Solid form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-D]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]pento-2-ennitrile

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

[0002] This specification discloses the solid form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]pento-2-ennitrile (compound (I)), a method of using the same, and a method of producing compound (I) including the solid form thereof. The solid form of compound (I) is a Bruton's tyrosine kinase (BTK) inhibitor with a low residual solvent content. [Background technology]

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

[0004] Compound (I), its pharmaceutically acceptable salts, and any of the solid forms thereof inhibit BTK and are useful for treating disorders and conditions mediated by BTK activity. Compound (I) is disclosed in Example 31 of Patent Document 1 and has the following chemical structure: [ka] (In the formula, *The compound has a stereochemical center (C). A procedure for producing an alternative compound (I) is described in Example 1 of Patent Document 2.

[0005] Compound (I) obtained by the procedures described in Patent Documents 1 and 2 contains residual solvent in amounts well exceeding the limits set forth in the International Conference on Harmonisation of Registration of Pharmaceuticals for Human Use ("ICH") guidelines. Generally speaking, manufacturing methods that result in residual solvent amounts near or exceeding the ICH limits are undesirable for producing active pharmaceutical ingredients (APIs).

[0006] The solid form of a bioactive compound such as compound (I) and its pharmaceutically acceptable salts is determined by its solubility, dissociability, true density, solubility, melting point, morphology, compaction behavior, particle size, flow properties, or solid stability. Qualitative and other specific physical, chemical, or pharmaceutical properties are of interest in the pharmaceutical industry, as they are desirable and even necessary for drug development. The solid form of a bioactive compound often determines its ease of manufacture, ease of isolation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and bioavailability in the body.

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

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

[0009] [Patent Document 1] WO2014 / 039899 [Patent Document 2] WO2015 / 127310 [Overview of the project] [Problems that the invention aims to solve]

[0010] Therefore, there is a need for novel solid forms useful for treating disorders and conditions mediated by BTK activity, such as compound (I) and its pharmaceutically acceptable salts, as well as reproducible and scalable methods for producing them. [Means for solving the problem]

[0011] Novel solid forms of compound (I), compositions containing the same, and methods for using and producing the same are disclosed herein. Importantly, in some embodiments, the solid form of compound (I) has a low amount of residual solvent. Furthermore, 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 production, pharmaceutical formulation, pharmacovigilant use, and / or storage. In some embodiments, the novel solid forms disclosed herein do not contain any detectable residual solvent in that solid form. In some embodiments, the solid form is substantially amorphous. Novel methods for producing compound (I) are also disclosed herein.

[0012] Some embodiments of this disclosure relate to a solid form of compound (I) characterized by having an average bulk density greater than 0.3 g / cc. Embodiments of this disclosure relate to a solid form of compound (I) characterized by having a tap density greater than 0.5 g / cc.

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

[0014] Some embodiments of this disclosure describe a wet particle size distribution greater than 70 μm. 10 The present invention relates to the solid form of compound (I) characterized by having a value. Some embodiments of the present disclosure are characterized by having a wet particle size distribution greater than 200 μm. 50 Compound (I) characterized by having a value Regarding body morphology. Some embodiments of this disclosure have a wet particle size distribution greater than 400 μm. 90 This relates to the solid form of compound (I) characterized by having a value.

[0015] Some embodiments of this disclosure are D with a wet particle size distribution of less than 10 μm. 10 The present invention relates to the solid form of compound (I) characterized by having a value. Some embodiments of the present disclosure are of compound (I) having a wet particle size distribution of less than 100 μm. 50 The present disclosure relates to the solid form of compound (I) characterized by having a value. Some embodiments of the present disclosure are of compound (I) having a wet particle size distribution of less than 200 μm. 90 This relates to the solid form of compound (I) characterized by having a value.

[0016] Some embodiments of this disclosure relate to the solid form of compound (I), characterized by having a mass loss of less than 5% by weight from 20°C to 240°C as determined by thermogravimetric analysis. Some embodiments of this disclosure relate to the glass transition temperature (T) at 0% relative humidity. g This relates to the solid form of compound (I), characterized by having a temperature higher than 90°C.

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

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

[0019] Some embodiments of this disclosure relate to a solid form of compound (I) in which the solid form substantially does not contain decomposition products. In some embodiments, the solid form of compound (I) substantially does not contain the dimer of compound (I). In some embodiments, the solid form of compound (I) has the following chemical structure: [ka] It substantially does not contain a dimer of compound (I) having [the specified compound].

[0020] Some embodiments of this disclosure relate to a solid form of compound (I) whose solid form is substantially amorphous.

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

[0022] Some embodiments of this disclosure relate to methods for inhibiting Bruton's tyrosine kinase (BTK) in mammals, comprising administering a therapeutically effective amount of at least one compound (I) in solid form to the mammal. In some embodiments, the solid form of at least one compound (I) is the solid form described herein. Some embodiments of this disclosure relate to methods for treating BTK-mediated diseases in mammals, comprising administering a therapeutically effective amount of at least one compound (I) in solid form to the mammal. 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 immunotoxic thrombocytopenia. In some embodiments, the mammal is human.

[0023] This specification also provides a method for producing 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 includes the step of washing a solution of compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, wherein the solution of compound (I) contains a first organic solvent, and the step of removing the first aqueous layer. In some embodiments, the method further includes the steps of 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, wherein the second aqueous layer contains compound (I). In some alternative embodiments, the method further comprises the steps of: 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 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 comprises the steps of: removing a second organic layer or a third organic layer; removing residual organic solvent in the second aqueous layer or a 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, the method further comprises the step of pulverizing 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 while 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 concentrates the first organic layer by adding a strong acid to the first organic layer and removing the organic solvent to obtain a residue containing compound (I). It also includes gaining.

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

[0029] In some embodiments, the method further includes adding a non-hydrated organic solvent to a 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 includes adjusting the pH of the first or second aqueous layer to a value of 1 to 5 by adding a basic aqueous solution.

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

[0032] In some embodiments, the method further includes adding a basic aqueous solution to a first or second aqueous layer to adjust the pH from 8 to 11 to form a precipitate containing compound (I). 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. In some embodiments, the method further includes drying the filtered and washed precipitate containing compound (I) to obtain a solid form of compound (I). In some embodiments, the method further includes slurring the isolated precipitate with water and filtering to isolate the solid form of compound (I).

[0033] In some embodiments, the method comprises dissolving the crystalline form of compound (I) in a solution containing a non-hydrated 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 a basic aqueous solution to adjust the pH to a value of 8 to 11 to obtain a precipitate of compound (I) in solid form; isolating the precipitate of compound (I) in solid form by filtration; rinsing the precipitate with water; and drying the precipitate to obtain the solid form of compound (I).

[0034] In some embodiments, the method includes the step of spray-drying a solution of compound (I).

[0035] In some embodiments, the method includes the steps of: washing a solution of compound (I) with a first acidic aqueous solution to form a first solution comprising a first organic layer and a first aqueous layer, wherein the solution of compound (I) comprises a first organic solvent; removing the first aqueous layer; and performing solvent exchange from the first organic solvent to a second organic solvent. In some embodiments, the method further includes the steps of: 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 includes the steps of: 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 includes the step of adding a reverse solvent to a third organic layer to form a precipitate containing compound (I). In some embodiments, the method further includes the steps of 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). [Brief explanation of the drawing]

[0036] [Figure 1] This figure shows an example of a combined differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plot for the solid form (comparative control 1 as specified herein) of compound (I), which was prepared substantially according to the method described in Step 1A of Example 1 of WO2015 / 127310. [Figure 2] This figure shows an example of a combined plot of DSC and TGA for the solid form (comparative control 2 in this specification) of compound (I), which was produced substantially according to the method detailed in Example 31 of WO2014 / 039899. [Figure 3]This figure shows an example of a TGA thermal curve for the solid form (comparative control 3 in this specification) of compound (I) produced substantially according to the method detailed in Step 1 of Example 1 of WO2015 / 127310. [Figure 4] This figure shows an example of a TGA thermal curve for the solid form (micronized) of compound (I) produced by the precipitation method described herein. [Figure 5] This figure shows an example of a TGA thermal curve for the solid form (non-micronized) of compound (I) produced by the precipitation method described herein. [Figure 6] This figure shows an example of a TGA thermal curve for the solid form of compound (I) produced by the spray drying method described herein. [Figure 7] This figure shows an example of a modulated DSC (mDSC) thermogram at 0% relative humidity for the solid form of compound (I) (comparative control 1 as specified herein) produced substantially according to the method detailed in Step 1A of Example 1 of WO2015 / 127310. [Figure 8] This figure shows an example of an mDSC thermogram at 0% relative humidity for the solid form (comparative control 2 in this specification) of compound (I), which was prepared substantially according to the method detailed in Example 31 of WO2014 / 039899. [Figure 9] This figure shows an example of an mDSC thermogram at 0% relative humidity for the solid form (comparative control 3 in this specification) of compound (I), which was produced substantially according to the method detailed in Step 1 of Example 1 of WO2015 / 127310. [Figure 10] This figure shows an example of an mDSC thermogram at 0% relative humidity for the solid form (non-micronized) of compound (I) produced by the precipitation method described herein. [Figure 11] This figure shows an example of an mDSC thermogram at 0% relative humidity for the solid form of compound (I) produced by the spray drying method described herein. [Figure 12]It is a figure showing an example of a scanning electron microscope (SEM) image of the filtered particles of compound (I) produced by precipitation with 0 wt% acetic acid (scale bar: 10 μm). [Figure 13] It is a figure showing an example of an SEM image of the filtered particles of compound (I) produced by precipitation with 3 wt% acetic acid. [Figure 14] It is a figure showing an example of an SEM image of the filtered particles of compound (I) produced by precipitation with 5 wt% acetic acid. [Figure 15] It is a figure showing an example of an SEM image of the filtered particles of compound (I) produced by precipitation with 8 wt% acetic acid. [Figure 16] It is a figure showing an example of a combined plot of DSC and TGA for the solid form of compound (I) produced by the conversion method described herein.

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] If compound (I) is represented as (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pento-2-ennitrile, it contains the corresponding (S) optical isomer as an impurity of less than 1% by weight. Therefore, if compound (I) is represented as a mixture of the (R) optical isomer and the (S) optical isomer of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetane-3-yl)piperazine-1-yl]pento-2-ennitrile, then the amount of the (R) or (S) optical isomer in the mixture is greater than 1% by weight. Similarly, if compound (I) is represented as the (E) isomer, it contains the corresponding (Z) isomer as an impurity of less than 1% by weight. Therefore, if compound (I) is represented as a mixture of the (E) and (Z) isomers of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazine-1-yl]pento-2-ennitrile, then the amount of the (E) or (Z) isomer in the mixture is greater than 1% by weight.

[0040] In this specification, compound (I) may also be referred to as a “drug,” “activator,” “therapeutic activator,” or “API.”

[0041] As used herein, "substantially pure" with respect to geometric isomers refers to compounds such as compound (I) in which more than 70% by weight of the compound is present as a predetermined isomer. For example, "the solid form of compound (I) is substantially the (E) isomer of compound (I)" means that the solid form of compound (I) contains at least 70% by weight of the solid form of compound (I) which is the (E) isomer, and "the solid form of compound (I) is substantially the (Z) isomer of compound (I)" means that the solid form of compound (I) contains at least 70% by weight of the solid form of compound (I) which is the (Z) isomer This refers to having at least 70% by weight in solid form. In some embodiments, at least 80% by weight of the solid form of compound (I) is the (E) form, or at least 80% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 85% by weight of the solid form of compound (I) is the (E) form, or at least 85% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 90% by weight of the solid form of compound (I) is the (E) form, or at least 90% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 95% by weight of the solid form of compound (I) is the (E) form, or at least 95% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 97% or 98% by weight of the solid form of compound (I) is the (E) form, or at least 97% or 98% by weight of the solid form of compound (I) is the (Z) form. In some embodiments, at least 99% by weight of the solid form of compound (I) is the (E) 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) means a solid form in which more than 70% by weight of the solid form is the compound in question. For example, "the solid form of compound (I) is substantially pure" means that the solid form of compound (I) constitutes at least 70% by weight of compound (I).

[0043] As used herein, "substantially free of" components in solid form, such as decomposition products (e.g., dimers of compound (I)), means that the component is present in less than 5% by weight of the solid form. The relative amount of a component in solid form is measured by standard methods and techniques known in the art. As used herein, the term "pharmaceutically acceptable salt" refers to the non-toxic salt form of the compound disclosed herein. Suitable pharmaceutically acceptable salts of compound (I) disclosed herein 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, SM et al., J. Pharma. Sci. 66:1~19 (1977). Non-limiting examples of medicinal salts disclosed in the article include: acetate; benzenesulfonate; benzoate; bicarbonate; tartrate; bromide; calcium edetate; cansylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estrate; esylate; fumarate; gluceptate; gluconate; glutamate; glycolyl arsanylate; hexylresorcinate; hydravamin; hydrobromide; hydrochloride; hydroxynaphthoate; iodide; isethionate; lactate; lactobionate; malate; malein Salts; mandelates; mesylates; methyl bromides; methyl nitrates; methyl sulfates; mucinates; napsylates; nitrates; pamoates (embonates); pantothenates; phosphates / diphosphates; polygalactuloses; salicylates; stearates; basic acetates; succinates; sulfates; tannates; tartrates; teosinates; triethiosides; 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 from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by other methods used in the art, such as ion exchange. Further non-limiting examples of pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfonates, and benzoic acid. Examples include salts, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptonates, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfons, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanes, and valersates. Non-limiting examples of pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4Examples of alkyl)4 salts are also included. The disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Non-limiting examples of alkali and alkaline earth metals include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. Other non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0045] As used herein, “pharmaceutically acceptable excipients” refers to single substances or excipients useful for manufacturing pharmaceutical compositions. For example, pharmaceutically acceptable excipients include single substances and excipients that are generally considered safe and acceptable for pharmacochemical use in mammals.

[0046] As used herein, the term “atmospheric conditions” refers to room temperature, open air, and unregulated humidity conditions. As used herein, the terms “room temperature” or “atmospheric temperature” refer to temperatures between 15°C and 30°C.

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

[0048] As used herein, the terms “to treat,” “treating,” or “treatment,” when used in relation to a disorder or condition, include any effect resulting in improvement of the disorder or condition, such as reduction, mitigation, modulation, improvement, or elimination. Improvement or reduction in the severity of any symptom of the disorder or condition can be readily assessed by standard methods and techniques known in the art.

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

[0050] The terms "cc" or "cm" used in this specification refer to... 3 " refers to a cubic centimeter.

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

[0052] In this specification, the term "amount" in "total amount of residual solvent" refers to gas. This refers to the quantity measured by electromagnetism.

[0053] The residual solvent species used herein correspond to those defined in the International Conference on Harmonisation of Technical Requirements for Registration of 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 solvents that should be avoided, according to ICH guidelines. Class 1 solvents include, but are not limited to, known human carcinogens, strongly suspected human carcinogens, and environmental hazards, and include benzene, carbon tetrachloride, 1,2-dichloroethane, and 111-tetrachloroethane.

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

[0056] As used herein, "Class 3 solvent" refers to a solvent with low toxicity to humans, according to ICH guidelines. There are no health-based exposure limits for Class 3 solvents under ICH guidelines. The permissible daily exposure (PDE) for Class 3 solvents is 50 mg per day. According to ICH guidelines, residual Class 3 solvents are permissible without justifiable reason if they are 50 mg per day or less (corresponding to 5000 ppm or 0.5%). Examples of Class 3 solvents include the following: 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 “reverse solvent” refers to any liquid in which the product is insoluble or very sparingly soluble (the solubility of the product is less than 0.01 mol / L).

[0058] As used herein, the term "reverse solvent precipitation" refers to a process in which supersaturation is achieved by adding a reverse solvent to the product solution, thereby inducing precipitation.

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

[0060] As used herein, the term "aqueous layer" refers to a layer containing 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 material whose molecules have long-range order at their positions. This refers to solid materials that do not exhibit a defined arrangement. Amorphous solids are generally supercooled liquids in which molecules are randomly arranged without clearly defined arrangements, such as molecular packing, and without long-range order. For example, amorphous materials are solid materials that do not show sharp characteristic signals in X-ray powder diffraction patterns (i.e., they are not crystalline as measured by XRPD). Instead, one or more broad peaks (e.g., halos) appear in their diffraction patterns. Broad peaks are characteristic of amorphous solids. For a comparison of 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 at the molecular positions. 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” which refers to a material that is non-crystalline (crystallinity of 0%).

[0064] As used herein, the term "DSC" refers to the differential scanning calorimetry analytical method.

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

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

[0067] As will be 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 a value measured by laser diffraction (e.g., D 10 , D 50 and D 90 It is expressed using the value.

[0068] The term "D" used in this specification 50 " refers to the median diameter of the particle size distribution.

[0069] The term "D" used in this specification 10 "This means that 10% of the particle population is D 10 This refers to particle sizes having the following characteristics.

[0070] The term "D" used in this specification 90 "This means that 90% of the particle collection is D 90 This refers to particle sizes having the following characteristics.

[0071] As used herein, "bulk density" refers to the mass of material particles divided by the total volume occupied by the particles. The total volume includes the volume of the particles, the volume of the voids between particles, and the volume of the internal pores. Bulk density is not an inherent property of 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. The total volume includes the volume of the particles, the volume of the voids between the particles, and the volume of the internal pores. Tap density is not an inherent property of 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 powders or powdered materials. The Hausner ratio is the ratio of the bulk density of a material to its tap density.

[0074] Embodiment Without limitation, some embodiments of this disclosure include the following:

[0075] 1. Compound (I): [ka] A solid form characterized by having an average bulk density greater than 0.3 g / cc. 2. The solid form according to Embodiment 1, characterized in that the average bulk density is greater than 0.4 g / cc. 3. The solid form according to Embodiment 1 or 2, characterized in that the average bulk density is greater than 0.5 g / cc. 4. A solid form according to any one of Embodiments 1 to 3, characterized in that its average bulk density is greater than 0.6 g / cc. 5. A solid form according to any one of Embodiments 1 to 4, characterized in that the average bulk density is 0.6 g / cc to 0.7 g / cc. 6. A solid form according to any one of Embodiments 1 to 5, characterized in that the average tap density is greater than 0.5 g / cc. 7. A solid form according to any one of Embodiments 1 to 6, characterized in that the average tap density is greater than 0.7 g / cc. 8. A solid form according to any one of Embodiments 1 to 7, characterized in that the average tap density is greater than 0.8 g / cc. 9. A solid form according to any one of Embodiments 1 to 7, characterized in that the average tap density is 0.7 g / cc to 0.9 g / cc. 10. A solid form according to any one of Embodiments 1 to 9, characterized in that the Hausner ratio is 1.2 or less. 11. D with a wet particle size distribution greater than 70 μm 10 A solid form according to any one of embodiments 1 to 10, characterized by having a value. 12. D with a wet particle size distribution greater than 200 μm 50 A solid form according to any one of embodiments 1 to 11, characterized by having a value. 13. D with a wet particle size distribution greater than 400 μm 90 A solid form according to any one of embodiments 1 to 12, characterized by having a value. 14. A solid form according to any one of Embodiments 1 to 13, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 5% by weight. 15. A solid form according to any one of Embodiments 1 to 14, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 3% by weight. 16. A solid form according to any one of Embodiments 1 to 15, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 2% by weight. 17. A solid form according to any one of Embodiments 1 to 16, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 1.5% by weight. 18. Any of Embodiments 1 to 17 in which the total amount of residual solvent in solid form is less than 1%. The solid form described in one document. 19. The solid form according to any one of Embodiments 1 to 18, wherein the total amount of residual solvent in the solid form is less than 0.5%. 20. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of Embodiments 1 to 19, characterized in that the temperature is higher than 90°C. 21. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of Embodiments 1 to 20, wherein the residual heptane content is less than 5000 ppm. 22. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or A solid form according to any one of Embodiments 1 to 21, wherein the residual heptane content is less than 500 ppm. 23. A solid form according to any one of Embodiments 1 to 22, wherein the amount of residual dichloromethane is less than 1500 ppm. 24. The solid form according to any one of Embodiments 1 to 23, wherein the amount of residual dichloromethane is less than 1000 ppm. 25. The solid form according to any one of Embodiments 1 to 24, wherein the amount of residual dichloromethane is less than 500 ppm. 26. The solid form according to any one of Embodiments 1 to 25, wherein the amount of residual dichloromethane is less than 100 ppm. 27. A solid form according to any one of Embodiments 1 to 23, wherein no detectable residual solvent is present in the solid form. 28. A solid form according to any one of Embodiments 1 to 27, wherein the solid form is substantially amorphous.

[0076] 29. Compound (I): [ka] A solid form characterized by having an average tap density greater than 0.5 g / cc. 30. The solid form according to Embodiment 29, characterized in that the average tap density is greater than 0.6 g / cc. 31. The solid form according to Embodiment 29 or 30, characterized in that the average tap density is greater than 0.7 g / cc. 32. A solid form according to any one of embodiments 29 to 31, characterized in that the average tap density is greater than 0.8 g / cc. 33. A solid form according to any one of embodiments 29 to 32, characterized in that the average tap density is 0.7 g / cc to 0.9 g / cc. 34. A solid form according to any one of embodiments 29 to 33, characterized in that the Hausner ratio is 1.2 or less. 35. D with a wet particle size distribution greater than 70 μm 10 A solid form according to any one of embodiments 29 to 34, characterized by having a value. 36. D with a wet particle size distribution greater than 200 μm 50 A solid form according to any one of embodiments 29 to 35, characterized by having a value. 37. D with a wet particle size distribution greater than 400 μm 90 A solid form according to any one of embodiments 29 to 36, characterized by having a value. 38. A solid form according to any one of embodiments 29 to 37, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 5% by weight. 39. A solid form according to any one of embodiments 29 to 38, characterized in that the mass loss from 20°C to 240°C determined by thermogravimetric analysis is less than 3% by weight. 40. A solid form according to any one of embodiments 29 to 39, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 2% by weight. 41. A solid form according to any one of embodiments 29 to 40, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 1.5% by weight. 42. The solid form according to any one of Embodiments 29 to 41, wherein the total amount of residual solvent in the solid form is less than 1%. 43. The solid form according to any one of Embodiments 29 to 42, wherein the total amount of residual solvent in the solid form is less than 0.5%. 44. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of embodiments 29 to 43, characterized in that the temperature is higher than 90°C. 45. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of embodiments 29 to 44, wherein the residual heptane content is less than 5000 ppm. 46. ​​The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or A solid form according to any one of embodiments 29 to 45, wherein the residual heptane content is less than 500 ppm. 47. A solid form according to any one of embodiments 29 to 46, wherein the amount of residual dichloromethane is less than 1500 ppm. 48. A solid form according to any one of embodiments 29 to 47, wherein the amount of residual dichloromethane is less than 1000 ppm. 49. A solid form according to any one of embodiments 29 to 48, wherein the amount of residual dichloromethane is less than 500 ppm. 50. A solid form according to any one of Embodiments 29 to 49, wherein the amount of residual dichloromethane is less than 100 ppm. 51. Any one of Embodiments 29 to 50 in which no detectable residual solvent exists in solid form. The solid form described below. 52. The solid form according to any one of embodiments 29 to 51, wherein the solid form is substantially amorphous.

[0077] 53.Compound (I): [ka] A solid form characterized by having a Hausner ratio of 1.2 or less. 54. D with a wet particle size distribution greater than 70 μm 10 A solid form according to embodiment 53, characterized by having a value. 55. D with a wet particle size distribution greater than 200 μm 50 A solid form according to embodiment 53 or 54, characterized by having a value. 56. D with a wet particle size distribution greater than 400 μm 90 A solid form according to any one of embodiments 53 to 55, characterized by having a value. 57. A solid form according to any one of embodiments 53 to 56, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 5% by weight. 58. A solid form according to any one of embodiments 53 to 57, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 3% by weight. 59. A solid form according to any one of embodiments 53 to 58, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 2% by weight. 60. A solid form according to any one of embodiments 53 to 59, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 1.5% by weight. 61. The solid form according to any one of embodiments 53 to 60, wherein the total amount of residual solvent in the solid form is less than 1%. 62. The solid form according to any one of embodiments 53 to 61, wherein the total amount of residual solvent in the solid form is less than 0.5%. 63. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of embodiments 53 to 62, characterized in that the temperature is higher than 90°C. 64. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of embodiments 53 to 63, wherein the residual heptane content is less than 5000 ppm. 65. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or A solid form according to any one of embodiments 53 to 64, wherein the residual heptane content is less than 500 ppm. 66. A solid form according to any one of embodiments 53 to 65, wherein the amount of residual dichloromethane is less than 1500 ppm. 67. A solid form according to any one of embodiments 53 to 66, wherein the amount of residual dichloromethane is less than 1000 ppm. 68. A solid form according to any one of embodiments 53 to 67, wherein the amount of residual dichloromethane is less than 500 ppm. 69. The solid form according to any one of embodiments 53 to 68, wherein the amount of residual dichloromethane is less than 100 ppm. 70. A solid form according to any one of embodiments 53 to 69, wherein no detectable residual solvent is present in the solid form. 71. A solid form according to any one of embodiments 53 to 70, wherein the solid form is substantially amorphous.

[0078] 72.Compound (I): [ka] The solid form of which has a wet particle size distribution greater than 70 μm. 10 A solid form characterized by having a value. 73. D with a wet particle size distribution greater than 200 μm 50 A solid form according to embodiment 72, characterized by having a value. 74. D with a wet particle size distribution greater than 400 μm 90 A solid form according to embodiment 72 or 73, characterized by having a value. 75. A solid form according to any one of embodiments 72 to 74, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 5% by weight. 76. A solid form according to any one of embodiments 72 to 75, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 3% by weight. 77. A solid form according to any one of embodiments 72 to 76, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 2% by weight. 78. A solid form according to any one of embodiments 72 to 77, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 1.5% by weight. 79. The solid form according to any one of embodiments 72 to 78, wherein the total amount of residual solvent in the solid form is less than 1%. 80. The solid form according to any one of Embodiments 72 to 79, wherein the total amount of residual solvent in the solid form is less than 0.5%. 81. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of embodiments 72 to 80, characterized in that the temperature is higher than 90°C. 82. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of embodiments 72 to 81, wherein the residual heptane content is less than 5000 ppm. 83. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or A solid form according to any one of embodiments 72 to 82, wherein the residual heptane content is less than 500 ppm. 84. A solid form according to any one of embodiments 72 to 83, wherein the amount of residual dichloromethane is less than 1500 ppm. 85. A solid form according to any one of embodiments 72 to 84, wherein the amount of residual dichloromethane is less than 1000 ppm. 86. A solid form according to any one of embodiments 72 to 85, wherein the amount of residual dichloromethane is less than 500 ppm. 87. Any of embodiments 72 to 86, wherein the residual dichloromethane content is less than 100 ppm. The solid form described in one document. 88. A solid form according to any one of embodiments 72 to 87, wherein no detectable residual solvent is present in the solid form. 89. A solid form according to any one of embodiments 72 to 88, wherein the solid form is substantially amorphous.

[0079] 90.Compound (I): [ka] A solid form of D with a wet particle size distribution of less than 10 μm 10 A solid form characterized by having a value. 91. D with a wet particle size distribution of 5 μm to 6 μm 10 The value, or D from 1 to 2 μm 10 A solid form according to embodiment 90, characterized by having a value. 92. D with a wet particle size distribution of less than 100 μm 50 A solid form according to embodiment 90 or 91, characterized by having a value. 93. D with a wet particle size distribution of less than 200 μm 90 A solid form according to any one of embodiments 90 to 92, characterized by having a value. 94. A solid form according to any one of embodiments 90 to 93, characterized in that the average bulk density is less than 0.3 g / cc. 95. A solid form according to any one of embodiments 90 to 94, characterized in that the average tap density is less than 0.3 g / cc. 96. A solid form according to any one of embodiments 90 to 95, characterized in that the mass loss from 20°C to 240°C determined by thermogravimetric analysis is less than 5% by weight. 97. A solid form according to any one of embodiments 90 to 96, characterized in that the mass loss from 20°C to 240°C determined by thermogravimetric analysis is less than 3% by weight. 98. A solid form according to any one of embodiments 90 to 97, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 2% by weight. 99. A solid form according to any one of embodiments 90 to 98, characterized in that the mass loss from 20°C to 240°C, as determined by thermogravimetric analysis, is less than 1.5% by weight. 100. The solid form according to any one of embodiments 90 to 99, wherein the total amount of residual solvent in the solid form is less than 1%. 101. A solid form according to any one of Embodiments 90 to 100, wherein the total amount of residual solvent in the solid form is less than 0.5%. 102. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of embodiments 90 to 101, characterized in that the temperature is higher than 90°C. 103. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of embodiments 90 to 102, wherein the residual heptane content is less than 5000 ppm. 104. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or The residual heptane content is less than 500 ppm, as described in any one of embodiments 90 to 103. The solid form. 105. A solid form according to any one of embodiments 90 to 104, wherein the amount of residual dichloromethane is less than 1500 ppm. 106. A solid form according to any one of embodiments 90 to 105, wherein the amount of residual dichloromethane is less than 1000 ppm. 107. A solid form according to any one of embodiments 90 to 106, wherein the amount of residual dichloromethane is less than 500 ppm. 108. A solid form according to any one of embodiments 90 to 107, wherein the amount of residual dichloromethane is less than 100 ppm. 109. A solid form according to any one of embodiments 90 to 108, wherein no detectable residual solvent is present in the solid form. 110. A solid form according to any one of embodiments 90 to 109, wherein the solid form is substantially amorphous.

[0080] 111.Compound (I): [ka] A solid form characterized by having a mass loss of less than 5% by weight between 20°C and 240°C, as determined by thermogravimetric analysis. 112. The solid form according to Embodiment 111, characterized in that the mass loss from 20°C to 240°C, as determined 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, as determined by thermogravimetric analysis, is less than 2% by weight. 114. A solid form according to any one of embodiments 111 to 113, characterized in that the mass loss from 20°C to 240°C, as determined 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. Glass transition temperature (T) at 0% relative humidity g A solid form according to any one of embodiments 111 to 116, characterized in that the temperature is higher than 90°C. 118. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or A solid form according to any one of embodiments 111 to 117, wherein the residual heptane content is less than 5000 ppm. 119. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or A solid form according to any one of embodiments 111 to 118, wherein the residual heptane content is less than 500 ppm. 120. A solid form according to any one of embodiments 111 to 119, wherein the amount of residual dichloromethane is less than 1500 ppm. 121. A solid form according to any one of embodiments 111 to 120, wherein the amount of residual dichloromethane is less than 1000 ppm. 122. A solid form according to any one of embodiments 111 to 121, wherein the amount of residual dichloromethane is less than 500 ppm. 123. A solid form according to any one of embodiments 111 to 122, wherein the amount of residual dichloromethane is less than 100 ppm. 124. A solid form according to any one of embodiments 111 to 123, wherein no detectable residual solvent is present in the solid form. 125. A solid form according to any one of embodiments 111 to 124, wherein the solid form is substantially amorphous.

[0081] 126.Compound (I): [ka] The solid form of which, at relative humidity 0%, has a glass transition temperature (T g A solid form characterized by a temperature higher than 90°C. 127. The residual methanol content is less than 3000 ppm; The residual isopropyl acetate content is less than 5000 ppm; and / or The solid form according to Embodiment 126, wherein the residual heptane content is less than 5000 ppm. 128. The residual methanol content is less than 500 ppm; The residual isopropyl acetate content is less than 4000 ppm; and / or The solid form according to embodiment 126 or 127, wherein the residual heptane content is less than 500 ppm. 129. A solid form according to any one of embodiments 126 to 128, wherein the amount of residual dichloromethane is less than 1500 ppm. 130. A solid form according to any one of embodiments 126 to 129, wherein the amount of residual dichloromethane is less than 1000 ppm. 131. A solid form according to any one of embodiments 126 to 130, wherein the amount of residual dichloromethane is less than 500 ppm. 132. A solid form according to any one of embodiments 126 to 131, wherein the amount of residual dichloromethane is less than 100 ppm. 133. A solid form according to any one of embodiments 126 to 132, wherein no detectable residual solvent is present in the solid form. 134. A solid form according to any one of embodiments 126 to 133, wherein the solid form is substantially amorphous. 135. A method for producing compound (I) in solid form, comprising adding a base to an aqueous solution containing compound (I). 136. The method according to Embodiment 135, wherein the base is an aqueous solution of a base. 137. The method according to embodiment 135 or 136, wherein the base is an aqueous solution of potassium hydroxide. 138. A method for producing compound (I) in solid form, 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 Remove the first water layer. A method that includes this. 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 comprises at least one non-hydrateable organic solvent. 143. The method according to Embodiment 142, wherein 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; The second organic solvent is added to the first organic layer, and the first organic solvent and the second organic solvent are not the same; and The method according to any one of Embodiments 138 to 144, further comprising adding a second acidic aqueous solution to form a second solution comprising a second organic layer and a second aqueous layer, wherein the second aqueous layer comprises compound (I). 146. The method according to Embodiment 145, wherein the partial removal of the first organic solvent from the first organic layer includes 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 the first organic acid to the first organic layer; Concentrate 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 furthermore, the first organic solvent and the third organic solvent are not the same; and Add the 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 including the method described above. 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 the first organic layer is concentrated and at least 70% of the first organic solvent is removed by 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 solution of a base. 154. The method according to any one of Embodiments 149 to 153, wherein the first base is an aqueous solution of potassium hydroxide. 155. Remove the second or third organic layer; Removing residual organic solvents from the second or third aqueous layer to form an aqueous solution of compound (I); and The second base is added to an 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 the removal of the organic solvent in the second or third aqueous phase includes distillation under reduced pressure. 157. The method according to Embodiment 155 or 156, wherein the second base is an aqueous solution of a base. 158. The method according to any one of embodiments 155 to 157, wherein the second base is an aqueous solution of potassium hydroxide. 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 is substantially free of 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 compound (I) in solid form, 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 Remove the first aqueous layer while leaving the first organic layer containing compound (I). A method that includes this. 163. The method according to Embodiment 162, wherein the organic solvent comprises at least one non-hydrated organic solvent. 164. The method according to Embodiment 163, wherein the non-hydrated organic solvent is selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, 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 with 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 with a pKa of 7 or less is acetic acid. 168. The method according to any one of embodiments 162 to 167, further comprising washing a first organic layer containing compound (I) with an aqueous sodium bicarbonate solution. 169. Adding a strong acid to the first organic layer; and The first organic layer is concentrated by removing the organic solvent to obtain a residue containing compound (I). The method according to any one of embodiments 162 to 168, further including the method described above. 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 a saline solution. 175. The method according to Embodiment 174, wherein the salt solution is an aqueous solution of sodium chloride. 176. Add a non-hydrated organic solvent to obtain a second organic layer and a second aqueous layer containing compound (I); and Remove the second organic layer. The method according to embodiment 174 or 175, further comprising: 177. The method according to Embodiment 174, wherein the residue containing compound (I) is washed with water or a saline solution one to three times. 178. By adding a basic aqueous solution, the pH of the first or second aqueous layer can be changed to a value between 1 and 5. The method according to any one of embodiments 169 to 177, further comprising adjusting to the following: 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 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 from 0% by weight to 8% by weight. 182. The method according to Embodiment 181, wherein the weak organic acid with a pKa of 7 or less is acetic acid. 183. The method according to Embodiment 181 or 182, further comprising adding a basic aqueous solution to the first or second aqueous layer to adjust the pH from 8 to 11 and forming 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 slurring the isolated precipitate with water and filtering to obtain a solid form of compound (I). 189. A method for producing compound (I) in solid form, Dissolving the crystalline form of compound (I) in a solution containing a non-hydrated organic solvent and saline solution; Add one equivalent of a strong acid to form an aqueous layer and an organic layer; Remove 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) 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 1 to 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 of 0°C to 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 of 9 to 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 solution with a pH of 3. 206. The method according to any one of embodiments 202 to 205, wherein the first organic solvent contains at least one non-hydrated organic solvent. 207. The method according to embodiment 206, 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. 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, methyltetrahydrofuran, toluene, methylcyclopentyl 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 with a pH of 3. 216. Adding a first base to a 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 any one of embodiments 212 to 215, further including the method described above. 217. The method according to Embodiment 216, wherein the first base is an aqueous solution of a base. 218. The method according to Embodiment 217, wherein the aqueous solution of the base 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 solution of potassium hydroxide. 220. The third 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, as in Embodiment 216~ The method described in any one of 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 comprises isopropyl acetate. 223. The method according to any one of embodiments 216 to 222, further comprising adding a reverse solvent to a third organic layer to form a precipitate containing compound (I). 224. The method according to Embodiment 223, wherein the reverse solvent comprises at least one of hexane, heptane, and octane. 225. The method according to Embodiment 223 or 224, further comprising isolating a 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 drying includes 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 The fourth solution is spray-dried to obtain the solid form of compound (I). The method according to any one of embodiments 225 to 227, further including the method described above. 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 is methanol. 231. The method according to any one of Embodiments 228 to 230, wherein the solid form of compound (I) is substantially free of 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 pulverizing the solid form of compound (I). 234. A solid form of compound (I) produced by the method described in 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) described in any one of embodiments 1 to 134, 199, 200, 234, or 235, At least one excipient that is acceptable as a pharmaceutical agent and A pharmaceutical composition containing the following: 237. The pharmaceutical composition according to Embodiment 236, wherein the pharmaceutical composition is in the form of a solid oral composition. 238. The pharmaceutical composition according to embodiment 236 or 237, wherein the pharmaceutical composition is in the form of a tablet or a capsule. 239. A method for inhibiting Bruton's tyrosine kinase (BTK) in a mammal requiring inhibition of BTK, comprising administering a therapeutically effective amount of compound (I) in solid form, as described in any one of embodiments 1 to 134, 199, 200, 234, or 235, to the mammal. 240. A method for providing treatment to a mammal in need of treatment for a disease mediated by Bruton's tyrosine kinase (BTK), comprising administering to the mammal a therapeutically effective amount of compound (I) in solid form as described in any one of embodiments 1 to 134, 199, 200, 234, or 235. 241. A method for providing treatment to a mammal in need of treatment for pemphigus vulgaris or pemphigus foliaceus, comprising administering to the mammal a therapeutically effective amount of compound (I) in solid form as described in any one of embodiments 1 to 134, 199, 200, 234, or 235. A way to do it. 242. A method for providing treatment to a mammal in need of treatment for immunothrombocytopenia, comprising administering to the mammal a therapeutically effective amount of compound (I) in solid form as described in any one of embodiments 1 to 134, 199, 200, 234, or 235. 243. The method according to any one of embodiments 239 to 242, wherein the mammal is a human.

[0082] Average bulk density in solid form Average bulk density reflects the amount of space occupied by a given amount of material. Average bulk density influences the behavior of the material during processing operations (e.g., compounding and compression). In some cases, average bulk density influences the selection of processing procedures for a 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) characterized by an average bulk density of 0.6 g / cc to 0.7 g / cc.

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

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

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

[0088] In some embodiments, the solid form of the Disclosure is characterized by having an average tap density greater than 0.50 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.55 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.60 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.65 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.70 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.75 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.80 g / cc. The solid form of the Disclosure is characterized by having an average tap density greater than 0.85 g / cc.

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

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

[0091] Hausner ratio in solid form The Hausner ratio indicates the fluidity of a powder, and a Hausner ratio greater than 1.35 is often considered to indicate low fluidity. Powder fluidity is a crucial requirement for most pharmaceutical manufacturing processes. To ensure consistent content uniformity, an acceptable fluidity of powder with a Hausner ratio of less than 1.34 is often required.

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

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

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

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

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

[0097] In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 200 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 205 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 210 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 215 μm. 50It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 220 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 225 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 230 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 235 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 240 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 245 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 250 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution greater than 255 μm. D 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 260 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 265 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 270 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution greater than 275 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a D with a wet particle size distribution greater than 280 μm. 50 It is characterized by having a value. In some embodiments, the solid form of the present disclosure is a wet particle size distribution 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 has a wet particle size distribution of 400 μm to 800 μm. 90 It is characterized by having a value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution of 400 μm to 700 μm. 90 It is characterized by having a value. In some embodiments, the solid form of the present disclosure has a wet particle size distribution of 450 μm to 700 μm. 90 It is characterized by having a value.

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

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

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

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

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

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

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

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

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

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

[0111] Amount of residual solvent in solid form Residual solvents are volatile organic compounds used or formed during the manufacture of a compound. Regulations, including those published by the U.S. Food and Drug Administration, require that compounds intended for use as active pharmaceutical ingredients contain substantially no toxicologically significant residual solvents. Headspace gas chromatography is generally used to measure the amount of residual solvent, but mass spectrometry is often used in conjunction to identify and quantify specific residual solvents.

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

[0113] In some embodiments, there is no detectable residual solvent 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 residual methanol content in the solid form of the disclosure is less than 2500 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 2000 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 1500 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 1000 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 900 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 800 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 700 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 600 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 500 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 400 ppm. In some embodiments, the residual methanol content in the solid form of the disclosure is less than 300 ppm. In some embodiments, the amount of residual methanol in the solid form of the Disclosure is less than 200 ppm. In some embodiments, the amount of residual methanol in the solid form of the Disclosure is less than 100 ppm. In some embodiments, there is no detectable residual methanol in the solid form of the Disclosure.

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

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

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

[0118] In some embodiments, the residual methanol content in the solid form of the Disclosure is less than 500 ppm, the residual isopropyl acetate content in the solid form is less than 4000 ppm, and the residual heptane content 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 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 Disclosure is less than 5000 ppm, the amount of residual heptane in the solid form is less than 5000 ppm, and there is no detectable residual methanol in the solid form.

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

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

[0122] In some embodiments, the solid form of the Disclosure contains an amount of Class 1 residual solvent within the limits specified in the ICH guidelines. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 1%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.9%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.8%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.7%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.6%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.5%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.4%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.3%. In some embodiments, in the solid form... The total amount of Class 1 residual solvent is less than 0.2%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.1%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.05%. In some embodiments, the total amount of Class 1 residual solvent in the solid form is less than 0.0025%. In some embodiments, there is no detectable Class 1 residual solvent in the solid form of the Disclosure.

[0123] In some embodiments, the solid form of the Disclosure contains an amount of Class 2 residual solvent within the limits specified in the ICH Guidelines. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 1%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.9%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.8%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.7%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.6%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.5%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.4%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.3%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.2%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.1%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.05%. In some embodiments, the total amount of Class 2 residual solvent in the solid form is less than 0.0025%. In some embodiments, there is no detectable Class 2 residual solvent in the solid form of the Disclosure.

[0124] Substantially pure solid form The solid form intended for use as an API in therapeutic compositions is substantially pure. Specifically, the substantially pure form is free from 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 Disclosure contains more than 70% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 75% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 80% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 85% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 90% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 95% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 97% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 98% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 99% by weight of compound (I). In some embodiments, the solid form of the Disclosure contains more than 99.5% by weight of compound (I).

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

[0127] In some embodiments, the solid form of the Disclosure substantially contains no dimer of compound (I). In some embodiments, the dimer of compound (I) is less than 5% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 4% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 3% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 2% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 1% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 0.5% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 0.25% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 0.1% by weight of the solid form of the Disclosure. In some embodiments, the dimer of compound (I) is less than 0.05% by weight of the solid form of the disclosure.

[0128] A substantially amorphous solid form In some embodiments, the solid form of the disclosure is substantially amorphous. When measured by XRPD, the APIs exhibit identical broad peaks and halos (i.e., appear as identical amorphous solids). However, how the amorphous solids are formed (e.g., by spray drying or by different precipitation methods) influences the different material properties (e.g., density, flowability, particle morphology, and particle size distribution) of the APIs. These material properties result in different dissolution and pharmacokinetic profiles, as they determine how the APIs interact with excipients in orally administered formulations (e.g., capsules and tablets) during processing. Specifically, the glass transition temperature (T g In amorphous solid forms with a relatively high T g It exhibits better physical stability than the lower amorphous solid form.

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

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

[0131] In some embodiments, the 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 solvent exchange from the first organic solvent to a second organic solvent.

[0132] In some embodiments, the removal of the first aqueous layer removes basic impurities that are more soluble than compound (I). In some embodiments, the removal of the first aqueous layer removes basic impurities that are more polar than compound (I). In some embodiments, the basic impurities have the following structure: [ka] (R)-3-(2-fluoro-4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine having, or a pharmaceutically acceptable salt thereof;

[0133] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazine-1-yl)propanol, or a pharmaceutically acceptable salt thereof; Pyrrolidine; and

[0134] The following structure: [ka] The compound comprises at least one of the following: 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazine-1-yl)-3-(pyrrolidine-1-yl)pentanenitrile, or a pharmaceutically acceptable salt thereof.

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

[0136] In some embodiments, the first organic solvent comprises at least one non-hydrated organic solvent. In some embodiments, 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. 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, at least 50% of the first organic solvent is removed by solvent exchange from the first organic solvent to the second organic solvent. In some embodiments, at least 60% of the first organic solvent is removed by solvent exchange from the first organic solvent to the second organic solvent. In some embodiments, at least 70% of the first organic solvent is removed by solvent exchange from the first organic solvent to the second organic solvent.

[0139] In some embodiments, the method further comprises washing a 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, the removal of the second organic layer removes impurities that are less water-soluble than compound (I). Then, impurities with lower polarity than compound (I) are removed.

[0141] In some embodiments, the impurities removed along with the second organic layer have the following structure: [ka] (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)-3-oxopropanenitrile having or a pharmaceutically acceptable salt thereof; and comprising at least one hexamethyldisiloxane.

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

[0143] In some embodiments, the method further comprises adding a first base to a 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.

[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, 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 third organic solvent comprises isopropyl acetate.

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

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

[0148] In some embodiments, the method further includes isolating a precipitate containing compound (I). In some embodiments, isolating a precipitate containing compound (I) includes drying the precipitate containing compound (I). In some embodiments, drying includes air drying, blow drying, or vacuum drying.

[0149] In some embodiments, the method further comprises dissolving a 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).

[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 listed in Table 1 below.

[0152] [Table 1]

[0153] In some embodiments, spray drying the fourth solution involves passing the fourth solution through a spray drying chamber with 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 involves passing the fourth solution through a spray drying chamber with 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 by a mass loss of less than 5% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a solid form of compound (I) characterized by a mass loss of less than 3% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a mass loss of less than 2% by weight at 20°C to 240°C as determined by thermogravimetric analysis. The present invention provides a solid form of compound (I) characterized by having a mass loss of less than 1.5% by weight at 20°C to 240°C determined by thermogravimetric analysis.

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

[0157] In some embodiments, the method provides fine particles of compound (I). In some embodiments, the method provides a wet particle size distribution of less than 10 μm of D 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method provides a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 100 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method provides a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method provides a wet particle size distribution of less than 10 μm. 10 Value, D less than 100 μm 50 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0158] In some embodiments, the method is used when the wet particle size distribution is 5 μm to 6 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 10 μm to 20 μm. 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 10 μm to 50 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0159] In some embodiments, the method is used when the wet particle size distribution is 5 μm to 6 μm. 10 Values ​​and D from 10 μm to 20 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 5 μm to 6 μm. 10 Values ​​and D from 10 μm to 50 μm 90The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 10 μm to 20 μm. 50 Values ​​and D from 10 μm to 50 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

[0161] In some embodiments, the method provides a solid form of compound (I) characterized by having the particle size distribution described above and an average bulk density of less than 0.3 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by having the particle size distribution described above and an average tap density of 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: [ka] The present invention provides a solid form of compound (I) that substantially does not contain a dimer of compound (I) having [a certain characteristic].

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

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

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

[0168] 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. The present invention provides a method comprising forming a first aqueous layer and removing the first aqueous layer.

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

[0170] In some embodiments, the first organic solvent comprises at least one non-hydrated organic solvent. In some embodiments, 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. In some embodiments, the first organic solvent is dichloromethane.

[0171] In some embodiments, the removal of the first aqueous layer removes a base impurity that is more soluble than compound (I). In some embodiments, the removal of the first aqueous layer removes a basic impurity that is more polar than compound (I). In some embodiments, the basic impurity has the following structure: [ka] (R)-3-(2-fluoro-4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine having, or a pharmaceutically acceptable salt thereof;

[0172] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazine-1-yl)propanol, or a pharmaceutically acceptable salt thereof; Pyrrolidine; and

[0173] The following structure: [ka] The compound comprises at least one of the following: 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazine-1-yl)-3-(pyrrolidine-1-yl)pentanenitrile, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the method further comprises: partially removing a first organic solvent from a first organic layer; adding a second organic solvent to the first organic layer, wherein the first and second organic solvents 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 includes distillation under reduced pressure. In some embodiments, the second organic solvent is isopropyl acetate.

[0175] In some embodiments, the method further includes removing a 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 includes distillation under reduced pressure.

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

[0177] In some embodiments, the impurities removed along with the second organic layer have the following structure: [ka] (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-yl)-3-oxopropanenitrile, or a pharmaceutically acceptable salt thereof; and at least one hexamethyldisiloxane.

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

[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) 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: [ka] The present invention provides a solid form of compound (I) that substantially does not contain a dimer of compound (I) having [a certain characteristic].

[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 residual isopropyl acetate content is less than 5000 ppm and / or the residual heptane content is less than 5000 ppm. In some embodiments, the method provides a solid form of compound (I) in which the residual isopropyl acetate content is less than 500 ppm and / or the residual heptane content 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) having a residual dichloromethane content of less than 1500 ppm. In some embodiments, the method provides a solid form of compound (I) having a residual dichloromethane content of less than 1000 ppm. In some embodiments, the method provides a solid form of compound (I) having a residual dichloromethane content of less than 500 ppm. In some embodiments, the method provides a solid form of compound (I) having a residual dichloromethane content of less than 100 ppm.

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

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

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

[0187] In some embodiments, the method is used when the wet particle size distribution is greater than 70 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 200 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 400 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 200 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Value greater than 200 μm (D) 50 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In one embodiment, the method is used when the wet particle size distribution is greater than 200 μm. 50 Values ​​and D greater than 400 μm 90 The present invention provides 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 by a mass loss of less than 5% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a solid form of compound (I) characterized by a mass loss of less than 4% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a solid form of compound (I) characterized by a mass loss of less than 3% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a solid form of compound (I) characterized by a mass loss of less than 2% by weight at 20°C to 240°C as determined by thermogravimetric analysis. In some embodiments, the method provides a solid form of compound (I) characterized by a mass loss of less than 1.5% by weight at 20°C to 240°C as determined by thermogravimetric analysis.

[0189] In some embodiments, the method is characterized by a glass transition temperature (T) at 0% relative humidity. g The present invention provides a solid form of compound (I) characterized by a temperature 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 includes pulverizing 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 wet particle size distribution of less than 10 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method provides a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 100 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Value, D less than 100 μm 50 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0193] In some embodiments, the method is used when the wet particle size distribution is 1 μm to 2 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 40 μm to 70 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 100 μm to 150 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0194] In some embodiments, the method is used when the wet particle size distribution is 1 μm to 2 μm. 10 Values ​​and D from 40 μm to 70 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 1 μm to 2 μm. 10 Values ​​and D from 100 μm to 150 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 40 μm to 70 μm. 50 Values ​​and D from 100 μm to 150 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

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

[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 with a pH of 3.

[0199] In some embodiments, the first organic solvent comprises at least one non-hydrated organic solvent. In some embodiments, 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. In some embodiments, the first organic solvent is dichloromethane.

[0200] In some embodiments, the removal of the first aqueous layer removes a base impurity that is more soluble than compound (I). In some embodiments, the removal of the first aqueous layer removes a basic impurity that is more polar than compound (I). In some embodiments, the basic impurity has the following structure: [ka] (R)-3-(2-fluoro-4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine having, or a pharmaceutically acceptable salt thereof;

[0201] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazine-1-yl)propanol, or a pharmaceutically acceptable salt thereof; Pyrrolidine; and

[0202] The following structure: [ka] The compound comprises at least one of the following: 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazine-1-yl)-3-(pyrrolidine-1-yl)pentanenitrile, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the method further 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 comprises compound (I) and the first organic solvent and the third organic solvent are not the same; and adding a first base to adjust the pH of the third aqueous layer from 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 includes 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 solution of a base. In some embodiments, the first base is an aqueous solution of potassium hydroxide.

[0208] In some embodiments, the method further includes removing a 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 includes distillation under reduced pressure.

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

[0210] In some embodiments, the impurities removed along with the third organic layer have the following structure: [ka] (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-yl)-3-oxopropanenitrile, or a pharmaceutically acceptable salt thereof; and at least one hexamethyldisiloxane.

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

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

[0213] 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: [ka] The present invention provides a solid form of compound (I) that substantially does not contain a dimer of compound (I) having [a certain characteristic].

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

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

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

[0218] In some embodiments, the method provides a solid form of compound (I) characterized by having an average tap density greater than 0.5 g / cc. The method provides a solid form of compound (I) characterized by having an average tap density greater than 0.6 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by having an average tap density greater than 0.7 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by having an average tap density greater than 0.8 g / cc. In some embodiments, the method provides a solid form of compound (I) characterized by having an average tap density between 0.7 g / cc and 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 is used when the wet particle size distribution is greater than 70 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 200 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 400 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 200 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Value greater than 200 μm (D) 50 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 200 μm. 50 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

[0222] In some embodiments, the method is characterized by a glass transition temperature (T) at 0% relative humidity. g The present invention provides a solid form of compound (I) characterized by a temperature 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 includes pulverizing 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 wet particle size distribution of less than 10 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, This method is used when the wet particle size distribution is less than 10 μm. 10 Values ​​and D less than 100 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Value, D less than 100 μm 50 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0226] In some embodiments, the method is used when the wet particle size distribution is 1 μm to 2 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 40 μm to 70 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 100 μm to 150 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

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

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

[0230] In some embodiments, the present disclosure provides 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 (≤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 is dichloromethane.

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

[0233] In some embodiments, the removal of the first aqueous layer removes basic impurities less polar than compound (I). In some embodiments, the basic impurities have the following structure: [ka] (R)-3-(2-fluoro-4-phenoxyphenyl)-1-(piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine having, or a pharmaceutically acceptable salt thereof;

[0234] The following structure: [ka] 2-methyl-2-(4-(oxetan-3-yl)piperazine-1-yl)propanol, or a pharmaceutically acceptable salt thereof; Pyrrolidine; and

[0235] The following structure: [ka] The compound comprises at least one of the following: 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazine-1-yl)-3-(pyrrolidine-1-yl)pentanenitrile, or a pharmaceutically acceptable salt thereof.

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

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

[0238] In some embodiments, the strong acid includes methanesulfonic acid.

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

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

[0241] In some embodiments, the method further includes cooling the residue containing compound (I) to a temperature of 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 a saline solution. In some embodiments, the saline solution is an aqueous solution of sodium chloride.

[0243] In some embodiments, the method further includes adding a non-hydrated 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-hydrated organic solvent is dichloromethane.

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

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

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

[0248] In some embodiments, removal of the second organic layer includes distillation under reduced pressure.

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

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

[0251] In some embodiments, adjusting the amount involves adding a further weak organic acid. In some embodiments, adjusting the amount involves adding a further acetic acid.

[0252] In some embodiments, the method further includes adding a basic aqueous solution to a first or second aqueous layer to adjust the pH from 8 to 11 and 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 allowed to form at 20°C for at least 3 hours.

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

[0257] In some embodiments, the method further comprises 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 containing compound (I) includes drying under reduced pressure with a small amount of heat. In some embodiments, drying the filtered and washed precipitate containing compound includes drying under reduced pressure with a small amount of heat at 25°C.

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

[0260] In some embodiments, the isolated precipitate is slurryed with water at 15°C for at least 1 hour before filtration. In some embodiments, filtration includes drying under reduced pressure with trace heat. In some embodiments, filtration includes drying under reduced pressure with trace heat at 25°C.

[0261] 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: [ka] The present invention provides a solid form of compound (I) that substantially does not contain a dimer of compound (I) having [a certain characteristic].

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

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

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

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

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

[0268] In some embodiments, the method is used when the wet particle size distribution is greater than 70 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 200 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 400 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 200 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Value greater than 200 μm (D) 50 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 70 μm. 10 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution greater than 200 μm. 50 Values ​​and D greater than 400 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

[0270] In some embodiments, the method is characterized by a glass transition temperature (T) at 0% relative humidity. g The present invention provides a solid form of compound (I) characterized by a temperature 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 includes pulverizing 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 wet particle size distribution of less than 10 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method provides a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 100 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the micronization method is a wet particle size distribution of less than 10 μm. 10 Value, D less than 100 μm 50 Values ​​and D less than 200 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0274] In some embodiments, the method is used when the wet particle size distribution is 1 μm to 2 μm. 10 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 40 μm to 70 μm. 50The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 100 μm to 150 μm. 90 The present invention provides a solid form of compound (I) characterized by having a value.

[0275] In some embodiments, the method is used when the wet particle size distribution is 1 μm to 2 μm. 10 Values ​​and D from 40 μm to 70 μm 50 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method is characterized by having a wet particle size distribution of 1 μm to 2 μm. 10 Values ​​and D from 100 μm to 150 μm 90 The present invention provides a solid form of compound (I) characterized by having a value. In some embodiments, the method involves wet particle size distribution D is 40 μm to 70 μm 50 Values ​​and D from 100 μm to 150 μm 90 The present invention provides a solid form of compound (I) characterized by having a value.

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

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

[0278] Conversion method for producing the solid form of compound (I) In some embodiments, the 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-hydrated 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 solution of a base 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; rinsing the precipitate with water; and drying the precipitate to obtain the solid form of compound (I).

[0279] In some embodiments, the non-hydrated organic solvent includes dichloromethane.

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

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

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

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

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

[0285] In some embodiments, drying the precipitate involves drying under reduced pressure with a small amount of heat. In some embodiments, drying the precipitate involves 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). ru.

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

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

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

[0291] Pemphigus is a rare B-cell-mediated autoimmune disease that causes debilitating intraepithelial rash and ulcers of the skin and / or mucous membranes. Pemphigus has a mortality rate of 10%, and is generally caused by infection due to skin damage and side effects of treatment, with approximately 0.1 to 0.5 cases per 100,000 people annually (Scully et al., 2002; Scully et al., 1999). The characteristic intraepithelial rash seen in pemphigus patients is caused by IgG autoantibodies binding to specific keratinocyte desmosome adhesion proteins, namely desmogleins 1 and 3 (Dsg1 and Dsg3), which reduce cell adhesion (Amagai M et al., 2012; Diaz LA et al., 2000). B cells play a crucial role in the production of these autoantibodies and in the mechanisms of cell resistance.

[0292] The solid form of compound (I) described herein is useful for treating immunogenic thrombocytopenia.

[0293] Immune thrombocytopenia (commonly known as ITP) is characterized by autoantibody-mediated destruction of platelets and decreased platelet production, leading to thrombocytopenia and increased susceptibility to morbid and fatal bleeding. Early evidence supports the role of BTK inhibition in patients with autoimmune cytopenia, as treatment with the BTK / EGFR / ITK inhibitor ibrutinib halted the recurring onset of severe autoimmune hemolytic anemia and ITP in patients with chronic lymphocytic leukemia (CLL) (Rogers 2016, Montillo 2017).

[0294] Pharmaceutical composition The solid forms described herein are useful as materials for producing pharmaceutical compositions containing an active pharmaceutical ingredient (API) and one or more pharmaceutically acceptable excipients, which are suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions are pharmaceutical products such as solid oral dosage forms, such as tablets and / or capsules.

[0295] In some embodiments, the Disclosure provides a pharmaceutical composition comprising at least one solid form of compound (I). In some embodiments, the 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 compatible with the composition in question and be "pharmaceutically acceptable" in the sense that its components are not harmful to the patient. Any conventional pharmaceutically acceptable excipient is considered to be within the scope of the Disclosure unless it is incompatible with compound (I), for example, produces any undesirable biological effect, or interacts undesirably with any other component of the pharmaceutically acceptable composition.

[0296] Some non-limiting examples of materials that can function as pharmaceutically acceptable excipients include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (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) Buffers such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphate buffer; and (21) Other non-toxic compatible substances used in pharmaceutical formulations.

[0297] The contents of Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, and the Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, are respectively incorporated herein by reference, and 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, orally, vaginally, or via implantable storage device. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-sacral, intrasternal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. In some embodiments, the compositions disclosed herein are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the pharmaceutical compositions disclosed herein are aqueous or oily suspensions. These suspensions are formulated by techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Acceptable media and solvents employed include water, Ringer’s solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are typically used as the solvent or suspension medium.

[0299] For this purpose, any sterile, fixed oil containing synthetic monoglycerides is employed. Fatty acids such as oleic acid and its glyceride derivatives, particularly in the form of their polyoxyethylated compounds, are used in addition to naturally medicinal oils such as olive oil or castor oil. These are useful in the manufacture of propellants. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are widely used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other widely used surfactants, such as Tween, Spans, and other emulsifiers or bioavailable enhancers, which are widely used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, are also used for formulation purposes.

[0300] The pharmaceutical compositions disclosed herein are administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or liquids. Where an aqueous suspension is required for oral use, the active ingredient is typically combined with an emulsifier and a suspending agent. Specific sweeteners, flavorings, or colorants are added as desired.

[0301] Alternatively, the pharmaceutical compositions disclosed herein are administered in the form of suppositories for rectal administration. The 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 as to melt in the rectum and release the drug. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0302] The pharmaceutical compositions of this disclosure are administered topically, particularly when the therapeutic target is an area or organ that is easily reachable by topical application, including in cases of diseases of the eye, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily manufactured. Topical application for the lower intestine is performed 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 this 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 a suitable lotion or cream 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 compositions of this disclosure may also be administered by nasal aerosol or inhalation. The compositions are manufactured by techniques well known in the art of pharmaceutical formulations and are prepared as solutions in physiological saline using benzyl alcohol or other suitable excipients, absorption enhancers to increase bioavailability, carbon fluoride, and / or other conventional solubilizers or dispersants.

[0305] dosage Generally, the solid form of compound (I) is administered in a therapeutically effective dose by any accepted method of administration of a drug that exhibits similar beneficial effects. The effective dose for any particular mammal (e.g., any particular human) depends on a wide variety of factors, including the disorder being treated and its severity; the specific pharmaceutical composition employed; the mammal's age, weight, overall health, sex, and dietary habits; the time of administration, route of administration, and duration of treatment; and similar factors well known in the medical technology field. In some embodiments, a therapeutically effective dose of at least one solid form of compound (I) is administered to the mammal in need. The therapeutically effective doses 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 more divided doses. Preferred dose levels are 0.01 to 250 mg / kg and 0.05 to 100 mg / kg per day. , or 0.1 to 50 mg / kg per day. In some embodiments, within this range, the dose can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, in some embodiments, the composition is provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the active ingredient.

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

[0307] All publications and patents described herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually incorporated by reference.

[0308] Any claim or specification provision containing "or" or "and / or" among at least one member of the group is considered satisfied if one, two or more, or all of the group members are present in, adopted, or related to the given product or method, unless the context suggests otherwise or is clearly indicated to mean the opposite. This disclosure includes embodiments in which only one member is present in, adopted, or related to the given product or method. This disclosure includes embodiments in which two or more, or all, of the group members are present in, adopted, or related to the given product or method.

[0309] Furthermore, this disclosure encompasses all modifications, combinations, and reorders in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, any claim dependent on another claim is modified to include at least one limitation found in any other claim dependent on the same base claim. Where 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. In general, where this disclosure or an aspect thereof is deemed to include a particular element and / or feature, it should be understood that embodiments of this disclosure or an aspect thereof consist of, or substantially consist of, such element and / or feature. For the sake of brevity, those embodiments are not described in the exact words of the specification. Where a scope is indicated, an endpoint is included. Furthermore, unless the context and the understanding of those skilled in the art suggest or express otherwise, the values ​​expressed as a range may be any specific value or subrange within the scope described in the different embodiments of this disclosure, up to one-tenth of the lower limit of that range, unless the context clearly suggests otherwise.

[0310] Those skilled in the art will recognize or confirm that many equivalents to the specific embodiments of the disclosure described herein can be obtained by using only ordinary experimental procedures. Such equivalents are intended to be encompassed in the following claims. [Examples]

[0311] The following examples are illustrative and are not intended to limit the scope of this disclosure.

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

[0313] Abbreviation: DCM = Dichloromethane DMA = Dimethylacetamide DME = Dimethoxyethane DMF = Dimethylformamide DMSO = Dimethyl sulfoxide alkyl = ethyl acetate EtOH = Ethanol IPA = Isopropyl alcohol IPAC = Isopropyl Acetate MeOH = methanol MTBE = Methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine PP = Polypropylene rpm = revolutions per minute TEA = Triethylamine TFA = Trifluoroacetic Acid THF = Tetrahydrofuran THP = Tetrahydropyran TMS = Tris(trimethylsilyl) TMSCI = Trimethylsilyl Chloride [Examples]

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

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

[0316] Acetic acid (2.0 equivalents) was added to the reactor at 0°C to 5°C, followed by water (5 equivalents). 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 separated over 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% by weight solution of citric acid. Stirring was continued at 0-5°C for 1-1.5 hours. Stirring was stopped, and the phases were separated over at least 0.5 hours. The lower aqueous layer was removed.

[0318] A jacketed reactor equipped with a top stirrer, condenser, nitrogen piping, temperature probe, and recirculating cooler / heater contained a 9% solution of NaHCO3 (1 volume) and an organic layer. 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 separated over at least 0.5 hours. The lower aqueous layer was removed. The pH of the lower aqueous layer was measured and found to be above 7.

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

[0320] The following procedure was 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 separated over at least 0.5 hours. The organic phase was removed.

[0321] IPAC (15 liters) was added to the reactor containing the aqueous layer. pH 10 phosphate buffer was added to the reactor, and the pH was adjusted to 10 with 14% NaOH solution. 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 It was dried in saltwater.

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

[0323] n-heptane (20 liters) was added to a jacketed reactor equipped with a top stirrer, condenser, nitrogen piping, temperature probe, and recirculation cooler / heater. The internal temperature was adjusted to 0 to 5°C, and then IPAC solution was added.

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

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

[0326] Precipitation method A A solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was quenched with acetic acid and water, and then washed with an aqueous solution of pH 3 to remove basic impurities that were more soluble in the aqueous layer than compound (I). Washing was repeated as needed to reduce impurities. Methanesulfonic acid was added to the dichloromethane solution, and the dichloromethane solution was concentrated by distillation under reduced pressure. Then, an aqueous solution of 1% NaCl and isopropyl acetate were added, and the pH was adjusted to approximately 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. Washing was repeated as needed to reduce related substance impurities. Residual isopropyl acetate was removed by distillation under reduced pressure. The aqueous solution containing compound (I) was cooled to 0 to 5°C, and then the pH was adjusted to approximately 9 with potassium hydroxide. Free base of compound (I) was precipitated and aged at 20°C for 20 hours. Next, the temperature of the mixture was adjusted from 20°C to 25°C to confirm that the hydrate impurity was less than 0.3% (<0.3%). The free base cake of compound (I) was filtered and washed as necessary to reduce conductivity. The cake was then dried on a filter under vacuum, nitrogen was removed to reduce the water content by Karl Fischer (KF < 50%), and then transferred to an oven for drying. The wet cake of free base of compound (I) was dried under vacuum at 25°C until the water content by Karl Fischer was less than 1.5% (KF < 1.5%), and then deaggregated by grinding to produce a homogeneous white amorphous solid as a mixture of the (E) isomer and the (Z) isomer, free from detectable amounts of isopropyl acetate or heptane. [Examples]

[0327] Precipitation method B The solution of compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO2014 / 039899) was quenched with acetic acid and water, and then washed with an aqueous solution of pH 3 to remove basic impurities that were more soluble in the aqueous layer than compound (I). Washing was repeated as needed to reduce residual solvent and impurities. Next, the dichloromethane solution was washed with saturated sodium bicarbonate (pH>7). After removing the dichloromethane by distillation under reduced pressure, water and isopropyl acetate were added. The pH of the aqueous layer was adjusted to pH 2.8-3.3 with a 2M aqueous sulfuric acid (H2SO4) solution at 0-5°C, and the mixture was stirred and allowed to settle. After phase separation and removal of the organic layer, the aqueous layer was washed three times with isopropyl acetate, and residual isopropyl acetate in the aqueous layer was removed by distillation under vacuum at a temperature below 25°C. The solution was basicized to pH 9-10 with a 5% aqueous KOH solution to obtain a slurry. The resulting suspension was stirred and heated to 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. [Examples]

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

[0329] Figures 12-15 are SEM images showing changes in the morphology of compound (I) particles during the filtration process to isolate 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 depended on the morphology, being fastest when acetic acid was 0 wt%. When acetic acid was 1 wt%, the filtration rate decreased significantly, and when acetic acid was between 2 wt% and 3 wt%, it improved. Morphologies with more open pores (e.g., more porous particles) resulted in improved filtration rates, while denser particles resulted in decreased filtration rates. [Examples]

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

[0331] Micronization of compound (I) particles obtained by the precipitation method. A fluid jet mill apparatus was used for laboratory-scale jet pulverization tests. The fluid jet mill apparatus consists of a 1.5-inch diameter flat cylindrical chamber fitted with four symmetrical jet nozzles positioned tangentially on its inner wall. Before feeding the material into the fluid jet mill in each test, the material was classified using a 355 μm sieve to remove any aggregates and avoid nozzle clogging when feeding the material into the pulverization chamber. The material to be processed was subjected to a vacuum (P_vent ~ P_grind 0.5 ~ 1.0 bar higher) generated by a venturi. The material was drawn into the grinding chamber via pressure. The solid feed rate (F_feed) was controlled by a manual valve and an infinite screw metering feeder. Compressed nitrogen was used to inject the feed material; compressed nitrogen was also used in the jet nozzles on the walls of the grinding chamber. The compressed fluid emitted from the nozzles expands from the P_grind, imparting a very high rotational speed in the chamber. Thus, the material is accelerated by the rotating and expanding gas and subjected to centrifugal force. The particles move outward and, influenced by the high-speed jet, are guided radially inward at very high speeds. The rapidly moving particles affect the slower moving particle path circulating near the periphery of the chamber. Abrasion occurs as the particles collide violently with each other. The particles, whose particle size has been reduced as a result of this series of collisions, are taken into the gas circulation flow and swept towards the central outlet against the action of centrifugal force. Larger particles in the gas flow are subjected to centrifugal force and returned to the grinding area. The fine particles are carried to the outlet by the exhaust gas and move from the grinding chamber into the collector.

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

[0333] [Table 2] [Examples]

[0334] Residual solvent amount The retention of process solvents (i.e., residual solvent) is specific to each molecule and depends on the van der Waals forces, which are inherent properties of each molecule. In addition, solvent retention depends on how the solid API is formed, isolated, washed, and dried (i.e., the manufacturing process). Because residual solvents can pose safety risks, formulation methods must be designed to minimize the amount of residual solvent (for example, so that the amount of residual solvent is below the limits set forth in ICH guidelines).

[0335] The residual solvent was analyzed by gas chromatography / mass spectrometry. Table 2 shows the amount of residual solvent in the solid form of compound (I) prepared by the spray drying method and the precipitation method described herein. The amounts of residual solvent in crude compound (I) listed in Table 2 are equivalent to the amounts of residual solvent in crude compound (I) prepared 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). Comparison 1 corresponds to the solid form of compound (I) produced substantially according to the method detailed in step 1A of Example 1 in WO2015 / 127310. Comparison 2 corresponds to the solid form of compound (I) produced substantially according to the method detailed in Example 31 in WO2014 / 039899.

[0338] The wet particle size distribution was measured using a Malvern Mastersizer 3000 laser diffraction particle size analyzer with a stirring speed set to 2200 rpm. Heptane containing 0.2 vol% Span 80 was used as the dispersant. To obtain the distribution measurements, the dispersant was packed into a Hydro MV medium-volume automated dispersion unit and prepared. The background was then measured. 80 to 100 mg of the sample was weighed into a 20 mL vial, to which approximately 3 mL of dispersant was added. The mass was adjusted based on particle size, with an obscuration of 5% to 16%. The entire sample was added to the Hydro MV unit, and the sample was analyzed five times after a 160-second pre-measurement delay. The analysis time was 20 seconds (10 seconds with the red laser and 10 seconds with the blue laser), with no delay between measurements. The obtained data were processed using Mie theory with a sample refractive index of 1.69 and an absorption coefficient of 0.1, using a general-purpose model with normal sensitivity and non-spherical particle type. The 15 sets of raw data were averaged to obtain an inclusive mean representing the average value of the sample. If the sample was deemed inconsistent, further adjustments were examined to determine which results were anomalous. All anomalous results were discarded. The samples were thoroughly mixed before sampling (e.g., several samples were divided equally using rotational refractory chromatography).

[0339] [Table 4] [Examples]

[0340] Measurement of average bulk density, average tap density, and Hausner ratio USP <616> The average bulk density and average tap density were measured using a modified method based on the following. The powder was placed in a clean, dry, and gravimetrically weighed 25 mL cylinder. The powder was added without compressing the sample until the total volume was between 20 mL and 25 mL. The mass of the powder and the initial volume (V0) were recorded. The average bulk density was measured as the average of the mass relative to the initial volume of multiple samples. To measure the average tap density, the samples were lightly tapped using a Copley JV2000 tap density tester with the following tap counts: 500, 750, and sets ranging from 1250 to 10,000 taps. The volume was recorded after each set of taps, and the sample was measured to a constant volume (V0). f The samples were lightly tapped until the tapped mass reached 0. The average tap density was measured as the average of the masses relative to a given volume of multiple samples. Each sample was analyzed twice. The Hausner ratio was defined as the ratio of the initial volume to a given volume (V0 / V0). f ) was calculated as follows.

[0341] Table 4 shows the average bulk density, average tap density, and Hausner ratio for several different solid forms of compound (I). As described above, 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. Similarly, as described above, 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] [Examples]

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

[0344] Table 5 shows thermogravimetric analysis data for several different solid forms of compound (I), including mass loss information from multiple iterative operations across different temperature ranges. As described above, 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. Similarly, control 2 corresponds to the solid form of compound (I) produced substantially according to the method detailed in Example 31 of WO2014 / 039899. 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 using differential scanning calorimetry Modulated differential scanning calorimetry (DSC) analysis was performed using a TA Instruments Q2000 DSC. Samples were heated at 2°C / min with a temperature modulation parameter of ±0.318°C (width) in the temperature range of -80°C to 200°C. Samples were analyzed using a closed aluminum pan. Examples of DSC thermograms of the solid form of compound (I) at 0% relative humidity ("RH") are shown in Figures 7-11.

[0347] Table 6 shows the glass transition temperature data for several different solid states of compound (I). As described above, control 1 corresponds to the solid state of compound (I) produced substantially according to the method detailed in step 1A of Example 1 of WO2015 / 127310. Also as described above, control 2 corresponds to the solid state of compound (I) produced substantially according to the method detailed in Example 31 of WO2014 / 039899. Also as described above, control 3 corresponds to the solid state of compound (I) produced substantially according to the method detailed in step 1 of Example 1 of WO2015 / 127310.

[0348] Table 7

Claims

1. Compound (I): 【Chemistry 1】 The amorphous solid is characterized in that its average bulk density is between 300 kg / m³ (0.3 g / cc) and 700 kg / m³ (0.7 g / cc), and its glass transition temperature (Tg) at 0% relative humidity is between 93°C and 97°C.

2. The amorphous solid according to Claim 1, further characterized in that the average tap density is between 700 kg / m³ (0.7 g / cc) and 900 kg / m³ (0.9 g / cc).

3. The amorphous solid according to claim 1 or 2, further characterized in that the Hausner ratio is between 1 and 1.

2.

4. The amorphous solid according to any one of claims 1 to 3, further characterized in that the wet particle size distribution has a D10 value between 70 μm and 150 μm.

5. The amorphous solid according to any one of claims 1 to 4, further characterized in that the wet particle size distribution has a D50 value between 200 μm and 400 μm.

6. The amorphous solid according to any one of claims 1 to 5, further characterized in that the wet particle size distribution has a D90 value between 400 μm and 800 μm.

7. The amorphous solid according to any one of claims 1 to 6, further characterized in that the mass loss from 20°C to 240°C determined by thermogravimetric analysis is between 0 and 5% by weight.

8. The amorphous solid according to any one of claims 1 to 7, further comprising the total amount of residual solvent in the solid being between 0 and 1%.

9. Furthermore, the amount of residual methanol is between 0 and 3000 ppm; and / or The amount of residual isopropyl acetate is between 0 and 5000 ppm; and / or The amorphous solid according to any one of claims 1 to 8, wherein the residual heptane content is between 0 and 5000 ppm.

10. Furthermore, the amount of residual methanol is between 0 and 500 ppm; and / or The amount of residual isopropyl acetate is between 0 and less than 4000 ppm; and / or An amorphous solid according to any one of claims 1 to 9, wherein the residual heptane content is between 0 and less than 500 ppm.

11. The amorphous solid according to any one of claims 1 to 10, further comprising a residual dichloromethane content between 0 and 1500 ppm.

12. Compound (I): 【Chemistry 2】 The amorphous solid is characterized by having a D10 value in which the wet particle size distribution is between 1 μm and 2 μm, or between 5 μm and 6 μm, and having a glass transition temperature (Tg) at 0% relative humidity between 93°C and 97°C.

13. The amorphous solid according to claim 12, further characterized in that the wet particle size distribution has a D50 value between 10 μm and 20 μm, or between 40 μm and 70 μm.

14. The amorphous solid according to claim 12 or 13, further characterized in that the wet particle size distribution has a D90 value between 10 μm and 50 μm, or between 100 μm and 150 μm.

15. The amorphous solid according to any one of claims 12 to 14, further characterized in that the average bulk density is between 0 and 300 kg / m³ (0.3 g / cc).

16. The amorphous solid according to any one of claims 12 to 15, further characterized in that the average tap density is between 0 and 300 kg / m³ (0.3 g / cc).

17. The amorphous solid according to any one of claims 12 to 16, further characterized in that the mass loss from 20°C to 240°C determined by thermogravimetric analysis is between 0 and 5% by weight.

18. The amorphous solid according to any one of claims 12 to 17, further comprising the total amount of residual solvent in the solid being between 0 and 1%.

19. Furthermore, the amount of residual methanol is between 0 and 3000 ppm; and / or The amount of residual isopropyl acetate is between 0 and 5000 ppm; and / or The amorphous solid according to any one of claims 12 to 18, wherein the residual heptane content is between 0 and 5000 ppm.

20. Furthermore, the amount of residual methanol is between 0 and 500 ppm; and / or The amount of residual isopropyl acetate is between 0 and 4000 ppm; and / or The amorphous solid according to any one of claims 12 to 19, wherein the residual heptane content is between 0 and 500 ppm.

21. The amorphous solid according to any one of claims 12 to 20, further comprising a residual dichloromethane content between 0 and 1500 ppm.

22. Compound (I): 【Transformation 3】 A method for producing an amorphous solid, Washing a solution containing compound (I) and at least one organic solvent from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate with an aqueous solution of at least one weak organic acid with a pKa between 0 and 7 from acetic acid, citric acid, formic acid, and propanoic acid 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) intact. The method comprising the above.

23. Further, adding a strong acid selected from methanesulfonic acid, sulfuric acid, and hydrochloric acid to the first organic layer; and The first organic layer is concentrated by removing the organic solvent to obtain a residue containing compound (I). The method according to claim 22, further comprising:

24. The method according to claim 22 or 23, further comprising washing the residue containing compound (I) with water or a saline solution.

25. Dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diiso Adding at least one non-hydrated organic solvent selected from propyl ether, methyltetrahydrofuran, and isopropyl acetate to obtain a second organic layer and a second aqueous layer containing compound (I); and Remove the second organic layer. The method according to claim 24, further comprising:

26. The method according to claim 24, wherein the residue containing compound (I) is washed with water or a saline solution one to three times.

27. ​​The method according to any one of claims 23 to 26, further comprising adjusting the pH of the first or second aqueous layer to a value of 1 to 5 by adding an aqueous solution of a base selected from sodium hydroxide, potassium hydroxide, or calcium hydroxide.

28. The method according to claim 27, further comprising measuring the amount of at least one residual weak organic acid selected from acetic acid, citric acid, formic acid, and propanoic acid having a pKa between 0 and 7, and adjusting the amount of the weak organic acid having a pKa between 0 and 7 from 0% by weight to 8% by weight.

29. The method according to claim 28, further comprising adding an aqueous solution of a base selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide to a first or second aqueous layer to adjust the pH to 8 to 11 and to form a precipitate containing compound (I).

30. The method according to claim 29, further comprising isolating the precipitate containing compound (I) by filtration and washing the precipitate containing compound (I) with water.

31. The method according to claim 30, further comprising drying the filtered and washed precipitate containing compound (I) to obtain an amorphous solid of compound (I).

32. The method according to claim 30, further comprising slurrying the isolated precipitate with water and filtering to obtain an amorphous solid of compound (I).

33. Compound (I): 【Chemistry 4】 A method for producing an amorphous solid, Dissolve the crystalline form of compound (I) in a solution containing at least one non-hydrated organic solvent selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate, and saline solution; Adding one equivalent of a strong acid selected from methanesulfonic acid, sulfuric acid, and hydrochloric acid to form an aqueous layer and an organic layer; Remove the organic layer; Concentrating the aqueous layer; A solid precipitate of compound (I) is obtained by adding a base aqueous solution selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide to adjust the pH to a value of 8 to 11; Isolating the solid precipitate of compound (I) by filtration; Rinsing the precipitate with water; and The precipitate is dried to obtain an amorphous solid of compound (I). The method comprising the above.

34. The method according to any one of claims 22 to 33, further comprising micronizing the amorphous compound (I).

35. Compound (I): 【Transformation 5】 A method for producing an amorphous form, Washing a solution of compound (I) with a first acidic aqueous solution to form a first solution comprising at least one first organic layer and a first aqueous layer selected from dichloromethane, ethyl acetate, carbon tetrachloride, chloroform, diethyl ether, diisopropyl ether, methyltetrahydrofuran, and isopropyl acetate, wherein the solution of compound (I) comprises a first organic solvent; Removing the first water layer; and Performing solvent exchange from a first organic solvent to a second organic solvent selected from alkyl acetate, methyltetrahydrofuran, toluene, methylcyclopentyl ether, methyl t-butyl ether, pentanone, acetone, acetonitrile, and alkylpropionate. The method comprising the above.

36. Washing a 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 Remove the second organic layer. The method according to claim 35, further comprising:

37. A third solution is formed comprising a third organic solvent and a third aqueous layer, wherein the third organic layer comprises compound (I), by adding a first aqueous solution selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide to a second aqueous layer, and a third organic solvent selected from alkyl acetate, methyltetrahydrofuran, toluene, methylcyclopentyl ether, methyl t-butyl ether, pentanone, acetone, acetonitrile, and alkylpropionate; Extracting the third aqueous layer using a third organic solvent; and Concentrating the third layer The method according to claim 36, further comprising:

38. The method according to claim 37, further comprising adding at least one reverse solvent selected from hexane, heptane, and octane to the third organic layer to form a precipitate containing compound (I).

39. The method according to claim 38, further comprising isolating a precipitate containing compound (I).

40. Dissolving a precipitate containing compound (I) in a fourth organic solvent containing at least one of methanol, ethanol, acetone, acetonitrile, and methyl ethyl ketone to form a fourth solution; and The fourth solution is spray-dried to obtain an amorphous solid of compound (I). The method according to claim 39, further comprising:

41. The method according to claim 40, further comprising micronizing an amorphous solid of compound (I).

42. A pharmaceutical composition, an amorphous solid of compound (I) according to any one of claims 1 to 21, Excipients that are acceptable as pharmaceuticals and The pharmaceutical composition comprising the above.

43. A therapeutically effective amount of an amorphous solid of compound (I) according to any one of claims 1 to 21 for use in inhibiting Bruton's tyrosine kinase (BTK) in mammals requiring BTK inhibition.

44. An amorphous solid of compound (I) according to any one of claims 1 to 21, in a therapeutically effective amount for use in the treatment of a mammal requiring treatment for pemphigus vulgaris or pemphigus foliaceus.

45. A therapeutically effective amount of an amorphous solid of compound (I) according to any one of claims 1 to 21, for use in a mammal requiring treatment for immunothrombocytopenia.

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