to a 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, wherein the third aqueous layer contains compound (I) and the first organic solvent and the third organic solvent are not the same; and further 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 solution. 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 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 containing compound (I). In some embodiments, removing residual organic solvent in the third aqueous phase comprises distillation under reduced pressure.

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

[0210] In some embodiments, the impurities removed together with the third organic layer have the following structure:

Chemical formula

[0211] In some embodiments, the second base is an aqueous base solution. 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 degradation 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) having the following structure:

Chemical formula

[0214] In some embodiments, the method provides a solid form of compound (I) in which 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 the 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 the 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 no detectable residual solvent is present in the solid form. In some embodiments, the method provides a solid form of compound (I) in which 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 isopropyl acetate is less than 500 ppm; and / or the amount of residual heptane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which no detectable residual methanol is present in the solid form.

[0216] In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1000 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 100 ppm.

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

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

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

[0220] In some embodiments, the method provides a solid form of compound (I) characterized by having a wet particle size distribution with a D 10 value greater than 70 μm. In some embodiments, the method provides a solid form of compound (I) characterized by having a wet particle size distribution with a D 50To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 400 μm D 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 200 μm 50 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value, a D greater than 200 μm 50 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 200 μm D 50 value and a D greater than 400 μm 90 value.

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

[0222] In some embodiments, the method provides a solid form of compound (I) characterized in that the glass transition temperature (T g ) is higher 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 method provides fine particles of compound (I). In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm in the wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm and a D 50 value of less than 100 μm in the wet particle size distribution. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm and a D 90 value of less than 200 μm in the wet particle size distribution. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm, a D 50 value of less than 100 μm and a D 90 value of less than 200 μm in the wet particle size distribution.

[0226] In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 10 value of from 1 μm to 2 μm in the wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 50Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 100 μm to 150 μm 90 Provided is a solid form of compound (I) characterized by having a value.

[0227] In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 50 value from 40 μm to 70 μm. Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 90 value from 100 μm to 150 μm. Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 40 μm to 70 μm 50 value and a D of 90 value from 100 μm to 150 μm.

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

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

[0230] In some embodiments, the present disclosure provides a method for producing a solid form of compound (I), the method comprising washing a solution containing compound (I) and an organic solvent with an aqueous solution of a weak organic acid having a pKa of 7 or less (≦7) to form a first organic layer and a first aqueous layer; and removing the first aqueous layer while leaving the first organic layer containing compound (I).

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

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

[0233] In some embodiments, removing the first aqueous layer removes basic impurities less polar than compound (I). In some embodiments, the basic impurity has the following structure:

Chemical formula

[0234] The following structure: [Chemical formula] 2-Methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanol having the following structure, or a pharmaceutically acceptable salt thereof; Pyrrolidine; and

[0235] The following structure: [Chemical formula] Comprising at least one of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)penta-nitrile having the following structure, or a pharmaceutically acceptable salt thereof.

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

[0237] In some embodiments, the strong acid comprises methanesulfonic acid. In some embodiments, the strong acid is methanesulfonic acid.

[0238] In some embodiments, concentrating the first organic layer includes distillation under reduced pressure.

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

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

[0241] In some embodiments, the method further comprises cooling the residue containing 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 containing compound (I) with water or an aqueous salt solution. In some embodiments, the aqueous salt solution is an aqueous solution of sodium chloride.

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

[0244] In some embodiments, the non-hydrating 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 of from 1 to 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 solution is an aqueous solution of an inorganic base. In some embodiments, the aqueous base solution 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 includes 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 the weak organic acid having a pKa of 7 or less to 0 wt% to 8 wt%.

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

[0251] In some embodiments, adjusting the amount includes adding additional weak organic acid. In some embodiments, adjusting the amount includes adding additional acetic acid.

[0252] In some embodiments, the method further includes adding an aqueous base solution to the first or second aqueous layer to adjust the pH to 8 to 11 to form a precipitate containing compound (I).

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

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

[0255] In some embodiments, the precipitate containing compound (I) is formed at 20 °C for at least 3 hours.

[0256] In some embodiments, the method further includes isolating the precipitate containing compound (I) by filtration and washing the isolated precipitate containing compound (I) with water.

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

[0258] In some embodiments, drying the filtered and washed precipitate comprising compound (I) includes drying under reduced pressure with a trace amount of heat. In some embodiments, drying the filtered and washed precipitate comprising the compound includes drying under reduced pressure with a trace amount of heat at 25°C.

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

[0260] In some embodiments, prior to filtering, the isolated precipitate is slurried with water at 15°C for at least 1 hour. In some embodiments, filtering includes drying under reduced pressure with a trace amount of heat. In some embodiments, filtering includes drying under reduced pressure with a trace amount of 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 has the following structure:

Chemical formula

[0262] In some embodiments, the method provides a solid form of compound (I) in which 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 the 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 the 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 no detectable residual solvent is present in the solid form. In some embodiments, the method provides a solid form of compound (I) in which 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 isopropyl acetate is less than 500 ppm; and / or the amount of residual heptane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which no detectable residual methanol is present in the solid form.

[0264] In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 1000 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) in which the amount of residual dichloromethane is less than 100 ppm.

[0265] In some embodiments, the method provides a solid form of compound (I) characterized by an average bulk density greater than 0.3 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average bulk density greater than 0.4 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average bulk density greater than 0.5 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average bulk density greater than 0.6 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average bulk density from 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 tapped density greater than 0.5 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average tapped density greater than 0.6 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average tapped density greater than 0.7 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average tapped density greater than 0.8 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by an average tapped density from 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 provides a solid form of compound (I) characterized by a wet particle size distribution having a D 10 value greater than 70 μm. In some embodiments, the method provides a solid form of compound (I) characterized by a wet particle size distribution having a D 50To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 400 μm D 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 200 μm 50 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value, a D greater than 200 μm 50 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 70 μm D 10 value and a D greater than 400 μm 90 To provide a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution greater than 200 μm D 50 value and a D greater than 400 μm 90 value. To provide a solid form of compound (I).

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

[0270] In some embodiments, the method provides a solid form of compound (I) characterized in that the glass transition temperature (T g ) is higher 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 method provides fine particles of compound (I). In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm in the wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm and a D 50 value of less than 100 μm in the wet particle size distribution. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm and a D 90 value of less than 200 μm in the wet particle size distribution. In some embodiments, the micronization method provides a solid form of compound (I) characterized in that it has a D 10 value of less than 10 μm, a D 50 value of less than 100 μm and a D 90 value of less than 200 μm in the wet particle size distribution.

[0274] In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 10 value of 1 μm to 2 μm in the wet particle size distribution. In some embodiments, the method provides a solid form of compound (I) characterized in that it has a D 50Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 100 μm to 150 μm 90 Provided is a solid form of compound (I) characterized by having a value.

[0275] In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 40 μm to 70 μm 50 Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a D of wet particle size distribution from 1 μm to 2 μm 10 value and a D of 100 μm to 150 μm 90 Provided is a solid form of compound (I) characterized by having a value. In some embodiments, the method has a wet particle size distribution with a D of 40 μm to 70 μm 50 value and a D of 100 μm to 150 μm 90 Provided is a solid form of compound (I) characterized by having a value.

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

[0278] Conversion method for producing a solid form of compound (I) In some embodiments, the present disclosure provides a method for producing a solid form of compound (I), comprising dissolving the crystalline form of the compound in a solution containing a non-hydrating organic solvent and brine; 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 of 8 to 11 to obtain a precipitate of the solid form of compound (I); isolating the precipitate of the solid form of the compound by filtration; washing the precipitate with water; and drying the precipitate to obtain the solid form of compound (I).

[0279] In some embodiments, the non-hydrating organic solvent contains dichloromethane. In some embodiments, the non-hydrating organic solvent is dichloromethane.

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

[0281] In some embodiments, concentrating the aqueous layer includes distillation under reduced pressure. In some embodiments, concentrating the aqueous layer includes distillation under reduced pressure at a temperature of 0°C to 5°C.

[0282] In some embodiments, the residual organic solvent is removed by concentrating the aqueous layer.

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

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

[0285] In some embodiments, drying the precipitate includes drying under reduced pressure with a small amount of heat. In some embodiments, drying the precipitate includes drying under reduced pressure with a small amount of 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 in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 5% by weight. In some embodiments, the method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 4% by weight. The method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 3% by weight. The method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 2% by weight. The method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 1.5% by weight. The method provides a solid form of compound (I) characterized in that the mass loss from 20°C to 200°C by thermogravimetric analysis is less than 1% by weight. ​

[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 for treating 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 for treating pemphigus vulgaris. In some embodiments, the solid forms of compound (I) described herein are used for treating pemphigus foliaceus.

[0291] Pemphigus is a rare B cell-mediated autoimmune disease that causes erosive intraepithelial eruptions and blisters in the skin and / or mucous membranes. Pemphigus has a 10% mortality rate, generally due to infection from skin lesions and side effects of treatment, and affects approximately 0.1 to 0.5 per 100,000 people per year (Scully et al., 2002; Scully et al., 1999). The characteristic intraepithelial eruptions seen in pemphigus patients are caused by IgG autoantibodies binding to specific keratinocyte desmosomal adhesion proteins, namely desmoglein 1 and 3 (Dsg1 and Dsg3), which reduces cell adhesion (Amagai M et al., 2012; Diaz LA et al., 2000). B cells play an important role in the production 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 platelet destruction mediated by autoantibodies and decreased platelet production, resulting in thrombocytopenia and bleeding that can lead to morbidity and death. There is initial evidence supporting the role of BTK inhibition in patients with autoimmune cytopenia in whom the onset of severe autoimmune hemolytic anemia and consecutive episodes of ITP stopped after initiation of treatment with ibrutinib, a BTK / EGFR / ITK inhibitor, in patients with chronic lymphocytic leukemia (CLL) (Rogers 2016, Montillo 2017).

[0294] Pharmaceutical composition The solid forms described herein contain an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable excipients and are useful as materials for manufacturing pharmaceutical compositions suitable for administration to human subjects. 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 pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable" in the sense that it is compatible with the composition in question and its components are not harmful to the patient. The use of any conventional pharmaceutically acceptable excipient is considered to be within the scope of the present disclosure if it is not compatible with compound (I), e.g., does not produce any undesirable biological effects or interact in an undesirable way with any other component of the pharmaceutically acceptable composition.

[0296] Some non-limiting examples of materials that function as pharmaceutically acceptable excipients include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) carboxymethylcellulose sodium, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (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) 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) buffering agents 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 buffer solution; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0297] Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, edited by D.B. Troy, Lippincott Williams & Wilkins, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York, each of which is incorporated herein by reference, also disclose pharmaceutically acceptable excipients and known techniques for their manufacture and use.

[0298] The pharmaceutical compositions disclosed herein are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implantation reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intraliver, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the disclosure are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions of the disclosure is an aqueous or oily suspension. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation 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. Acceptable media and solvents employed include water, Ringer's solution, and isotonic sodium chloride solution. Also, a sterile fixed oil is usually employed as the solvent or suspending medium.

[0299] For this purpose, any sterile fixed oil containing synthetic mono- or diglycerides is employed. Fatty acids such as oleic acid and its glyceride derivatives, particularly in the form of their polyoxyethylated compounds, are useful in the manufacture of injectables similar to natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersing agents such as carboxymethyl cellulose or similar dispersing agents widely used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other widely used surfactants such as Tweens, Spans, and other emulsifiers or biologically available enhancers widely used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms are also used for the purpose of formulation.

[0300] The pharmaceutical compositions disclosed herein are administered orally in any orally acceptable dosage form including, without limitation, capsules, tablets, aqueous suspensions or solutions. When an aqueous suspension is required for oral use, the active ingredient is usually combined with an emulsifying agent and a suspending agent. If desired, certain sweetening, flavoring or coloring agents may be 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 they melt in the rectum and release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0302] The pharmaceutical compositions of the present disclosure are also administered topically, particularly when the therapeutic target is an area or organ that is readily accessible by topical administration, including cases of diseases of the eye, skin or lower intestinal tract. Suitable topical formulations for each of these areas or organs are readily prepared. Topical administration for the lower intestinal tract is effected by rectal suppositories or suitable enemas. Topical transdermal patches are also used.

[0303] For topical administration, the pharmaceutical composition is formulated into a suitable ointment containing 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 compositions disclosed herein are formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in at least one pharmaceutically 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 composition of the present disclosure is also administered by nasal aerosol or inhalation. The composition is manufactured by techniques well known in the art of pharmaceutical formulations and employs benzyl alcohol or other suitable excipients, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents and is manufactured as a solution in physiological saline.

[0305] Dosage Generally, the solid forms of compound (I) are administered in a therapeutically effective amount by any of the acceptable modes of administration of agents that exhibit similar beneficial properties. The effective dosage for any particular mammal (e.g., any particular human) will depend on a variety of factors including the disorder being treated and the severity of the disorder; the specific pharmaceutical composition employed; the age, weight, general health, sex and eating habits of the mammal; the time of administration, 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 divided doses. Suitable dosage levels are from 0.01 to 250 mg / kg per day, from 0.05 to 100 mg / kg per day or from 0.1 to 50 mg / kg per day. In some embodiments, within this range, the dosage can be from 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 tablets containing from 1.0 to 1000 milligrams of the active ingredient, e.g., 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient.

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

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

[0308] Claims or specification passages that include "or" or "and / or" between at least one member of a group are considered satisfied when one, two or more, 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 meaning or some other meaning. The present disclosure includes embodiments where only one member is present in, employed in, or relevant to a given product or method. The present disclosure includes embodiments where two or more or all of the group members are present in, employed in, or relevant to a given product or method.

[0309] Further, the present disclosure includes all modifications, combinations, and rearrangements in which at least one limitation, element, term, and descriptive term from at least one of the recited claims is introduced into another claim. For example, any claim that depends on another claim is modified to include at least one limitation found in any other claim that depends on the same basic claim. When elements are presented as a list, for example in Markush group form, each subgroup of those elements is also disclosed, and any element is excluded from the group. Generally, when the present disclosure or an aspect of the present disclosure is considered to include a particular element and / or feature, it should be understood that embodiments of the present disclosure or an aspect of the present disclosure consist of or consist essentially of that element and / or feature. For the purpose of brevity, those embodiments are not specifically described verbatim in the specification. When ranges are indicated, endpoints are included. Also, unless the context and the understanding of those skilled in the art suggest or indicate otherwise, values expressed as ranges are to be construed as including any specific value or sub-range within the scope of the description in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0310] One of ordinary skill 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. Such equivalents are intended to be encompassed by the following claims.

Examples

[0311] The following examples are intended to be illustrative and are in no way intended to limit the scope of the present disclosure.

[0312] The synthetic schemes described below are intended to provide general guidance regarding 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] Abbreviations: 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

Example

[0314] Spray drying method A (Prepared according to Example 31 on pages 86 - 87 of WO2014 / 039899) A solution of compound (I) in dichloromethane was washed with a phosphate buffer at pH 3 to remove basic impurities having higher solubility in the aqueous layer than compound (I). Subsequently, the dichloromethane solution was washed with a buffer at pH 7, and the solvent was exchanged with isopropyl acetate. Then, the isopropyl acetate solution was washed with a phosphate buffer at pH 3, compound (I) was taken into the aqueous layer, and non - basic impurities were removed. The pH of the aqueous layer was adjusted to pH 9 with 10% sodium hydroxide, and the aqueous layer was extracted with isopropyl acetate. It was concentrated under vacuum, compound (I) was precipitated from heptane at 0 °C, filtered, and dried to obtain a white amorphous solid as a mixture of (E) isomer and (Z) isomer as wet compound (I). Wet compound (I) was dissolved in methanol and spray - dried with the inlet temperature of the dryer set at 125 °C to 155 °C and the outlet temperature of the dryer set at 48 to 58 °C to obtain the free base of stable amorphous compound (I) with the amounts of isopropyl acetate and heptane being less than 0.5% and less than 0.05% respectively.

Example

[0315] Spray - drying method B

Chem.

[0316] After adding acetic acid (2.0 equivalents) to the reactor at 0 °C to 5 °C, water (5 equivalents) was added. Stirring was continued at 0 °C to 5 °C for 1 to 1.5 hours. Water (10 equivalents) 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 two-phase mixture was stirred for 15 to 20 minutes. Stirring was stopped and the phases were allowed to separate for at least 0.5 hours. 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 at 0 to 5 °C for 1 to 1.5 hours. Stirring was stopped and the phases were allowed to separate for at least 0.5 hours. The lower aqueous layer was removed.

[0318] A solution of about 9% of NaHCO3 (1 volume) and the organic layer were added to a jacketed reactor equipped with a top stirrer, condenser, nitrogen piping, temperature probe and recirculating liquid cooler / heater. The internal temperature was adjusted to 20 °C to 25 °C and the two-phase mixture was stirred for 15 to 20 minutes. Stirring was stopped and the phases were allowed to separate for at least 0.5 hours. The lower aqueous layer was removed. When the lower aqueous layer was measured, the pH exceeded 7.

[0319] The organic layer was added to a jacketed reactor equipped with a top stirrer, condenser, nitrogen piping, temperature probe and recirculating liquid 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. A phosphate buffer solution with a pH of 2.3 was added to the reactor at an internal temperature of 20 °C to 25 °C following water (15 volumes). The pH was adjusted to 3. Stirring was stopped and the phases were allowed to separate for at least 0.5 hours. The organic phase was removed.

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

[0321] IPAC (15 volumes) was added to a reactor containing an aqueous layer. A phosphate buffer solution with a pH of 10 was added to the reactor, and the pH was adjusted to 10 with a 14% NaOH solution. Stirring was continued for 1.5 to 2 hours. Stirring was stopped, and the phases were separated over at least 0.5 hours. The aqueous layer was discarded. The organic layer was dried with 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 volumes) was added to a jacketed reactor equipped with a top stirrer, condenser, nitrogen piping, temperature probe, and recirculating liquid cooler / heater. The internal temperature was adjusted to 0 to 5 °C, and an IPAC solution was added.

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

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

Example

[0326] Precipitation Method A (Prepared according to Example 31 on pages 86 - 87 of WO2014 / 039899) The solution of compound (I) in dichloromethane was quenched with acetic acid and water, then washed with an aqueous solution at pH 3 to remove basic impurities that are more soluble in the aqueous layer than compound (I). The washing was repeated if necessary to reduce the impurities. Methanesulfonic acid was added to the dichloromethane solution, and the dichloromethane solution was concentrated by distillation under reduced pressure. Then, 1% aqueous NaCl solution and isopropyl acetate were added, and 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 if necessary to reduce related substance impurities. Residual isopropyl acetate was removed by distillation under reduced pressure. The aqueous solution containing compound (I) was cooled from 0 to 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. Then, the temperature of the mixture was adjusted from 20 °C to 25 °C, and it was confirmed that the hydrate impurity was less than 0.3% (<0.3%). The cake of the free base of compound (I) was filtered and washed if necessary to reduce the conductivity. Then, the cake was dried on the filter under vacuum, purged with nitrogen, and the water content by Karl Fischer was reduced (KF < 50%), and then transferred to an oven for drying. The wet cake of the free base of compound (I) was dried at 25 °C under vacuum until the water content by Karl Fischer was less than 1.5% (KF < 1.5%), and then deagglomerated by grinding to produce a uniform white amorphous solid as a mixture of (E) isomer and (Z) isomer in which no detectable amount of isopropyl acetate or heptane is present.

Example

[0327] Precipitation Method B (Prepared according to Example 31 on pages 86 - 87 of WO2014 / 039899) A solution of compound (I) in dichloromethane was quenched with acetic acid and water, and then washed with an aqueous solution at pH 3 to remove basic impurities that are more soluble in the aqueous layer than compound (I). The washing was repeated if necessary to reduce residual solvents and impurities. Subsequently, the dichloromethane solution was washed with saturated sodium bicarbonate (pH > 7). After removing dichloromethane by distillation under reduced pressure, water and isopropyl acetate were added. The pH of the aqueous layer was adjusted to 2.8 - 3.3 with a 2M aqueous sulfuric acid (H2SO4) solution at 0 - 5 °C, the mixture was stirred and allowed to settle. After removing the organic layer by phase separation, 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 a 5% aqueous KOH solution to form a slurry. The resulting suspension was stirred, warmed from 20 °C to 25 °C, and aged for 20 hours. The product was filtered, washed with water, and dried to obtain a white solid in 86% yield.

Example

[0328] Precipitation method C (Manufactured according to Example 31 on pages 86 - 87 of WO2014 / 039899) The solution of compound (I) in dichloromethane was quenched with acetic acid and water, then washed to remove basic impurities with higher solubility in the aqueous layer than compound (I). The washing was repeated if 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°C and then washed with an aqueous solution of sodium chloride. The organic phase was discarded. The washing of the aqueous layer with dichloromethane was repeated if necessary to remove a low amount of impurities. The pH of the aqueous solution was adjusted to about 3 with an aqueous solution of potassium hydroxide. The 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 from 0 wt% to 8 wt%. When the acidic aqueous solution was washed with an aqueous solution of sodium bicarbonate or another aqueous solution of an inorganic base, the amount of acetic acid was 0 wt%. Optionally, additional acetic acid was added to obtain an acetic acid amount of 0 wt% to 8 wt%. An aqueous solution of potassium hydroxide was continuously added to the aqueous solution to adjust 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. Then, the wet cake was dried under reduced pressure with a small amount of heat. Alternatively, instead of washing the wet cake with water, the wet cake was reslurried with 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 a small amount of heat at 25°C.

[0329] Figures 12 to 15 are examples of SEM images showing the change in the morphology of the particles of compound (I) during the filtration step of isolating compound (I) based on the amount of acetic acid added during the initial step 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). The filtration rate was affected by the morphology and was the highest when the acetic acid was 0 wt%. When the acetic acid was 1 wt%, the filtration rate decreased significantly, and when the acetic acid was from 2 wt% to 3 wt%, it improved. For morphologies with more open pores (e.g., more porous particles), the filtration rate improved, while for denser particles, the filtration rate decreased.

Example

[0330] Conversion of the crystalline form of compound (I) to the 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 an aqueous salt solution. Then, about 1 equivalent of methanesulfonic acid was added. The pH was about 2. The layers were separated. The aqueous layer was concentrated at a temperature from 0 °C to 5 °C to remove the residual dichloromethane, and then an aqueous KOH solution (about 5%) was gradually added to adjust the pH to a value of 9 to 10. When the aqueous KOH solution was added, the amorphous form of compound (I) precipitated. The slurry was gradually warmed to room temperature and then stirred for about 24 hours and then filtered, and the wet cake was washed with water. The wet cake was dried under vacuum with a small amount of heat at about 30 °C to obtain 7 grams of a white or off-white solid (yield 87% and purity 98.4%). By XRPD, the product was shown to be the amorphous solid form of compound (I).

Example

[0331] Micronization of the particles of compound (I) obtained by the precipitation method A fluid jet mill device was used for laboratory-scale jet milling tests. The fluid jet mill device comprises a 1.5-inch diameter flat cylindrical chamber with four symmetric jet nozzles arranged tangentially on the inner wall. Before feeding the material into the fluid jet mill in each test, the material was classified with a 355 μm sieve to remove any aggregates and avoid nozzle clogging during the feeding of the material into the micronization chamber. The material to be processed was drawn into the grinding chamber through a vacuum (0.5 - 1.0 bar higher than P_vent~P_grind) generated by a venturi. The solid feed flow rate (F_feed) was controlled by a manual valve and an infinite screw feeder. Compressed nitrogen was used to inject the feed material; compressed nitrogen was also used for the jet nozzles on the walls of the grinding chamber. The compressed fluid emitted from the nozzle expands from P_grind and imparts a very high rotational speed in the chamber. Thus, the material is accelerated by the rotating and expanding gas and is subject to centrifugal force. The particles move outward and are radially induced inward at a very high speed under the influence of the high-speed jet. The rapidly moving particles affect the slower moving particle path circulating near the periphery of the chamber. Abrasion occurs due to the particles colliding violently with each other. Particles with reduced particle size due to this series of collisions are taken into the circulating gas flow and swept towards the central outlet against the action of the centrifugal force. Larger particles in the gas flow are subject to centrifugal force and are returned to the grinding zone. The fine particles are carried to the outlet by the exhaust gas and move from the grinding chamber into the collector. The feeder has a continuous feed rate control function, but in order to control the feed rate more precisely, the entire range of the feed rate was arbitrarily divided into 10 positions. To calibrate F_feed, the feeder was disconnected from the grinding chamber, and 10 g of the powder of compound (I) was fed through a feeder operating at each feed rate position. The mass of the powder flowing through the feeder over 6 minutes was recorded. The obtained 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 container, and the grinding chamber was inspected to examine the powder accumulation.

[0332] ​

[0333]

Table 2

Examples

[0334] Residual solvent amount The retention of the process solvent (i.e., the residual solvent) is specific to each molecule and is determined by the van der Waals forces, which are the unique properties of each molecule. In addition, the retention of the solvent is determined by how the solid API is formed, isolated, washed, and dried (i.e., the manufacturing process). Since residual solvents may pose a safety risk, the formulation method needs to be designed to minimize the amount of residual solvent (e.g., such that the amount of residual solvent is less than the limit defined in the ICH guidelines).

[0335] The analysis of residual solvents was carried out by gas chromatography / mass spectrometry. The amounts of residual solvents in the solid forms of compound (I) produced by the spray drying method described herein and the precipitation method described herein are shown in Table 2. The amounts of residual solvents in the crude compound (I) listed in Table 2 are equivalent to those in the 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 the solid form of compound (I) produced substantially according to the method detailed in step 1A of Example 1 of WO2015 / 127310. Comparative control 2 corresponds to the solid form of compound (I) produced substantially according to the method detailed in Example 31 of WO2014 / 039899.

[0338] The stirring speed was set at 2200 rpm, and the wet particle size distribution was measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer. Heptane containing 0.2% by volume of Span80 was used as the dispersant. To obtain the distribution measurement values, the dispersant was filled and adjusted in a Hydro MV medium volume automatic dispersion unit. Then the background was measured. A sample of 80 to 100 mg was weighed into a 20 mL vial, and approximately 3 mL of the dispersant was added thereto. The obscuration was adjusted from 5% to 16% and the mass was adjusted based on the particle size. The entire sample was added to the Hydro MV unit, and the sample was analyzed 5 times after a pre-measurement delay of 160 seconds. The analysis time was 20 seconds (10 seconds with a red laser and 10 seconds with a blue laser), and no delay was caused between measurements. The obtained data was processed using the Mie theory with a refractive index of 1.69 and an absorption coefficient of 0.1 for the sample, using a general-purpose model with normal sensitivity and a non-spherical particle type. Fifteen sets of raw data were averaged to obtain an inclusive average representing the average value of the sample. If the sample was determined to be inconsistent, further adjustments were examined to determine which results were irregular. All irregular results were discarded. The sample was thoroughly mixed before sampling (for example, some samples were aliquoted using a rotary riffler).

[0339] [Table 4]

Example

[0340] Measurement of average bulk density, average tapped density and Hausner ratio Using a modified method based on USP<616>, the bulk density and the tapped density were measured. The powder was placed into a clean, dry, pre-weighed 25 mL cylinder. Without compressing the sample, the powder was added such that the total volume was between 20 mL and 25 mL. The mass of the powder and the initial volume (V0) were recorded. The bulk density was measured as the average value of the mass with respect to the initial volume of multiple samples. To measure the tapped density, the samples were lightly tapped using a Copley JV2000 tapped density tester with sets of the following number of taps: 500, 750, and from 1250 to 10,000 taps. After each set of taps, the volume was recorded and the samples were lightly tapped until a constant volume (V f ) was reached. The tapped density was measured as the average value of the mass with respect to the constant volume of multiple samples. Each sample was analyzed twice. The Hausner ratio was calculated as the ratio of the initial volume to the constant volume (V0 / V f ).

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

[0342]

Table 5

Example

[0343] Thermogravimetric Analysis Thermogravimetric analysis of the samples was performed using a TA Instruments Q5000 TGA. Examples of TGA thermograms showing the mass loss described below over a similar temperature range are shown in Figures 1 - 6.

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

[0345]

Table 6

Examples

[0346] Thermal analysis of differential scanning calorimetry Modulated differential scanning calorimetry (DSC) analysis was performed using a TA Instruments Q2000 DSC. The sample was heated at 2 °C / min with a temperature modulation parameter of ±0.318 °C (width) in the temperature range from -80 °C to 200 °C. The sample was analyzed using a closed aluminum pan. Examples of DSC thermograms of the solid forms of Compound (I) at a relative humidity (“RH”) of 0% are shown in Figures 7 to 11.

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

[0348]

Table 7

Claims

Claim 1 Compound (I): 【Chemical 1】 A solid form thereof, wherein the average bulk density is greater than 0.3 g / cc. Claim 2 The solid form according to claim 1, wherein the average tapped density is from 0.7 g / cc to 0.9 g / cc. Claim 3 The solid form according to claim 1 or 2, wherein the Hausner ratio is 1.2 or less. Claim 4 The wet particle size distribution has a D value greater than 70 μm １０ The solid form according to any one of claims 1 to 3, characterized by having the value. Claim 5 The wet particle size distribution has a D value greater than 200 μm ５０ The solid form according to any one of claims 1 to 4, characterized by having a value Claim 6 The wet particle size distribution has a D value greater than 400 μm ９０ The solid form according to any one of claims 1 to 5, characterized by having a value Claim 7 The solid form according to any one of claims 1 to 6, wherein the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 5% by weight. Claim 8 The solid form according to any one of claims 1 to 7, wherein the total amount of residual solvent in the solid form is less than 1%. Claim 9 The glass transition temperature (T ｇ ), which is higher than 90°C, of the solid form according to any one of claims 1 to 8. Claim 10 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, the solid form according to any one of claims 1 to 9. Claim 11 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, the solid form according to any one of claims 1 to 10. Claim 12 The solid form according to any one of claims 1 to 11, wherein the amount of residual dichloromethane is less than 1500 ppm. Claim 13 The solid form according to any one of claims 1 to 12, wherein the solid form is substantially amorphous. Claim 14 Compound (I): 【Chemical Formula 2】 in a solid form, wherein the wet particle size distribution has a D value of less than 10 μm １０ for the solid form characterized by having such a value. Claim 15 The wet particle size distribution has a D value of 5 μm to 6 μm or a D value of 1 μm to 2 μm １０ value, and the solid form according to claim 14, characterized in that it has a D value of 1 μm to 2 μm １０ value. Claim 16 The wet particle size distribution has a D value of less than 100 µm ５０ The solid form according to claim 14 or 15, characterized by having a value of Claim 17 The wet particle size distribution has a D value of less than 200 μm ９０ The solid form according to any one of claims 14 to 16, characterized in that it has a value Claim 18 The solid form according to any one of claims 14 to 17, wherein the average bulk density is less than 0.3 g / cc. Claim 19 The solid form according to any one of claims 14 to 18, wherein the average tapped density is less than 0.3 g / cc. Claim 20 The solid form according to any one of claims 14 to 19, wherein the mass loss from 20 °C to 240 °C by thermogravimetric analysis is less than 5% by weight. Claim 21 The solid form according to any one of claims 14 to 20, wherein the total amount of residual solvent in the solid form is less than 1%. Claim 22 The glass transition temperature (T ｇ ) at a relative humidity of 0% is higher than 90°C, and the solid form according to any one of claims 14 to 21 is characterized thereby. Claim 23 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, the solid form according to any one of claims 14 to 22.

24. 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, the solid form according to any one of claims 14 to 23.

25. The amount of residual dichloromethane is less than 1500 ppm, the solid form according to any one of claims 14 to 24.

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

27. A method for producing a solid form of compound (I), Washing a solution containing 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 containing a first organic layer and a first aqueous layer; and Removing the first aqueous layer while leaving the first organic layer containing compound (I) The method as described above.

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) The method according to claim 27, further comprising the above.

29. The method according to claim 27 or 28, further comprising washing the residue containing compound (I) with water or an aqueous salt solution.

30. Adding a non-hydrating organic solvent to obtain a second organic layer and a second aqueous layer containing compound (I); and Removing the second organic layer The method according to claim 29, further comprising the above.

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

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

33. The method according to 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 layer and adjusting the amount of weak organic acid having a pKa of 7 or less to 0 wt% to 8 wt%.

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

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

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

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

38. A method for producing a solid form of compound (I), comprising: dissolving the crystalline form of compound (I) in a solution containing a non-hydrating organic solvent and brine; 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 from 8 to 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). The method as described above.

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

40. 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 containing a first organic layer and a first aqueous layer, wherein the solution of compound (I) contains 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 as described above.

41. washing the first organic layer with a second acidic aqueous solution to form a second solution containing a second organic layer and a second aqueous layer, wherein the second aqueous layer contains compound (I); and removing the second organic layer. The method according to claim 40, further comprising the above steps.

42. adding a first base to the second aqueous layer to form a third solution containing a third organic layer and a third aqueous layer, wherein the third organic layer contains compound (I); extracting the third aqueous layer using a third organic solvent; and concentrating the third organic layer. The method according to claim 41, further comprising the above steps.

43. The method according to claim 42, further comprising adding an antisolvent to the third organic layer to form a precipitate containing compound (I).

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

45. ​ 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 according to claim 44, further comprising the above steps.

46. The method according to claim 45, further comprising micronizing the solid form of compound (I).

47. A pharmaceutical composition comprising The solid form of compound (I) according to any one of claims 1 to 26, and At least one pharmaceutically acceptable excipient The above pharmaceutical composition.

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

49. A method for treating a mammal in need of treatment for pemphigus vulgaris or pemphigus foliaceus, comprising administering to the mammal a therapeutically effective amount of the solid form of compound (I) according to any one of claims 1 to 26.

50. A method for treating a mammal in need of treatment for immune thrombocytopenia, comprising administering to the mammal a therapeutically effective amount of the solid form of compound (I) according to any one of claims 1 to 26.

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