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

Abstract

2-[3-[4-Amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile (identified herein as Compound (I) and also known as PRN 1008 or rilsabrutinib), as a pharmaceutically acceptable salt selected from HCl, oxalic acid and / or maleate, or as a pharmaceutically acceptable methylparaben co-crystal, and pharmaceutical compositions comprising substantially crystalline solid forms and substantially crystalline forms thereof are provided herein. 【Chemical 1】 TIFF2025521259000024.tif46170

Description

Technical Field

[0001] The present disclosure relates to solid forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile (identified herein as Compound (I) and also known as PRN1008 or rilzabrutinib), a potent inhibitor of Bruton's tyrosine kinase ("BTK") useful for the treatment of cancer and other pathologies including autoimmune diseases. The present disclosure further relates to pharmaceutical compositions comprising said forms.

Background Art

[0002] The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in most hematopoietic cells including B cells, mast cells, and macrophages. BTK plays a role in B cell development and activation. BTK activity is involved in the etiology of several disorders and pathologies including B cell-related blood cancers (such as non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (such as immune thrombocytopenia (ITP), rheumatoid arthritis, Sjögren's syndrome, pemphigus, inflammatory bowel disease (IBD), lupus nephritis, atopic dermatitis, warm autoimmune hemolytic anemia, asthma and other acute respiratory difficulties, and chronic idiopathic urticaria).

[0003] Thus, pharmaceutical compositions comprising a therapeutically effective amount of a BTK inhibitor may be useful for the treatment of certain cancers and autoimmune diseases.

[0004] When treating certain cancers and autoimmune diseases with BTK inhibitors, it is also desirable that the therapeutic agent be readily absorbed by the body and administered in a storage-stable form. The pharmaceutically active substance used to prepare the therapeutic agent should be as pure as possible, and its stability during long-term storage should be ensured under various environmental conditions. These properties are useful for preventing the appearance of unintended degradation products in the pharmaceutical composition, which can potentially be toxic or simply reduce the efficacy of the composition.

[0005] Furthermore, a common concern regarding the large-scale manufacture of pharmaceutical compounds is that the active substance has a crystalline morphology that ensures consistent processing parameters and pharmaceutical quality. In this regard, solid-state changes in the pharmaceutical composition that improve its physical and chemical stability can provide significant advantages over less stable forms of the same drug.

[0006] When a compound crystallizes from a solution or slurry, it can crystallize in various space lattice arrangements, which is a property called "polymorphism". Each of the crystal forms is a "polymorph". Polymorphs of a given substance have the same chemical composition, but they can differ from each other with respect to one or more physical properties such as solubility, dissociation, true density, dissolution, melting point, crystal form, compaction behavior, fluidity, and / or solid stability. Thus, different polymorphs can exhibit significant advantages and disadvantages in the preparation of pharmaceutical compositions.

[0007] Compound (I) is a BTK inhibitor having the following structure:

Chemical formula

[0008] Compound (I) is disclosed and claimed in U.S. Patent No. 9,266,895, Example 31 thereof (corresponding to International Publication No. WO 2014 / 039899). The procedure described in U.S. Patent No. 9,266,895 provides Compound (I) as a white amorphous solid after solvent extraction, and the residual solvent is present at levels exceeding limits suitable for the preparation of pharmaceutical compositions.

[0009] Alternative procedures for manufacturing Compound (I) and its solid forms are disclosed in International Publication No. WO 2015 / 127310 and U.S. Patent Application Publication No. US 2021 / 0198264. Publication No. US 2021 / 0198264 discloses a process for manufacturing Compound (I) to produce an amorphous form of the compound in which pharmaceutically acceptable levels of residual solvents (e.g., methanol, isopropyl acetate, and heptane) remain. In some embodiments described in Publication No. US 2021 / 0198264, detectable levels of such residual solvents do not remain in the final product.

[0010] Specific crystalline forms of Compound (I) are disclosed in U.S. Patent Application Publication No. US 2021 / 0221818 (corresponding to International Publication No. WO 2021 / 150723) and include the crystalline forms designated as Form A, Form B, and Form C therein.

[0011] However, manufacturing a pharmaceutical composition for the effective treatment of a disease also requires that the compound can be manufactured in a storage-stable form and easily formulated into a composition that can be readily absorbed by the body not only by immediate absorption but also by modified-release and extended-release formulations. The pharmaceutically active substance used to prepare the therapeutic agent should be as pure as possible and maintain its stability during long-term storage under various environmental conditions. These properties are useful for preventing the formation of degradation products in pharmaceutical compositions that can potentially be toxic or simply reduce the efficacy of the composition.

[0012] When an unstable crystalline form is used, the crystal morphology can change during manufacture and / or storage, leading to quality control issues and formulation variability. Such changes can affect the reproducibility of the manufacturing process and thereby result in a final formulation that does not meet the high-quality and stringent requirements imposed on the formulation of pharmaceutical compositions.

[0013] Therefore, a crystalline form of compound (I) having sufficient stability and ability for bioabsorption is needed to prepare effective pharmaceutical formulations and therapeutic agents comprising compositions designed for extended release and modified release.

Summary of the Invention

Means for Solving the Problems

[0014] The present disclosure relates to new solid forms of compound (I) that provide some surprisingly improved solubility and stability compared to Form B of compound (I) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), or compared to other solids, salts or crystalline forms of compound (I) previously disclosed.

[0015] Disclosed herein are substantially crystalline forms of compound (I) selected from the HCl salt form, the oxalate form, and the maleate form.

[0016] Also disclosed herein are cocrystalline forms of compound (I), optionally substantially crystalline forms of compound (I) as a cocrystal comprising a substantially crystalline compound (I) and a coformer, where in one embodiment the coformer is methylparaben.

[0017] The present disclosure also relates to pharmaceutical compositions comprising at least one solid form of compound (I) described herein and a pharmaceutically acceptable excipient.

[0018] The present disclosure further provides a solid dosage formulation for administration to a subject in need of treatment, which gives improved solubility, stability and / or bioabsorbability as compared to Form B of Compound (I) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), and relates to a pharmaceutical composition comprising a substantially crystalline form of Compound (I) disclosed herein formulated with at least one excipient selected from a filler, a drug release modifier, a disintegrant, and a lubricant.

[0019] The present disclosure further relates to a pharmaceutical composition comprising a substantially crystalline form of Compound (I) described herein.

[0020] Also disclosed herein is a method of treating a disease in a subject mediated by the activity of BTK by administering to the subject a pharmaceutical composition comprising at least one substantially crystalline form of Compound (I) described herein.

[0021] The accompanying drawings, which are briefly described below, are incorporated herein and constitute a part of this specification. The drawings illustrate some embodiments of the present disclosure and should be considered in conjunction with the description.

Brief Description of the Drawings

[0022]

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Figure 15A - B

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Figure 24A - C

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[0023] Reference is now made in detail to specific embodiments illustrated in the following examples and the accompanying drawings. It will be understood that the present disclosure provides exemplary embodiments, but is not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents that can be recognized by those skilled in the art from the present disclosure.

[0024] Any section headings used herein are for organizational purposes only and should in no way be construed as limiting the desired subject matter.

[0025] I. DEFINITIONS As used herein, the term "a" or "an" entity refers to one or more of that entity. For example, "compound" refers to one or more compounds or at least one compound, unless otherwise specified. Accordingly, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

[0026] The term "about", as used herein prior to one or more specific numerical values, is intended to indicate that a range of values is included within that of the specific value to an extent that one of ordinary skill in the art would consider the range equivalent to the specific recited value (e.g., having the same function or result). When "about" is before a list of numerical values or ranges, the term modifies all of the values or ranges given in the list.

[0027] For example, when "about" is used herein with reference to a peak point of an XRPD pattern, "about" indicates that the numerical value of the peak point can be within ±0.2 of a particular number shown. As will be appreciated by one of ordinary skill in the art, specific XRPD peaks are not exact and can vary in either direction depending on experimental conditions including sample size and purity.

[0028] As used herein, "birefringence" refers to a crystal having two refractive indices. Birefringence is also known as double refraction and occurs in anisotropic crystal forms.

[0029] As used herein, "cocrystal", "cocrystal of compound (I)", or "compound (I) cocrystal" means that compound (I) is present in crystalline form and is non-covalently bonded in the crystal lattice in stoichiometric ratio with at least one coformer.

[0030] "Coformer" means a compound or compounds other than compound (I) in the crystal lattice including a cocrystal. For example, with respect to a cocrystal of compound (I) made herein, the coformer is a molecule in the cocrystal other than compound (I), such as methylparaben. The cocrystal can also contain a stoichiometric amount of water with respect to compound (I) and methylparaben, such as a monohydrate or dihydrate for example.

[0031] Compound (I) as used herein means 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile having the following structure: [Chemical formula]

[0032] Compound (I) as used herein refers to all its stereoisomers or enantiomers, and all mixtures of stereoisomers and enantiomers. In this specification, compound (I) may be referred to as a "drug", "active agent", "therapeutically active agent", or "API".

[0033] "Form B", "Form B of Compound (I)" or "Compound (I) Form B" as used herein refers to the crystalline form of Compound (I) described as Form B in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), and those skilled in the art will recognize and confirm it by the characterization data and / or procedures disclosed in the cited publication. The "Form B" disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet) is a different crystalline form from Form B of the oxalate salt and / or Form B of the maleate salt disclosed herein.

[0034] "Substantially crystalline" or "substantially crystalline form" means that the crystalline form of the compound (including mixtures of crystalline compounds) in the sample is present in an amount exceeding 50% by weight compared to the amorphous form of the compound in the sample, and optionally, in an amount of at least 60% by weight or more, or at least 70% by weight or more, which can be easily measured by analytical tools available to those skilled in the art.

[0035] "Substantially pure" or "substantially pure crystalline" means that the single crystal form of the compound is present in an amount of 90% by weight or more, optionally in an amount of 95% or more, and also optionally in an amount of 99% or more in the sample, compared to all other crystal forms or amorphous forms of the compound and / or all other components in the sample including residual solvents or excipients.

[0036] As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient useful in the preparation of a pharmaceutical composition. For example, pharmaceutically acceptable excipients include carriers and excipients that are generally safe and generally considered acceptable for pharmaceutical use in mammals.

[0037] As used herein, the terms "room temperature" or "ambient conditions" refer to room temperature, outdoors, and uncontrolled humidity conditions at a temperature typically in the range of about 15°C to about 30°C.

[0038] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to a decrease or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0039] As used herein, the terms "treat", "treating", or "treatment", when used in connection with a disorder or condition, include any effect, such as alleviation, reduction, modulation, amelioration, or elimination that results in an improvement of the disorder or condition. Improvement of any symptom of a disorder or condition or reduction of its severity can be readily evaluated according to standard methods and techniques known in the art.

[0040] As used herein, the term "solid form" refers to the physical form of a compound that is not primarily in a liquid or gaseous state, including amorphous and crystalline forms.

[0041] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the positions of its molecules. An amorphous solid is generally a supercooled liquid in which the molecules are arranged in a random manner such that there is no well-defined arrangement, e.g., molecular packing and long-range order. For example, an amorphous material is a solid material that does not have sharp characteristic signals in its X-ray power diffractogram (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its diffraction pattern. The broad peaks are characteristic of amorphous solids. For example, for a comparison of the diffraction patterns of amorphous and crystalline materials, see U.S. Patent Application Publication No. 2004 / 0006237.

[0042] As used herein, the term "DSC" refers to an analytical method of differential scanning calorimetry.

[0043] As used herein, the term "TGA" refers to an analytical method of thermogravimetric (also called thermogravimetric) analysis.

[0044] II. Embodiments The present disclosure relates to a new solid form of compound (I) that provides surprisingly improved solubility and / or stability compared to compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet), or compared to other solids, salts or crystalline forms of compound (I) previously disclosed.

[0045] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile selected from its HCl salt, oxalate salt, or maleate salt form.

[0046] In some embodiments, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile:HCl birefringent crystalline salt. In some embodiments, the aforementioned HCl birefringent crystalline salt is characterized by an XRPD pattern substantially the same as that of FIG. 1 herein.

[0047] In some embodiments, the substantially crystalline form of the present disclosure is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile:HCl crystalline salt hydrate. In some embodiments, the aforementioned HCl crystalline salt hydrate is characterized by at least one of an XRPD pattern substantially the same as that of FIG. 2 herein; and / or a DSC / TGA profile substantially the same as that of FIG. 3 herein.

[0048] In some embodiments, the substantially crystalline form of the present disclosure is 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-ennitrile: HCl crystalline salt Form A. In some embodiments, the aforementioned HCl crystalline salt Form A is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 4; and / or an XRPD pattern substantially the same as that in FIG. 5; and / or a DSC profile substantially the same as that in FIG. 6; and / or a TGA profile substantially the same as that in FIG. 7. In some embodiments, the aforementioned HCl crystalline salt Form A is characterized by an XRPD pattern comprising four or more peaks selected from the peaks of about 9.7±0.2, 14.9±0.2, 17.6±0.2, 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 29.3±0.3 in units of 2-theta degrees.

[0049] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-ennitrile: oxalic acid birefringent crystalline salt Form A. In some embodiments, the aforementioned oxalic acid birefringent crystalline salt Form A is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 8; and / or a DSC / TGA profile substantially the same as that in FIG. 9.

[0050] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile: maleic acid birefringent crystalline salt. In some embodiments, the aforementioned maleic acid birefringent crystalline salt is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 10; and / or a DSC / TGA profile substantially the same as that in FIG. 11.

[0051] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile: oxalic acid crystalline salt hydrate form A. In some embodiments, the aforementioned oxalic acid crystalline salt hydrate form A is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 14; and / or a DSC profile substantially the same as that in FIG. 15A. In some embodiments, the aforementioned oxalic acid crystalline salt hydrate form A is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 16; and / or an XRPD pattern substantially the same as that in FIG. 17; and / or a TGA profile substantially the same as that in FIG. 18; and / or a DCS / TGA profile substantially the same as that in FIG. 19. In some embodiments, the aforementioned oxalic acid crystalline salt hydrate form A is characterized by an XRPD pattern including four or more peaks selected from the peaks of about 4.8±0.2, 9.3±0.2, 14.0±0.2, 14.2±0.2, 17.0±0.2, 18.7±0.2, 19.6±0.2 and 22.6±0.2 in units of 2-theta degrees.

[0052] In one embodiment, the present disclosure includes 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile: oxalic acid crystal salt hydrate form B. In some embodiments, the above-mentioned oxalic acid crystal salt hydrate form B is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 12; and / or a DSC / TGA profile substantially the same as that in FIG. 13; and / or a DSC profile substantially the same as that in FIG. 15B.

[0053] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile: maleic acid crystal salt form B·MeCN solvate. In some embodiments, the above-mentioned maleic acid crystal salt form B·MeCN solvate is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 20; and / or a DSC / TGA profile substantially the same as that in FIG. 21.

[0054] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile: maleic acid crystal salt Form A. In some embodiments, the maleic acid crystal salt Form A described above is characterized by at least one of an XRPD pattern substantially the same as that in FIG. 22; and / or a TGA profile substantially the same as that in FIG. 23. In some embodiments, the maleic acid crystal salt Form A described above is characterized by an XRPD pattern including four or more peaks selected from the peaks of about 9.7±0.2, 14.9±0.2, 17.6±0.2, 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 22.8±0.2 with 2-theta degree as the unit.

[0055] In one embodiment, the present disclosure includes a substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile, which is a methylparaben cocrystal. In some embodiments, the above-mentioned methylparaben cocrystal of the present disclosure is characterized by at least one of an XRPD pattern substantially the same as FIG. 27; and / or a DCS / TGA profile substantially the same as FIG. 28. In some embodiments, the above-mentioned methylparaben cocrystal is characterized by an XRPD pattern including four or more peaks selected from the peaks of about 4.6±0.2, 10.8±0.2, 16.6±0.2, 18.3±0.2, 19.3±0.2, 20.2±0.2, 21.6±0.2 and 22.5±0.2 in units of 2-theta degrees. In other embodiments, the substantially crystalline form of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile is selected from HCl salts, oxalates, maleates, or methylparaben cocrystals that are at least 50% crystalline, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

[0056] Further embodiments disclosed herein include pharmaceutical compositions comprising at least one substantially crystalline form of any of the alternative embodiments herein and a pharmaceutically acceptable excipient; optionally, the pharmaceutical composition is optionally formulated for the treatment of a disorder in a subject mediated by BTK kinase, of 2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile in a salt form, for modified or extended release to a subject.

[0057] Pharmaceutical composition The crystalline forms described herein incorporate a pharmaceutical active ingredient (API), as well as one or more pharmaceutically acceptable excipients, and are useful as materials for preparing pharmaceutical compositions suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions will be pharmaceuticals such as, for example, solid oral dosage forms such as tablets and / or capsules.

[0058] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of compound (I) selected from HCl salt, oxalate, maleate, or methylparaben cocrystals. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one crystalline form of compound (I) described herein and at least one additional pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable" in the sense that it is not harmful to the subject composition and its components and is compatible with them. The use thereof is contemplated to be within the scope of the present disclosure so long as conventional pharmaceutically acceptable excipients are not incompatible with compound (I), such as producing undesirable biological effects or interacting detrimentally with other components of the pharmaceutically acceptable composition in other ways.

[0059] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of a compound (I) selected from HCl salt, oxalate, maleate, or methylparaben cocrystal, formulated with one or more excipients for use in providing extended release or modified release dosage administration to a subject.

[0060] Some non-limiting examples of materials that can act as pharmaceutically acceptable excipients include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical formulations. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, Eds. J. Swarbrick and J. C. Boylan, 1988 - 1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference, also disclose additional non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for preparing and using them.

[0061] The pharmaceutical compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, intranasally, buccally, vaginally, or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramedullary, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the disclosure are administered orally, intraperitoneally, or intravenously. The pharmaceutical compositions of the disclosure in sterile injectable form can be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

[0062] For this purpose, any bland fixed oil containing synthetic mono- or diglycerides can be utilized. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants such as Tween, Span, and other emulsifying or bioavailability enhancing agents commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[0063] The pharmaceutical compositions disclosed herein can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. When an aqueous suspension is required for oral use, the active ingredient is typically combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added.

[0064] In some embodiments, pharmaceutical compositions comprising the crystalline salt forms disclosed herein can be used as inhibitors of Bruton's tyrosine kinase (BTK) and in the treatment of diseases mediated by BTK in mammals in need thereof. Such diseases and methods of treatment with the crystals disclosed herein include acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune retinopathy, axonal & neuronal neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating neuropathies, Devic's disease (neuromyelitis optica), experimental allergic encephalomyelitis, giant cell arteritis (temporal arteritis), Guillain - Barré syndrome, Lambert - Eaton syndrome, chronic Meniere's disease, myasthenia gravis, neuromyotonia, opsoclonus - myoclonus syndrome, optic neuritis, paraneoplastic cerebellar degeneration, peripheral neuropathy, perivenous encephalomyelitis, restless legs syndrome, stiff person syndrome, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis / giant cell arteritis, transverse myelitis, multiple sclerosis, autonomic neuropathy, age - related macular degeneration (exudative and atrophic), corneal transplantation, encephalitis, meningitis, vasculitis, or systemic lupus erythematosus (SLE); rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, lupus, uveitis, myasthenia gravis, warm autoimmune hemolytic anemia, immune thrombocytopenia (ITP), Wegener's granulomatosis, Sjögren's disease, Sjögren's dry eye, non - Sjögren's dry eye disease, psoriasis, pemphigus, urticaria (such as chronic idiopathic urticaria), asthma, diseases related to IgG4 regulation, diffuse large B - cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B - cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B - cell non - Hodgkin lymphoma, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytosis, extranodal marginal zone B - cell lymphoma, nodal marginal zone B - cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B - cell lymphoma, intravascular large B - cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis may be selected.

Example

[0065] As used in the following examples or elsewhere in this specification, the following table of abbreviations may be useful.

[0066]

Table 1

[0067]

Table 2

[0068] Measuring Instruments The following measuring instruments and procedures were used to collect the data described in the examples of this specification. One of ordinary skill in the art will recognize that alternative measuring instruments and procedures that are available to and known by one of ordinary skill in the art can be optionally used to collect characterization data such as NMR, PLM, XRPD, TGA, and DSC / TGA data.

[0069] Option A Measuring Instrument XRPD. XRPD data was collected using a PANalytical X’Pert Pro diffractometer with a Ni-filtered Cu Kα (45 kV / 40 mA) line, a step size of 0.02° 2θ, and an X’celerator™ RTMS (Real Time Multi-Strip) detector. Incident beam side configuration: fixed divergence slit (0.25°), 0.04 rad soller slit, anti-scatter slit (0.25°), and 10 mm beam mask. Diffracted beam side configuration: fixed divergence slit (0.25°) and 0.04 rad soller slit. The sample was placed flat on a zero-background Si wafer.

[0070] DSC. Data was collected using a TA Instruments Q100 or Q2000 differential scanning calorimeter with an autosampler and a refrigerated cooling system under a 40 mL / min N2 purge. The DSC thermogram of the sample was obtained at 10 °C / min in a crimped Al pan.

[0071] TGA. The data was collected by a TA Instruments Q50 thermogravimetric analyzer in a Pt or Al pan under a 40 mL / min N2 purge. The TGA thermogram of the sample was obtained at 10 °C / min.

[0072] Option B Instrument XRPD. The XRPD data was collected, alternatively, by a Bruker AXS C2 General Area Detector Diffraction System (GADDS) diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automatic sample positioning, and a Vantec-500 two-dimensional area detector. The X-ray optics consisted of a single Goebel multilayer mirror coupled with a 0.3 mm pinhole collimator. The beam spread, i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm. The θ-θ continuous scan mode was utilized at a sample-detector distance of 20 cm, which gave an effective 2θ range of 1.5° to 32.5°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection and analysis was Bruker GADDS and Diffrac Plus EVA for Win7 / XP, respectively. Samples experimented under ambient conditions were prepared as flat specimens using the as-received powder without grinding. The sample was prepared by lightly pressing the powder to obtain a flat surface for analysis and analyzed on a glass slide.

[0073] DSC. Alternatively, the data was collected by a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, each sample of 0.5 - 3 mg was heated from 25 °C to approximately 230 °C at 10 °C / min in a pinholed aluminum pan. A purge of dry nitrogen at 50 ml / min was maintained over the sample. The instrument control software was TRIOS, and the data was analyzed using TRIOS or Universal Analysis.

[0074] TGA. TGA data was collected using a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, each sample of 5 - 10 mg was placed in a pre-weighed aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / min. A nitrogen purge of 25 ml / min was maintained over the sample. The instrument control software was TRIOS, and data was analyzed using TRIOS or Universal Analysis.

[0075] PLM. Samples were analyzed using a Leica LM / DM polarized light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a glass slip. Samples were observed with an appropriate magnification and partial polarization in combination with a λ-analyzer filter. Images were captured using Studio Capture or Image ProPlus software.

[0076] NMR. 1 1H NMR spectra were collected using a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Samples were typically prepared in DMSO-d6 solvent. Automated experiments were obtained using standard Bruker-mounted experiments (1H) using ICON-NMR settings within Topspin software. Offline analysis was performed using ACD Spectrus Processo.

[0077] Exemplary Synthesis of Starting Material - Compound (I) Form B Form B of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet) was used as the starting material in each of the procedures described in Examples 1 to 9 below and as the comparative sample in Examples 10 to 14. Form B of compound (I) can be prepared according to the procedures described in Examples 2 to 4 of U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), which is incorporated herein by reference, optionally according to Example 4 therein.

[0078] The following preparation of Form B of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet) is provided so that those skilled in the art can prepare BTK inhibitor compounds. The synthetic routes should not be considered as limiting the scope of the present disclosure and are merely examples and representatives thereof.

[0079] In the single-substitution method, 96 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2,5-dienenitrile was dissolved in 0.3 mL of ethyl acetate. The resulting solution was seeded with NaCl and stirred at room temperature. After stirring overnight, a turbid solution was obtained, which was sonicated for 5 minutes. After further stirring for 2 days, a suspension was obtained, which was filtered (centrifugal unit filter, PTFE, 0.22 μm) to obtain crystalline Form B disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet).

[0080] In another alternative method, 430 g of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile (Compound (I)) in Form C was combined with ethanol (4.1 L) at approximately 15 °C to form a slurry. Then, Form B seeds crystals disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were added (up to approximately 5 wt%), and the slurry was stirred for approximately 2 days. The slurry was filtered and dried under vacuum while heating to obtain approximately 300 g of crystalline Form B of Compound (I) as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) (yield 74%).

[0081] Form C can also be prepared according to the procedures described in Examples 5 to 8 of US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet), which is incorporated herein by reference. For example, it can be prepared as described in Example 5 thereof. 100 mg of amorphous (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]penta-2-enenitrile was combined with acetonitrile (0.5 mL). The solution was seeded with crystalline Form B of Compound (I) as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) and stirred at room temperature for 48 hours. After approximately 48 hours, a thick white free-flowing slurry was obtained and determined to be Form C (estimated yield over 50%).

[0082] Example 1 - Solubility and Solvent Evaluation The solubility of Form B crystals of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) was evaluated in a variety of solvents to facilitate the selection of solvent systems and corresponding addition strategies for subsequent screening experiments in Example 2. Solubility was visually estimated at room temperature in 12 common solvents. Form B crystals (about 20 mg) of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were weighed into each of 12 vials, followed by addition of 200 μL of solvent at room temperature and observation for 15 minutes. If the solid did not dissolve in 200 μL at room temperature, a second aliquot of 800 μL of solvent was added at room temperature and dissolution was visually confirmed. The results are shown in Table 1.

[0083]

Table 3

[0084] Example 2 - Compound (I): HCl Birefringent Crystal Salt 2.1 HCl Crystal Screen Focusing on the HCl salt, 12 experiments were conducted using Form B crystals of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet). The experiments were designed to generate data on whether HCl crystallization salts can be obtained in various solvent systems and experimental conditions, under what conditions they can be obtained, and the properties of the products produced. This experiment was conducted using the solutions / gums / suspensions generated from the solubility experiment in Example 1 as starting materials. 4M HCl in 1 equivalent of 1,4-dioxane was added to 12 samples made during the above evaluation (Example 1) in 12 aprotic solvents (MeCN, acetone, DCM, MIBK, EtOAc, THF, IPE, toluene, cyclohexane, DMC, MTBE, cyclohexanone), and then a five-step crystallization procedure was utilized. The experiment proceeded as follows: 1. HCl in 1 equivalent of 1,4-dioxane was added to the solution / gum / suspension obtained from the 12 solubility experiments of Example 1; 2. The solution / gum / suspension was stirred while cycling the temperature between 25 °C and 5 °C for 2 days (TC1 crystallization); 3. The solvent was rapidly evaporated under reduced pressure by GeneVac, and 200 μL of the solvent was re-aliquoted (FEV); 4. The solution / gum / suspension was stirred while cycling the temperature between 25 °C and 5 °C for 5 days (TC2 crystallization); 5. The solution / gum / gel was stirred at 25 °C for 1 hour, cooled to 4 °C, and maintained at 4 °C for 2 days (RC); 6. The solvent was evaporated at room temperature for 5 days in an N2 bleed chamber (EV).

[0085] PLM and XRPD analyses were performed in situ for each of the 12 samples in each mode of crystallization (TC1, FEV, TC2, RC, and EV). The results are reported in Table 2 below. Based on the PLM and XRPD results, birefringent (i.e., "double refracting") crystals were obtained only in the following two cases: (1) after TC2 (step 4) using MeCN as the solvent, and (2) after EV (step 5) using DMC as the solvent. The remaining experiments yielded either Form B crystals or an amorphous form of Compound (I) as disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet). XRPD patterns of the two birefringent samples were obtained and reported in Figure 1. As shown by the XRPD patterns, the two samples had substantially the same form. Thermal analysis also indicated that they contained a hydrated form.

[0086]

Table 4

[0087] 2.2. Scale-up and characterization of Compound (I): HCl crystal salt Form A. The birefringent crystalline HCl salt product obtained from Example 2.1 was scaled up to 100 mg and 1.4 g and further characterized. At the 100 mg scale, approximately 100.6 mg of Compound (I) Form B crystals disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were mixed with MeCN (1 mL) at room temperature to form a slurry. To the slurry was added a 4 M HCl solution in 1,4-dioxane (1 equivalent). The resulting solution was seeded with the birefringent HCl crystal salt product (1 mg) obtained from Example 2.1; the seed crystals persisted. The slurry was stirred at room temperature for 2 days. The solid was filtered and air-dried for 2 hours to obtain 78 mg of Compound (I) HCl crystal salt Form A.

[0088] 2.3. Preparation and Characterization of Compound (I):HCl Crystal Salt Hydrate. Approximately 1.6 g of Compound (I) Form B disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) was mixed with MeCN (16 mL) at room temperature. To this slurry was added a 4 M HCl solution in 1,4-dioxane (1 equivalent). The solution was seeded with Compound (I) HCl crystal salt Form A (70 mg); the seed crystals persisted. The slurry was stirred at room temperature for 3 days. The solid was filtered and air-dried for 16 hours to obtain 1.4 g of a product containing Compound (I) monohydrochloride crystal salt as a hydrate (1.9 equivalents). (Yield 90%). The XRPD of the sample is shown in Figure 2 to confirm the crystalline product. The results of the DSC and TGA thermograms are shown in Figure 3; the DSC showed a broad endotherm between 25 °C and 140 °C and an endotherm with an onset at 160.8 °C. The TGA showed a 4.6% weight loss of water (1.9 equivalents) between 25 °C and 140 °C. The HPLC purity was 99.4% of the E-isomer.

[0089] Example 3 - Preparation and Characterization of Compound (I) HCl Crystal Salt Form A When about 10 g of compound (I) in Form B free base, disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), was stirred in acetonitrile (about 100 mL), a suspension was obtained. A saturated HCl solution in isopropanol (about 3 mL) was added. After about 3 minutes, a suspension was formed. The slurry was stirred for about 3 days and then filtered and washed with acetonitrile. The resulting crystals were dried under vacuum at 30 °C to obtain 7.8 g of the HCl crystal salt Form A of compound (I) as an anhydrous white solid with a purity of 99.7% of the E isomer of compound (I) and a combined purity of 99.8% of the E isomer and the Z isomer.

[0090] 3.1. XRPD of Example 3 (Compound (I) HCl Crystal Salt Form A). The XRPD diffractogram of compound (I):HCl crystal salt Form A was obtained by the instrument and procedure described above in the Instrument section (Option A). The XRPD patterns shown in Figures 4 and 5 were obtained in replicate experiments, and Figure 5 shows the peak numbers. The peaks identified in Figure 5 include those listed in Tables 3A and 3B below; optionally, the peaks reported in Table 3B may be considered representative.

[0091]

Table 5

[0092]

Table 6

[0093] 3.2. TGA Profile of Example 3 (Compound (I) HCl Crystal Salt Form A). The TGA thermogram of Example 3 (Compound (I) HCl Crystal Salt Form A) was obtained by the instrument and procedure described above in the Instrument section (Option A). The results are shown in Figure 6.

[0094] 3.3. DSC / TGA Thermogram of Compound (I):HCl Crystal Salt Form A The DSC was performed on the sample of Example 3 using the measuring instrument and procedure described above in the section Measuring instrument (Option A). The results are shown in Figure 7; the temperatures of the exothermic and endothermic transitions recorded by DSC analysis are shown in Figure 7 as onset values.

[0095] Example 4 - Initial counterion tests: Oxalic acid and maleic acid crystalline salts Forty-eight crystallization experiments were carried out with Compound (I), crystalline form B, using eight counterions and six solvents as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet). The salt test experiments were carried out using the substantially pure E-isomer of Compound (I) crystalline form B. Compound (I) form B has two ionizable basic sites with calculated pK a values of 5.3 and 3.6. A total of eight counterions showing suitable pK a values were selected and added as anhydrous solids (1 equivalent) to test salt formation. Table 4 summarizes the counterions and the equivalents used.

[0096]

Table 7

[0097] Six aprotic solvents (MeCN, toluene, MIBK, EtOAc, DMC, acetone) were selected for the salt test experiments considering the solubility (Example 1, Table 1), polarity, and chemical diversity of Compound (I) form B crystals as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet). Using the five-step procedure described below, the samples were investigated in situ by PLM for birefringence at each step. When the sample was birefringent, the crystals were isolated, analyzed, and classified by XRPD pattern. All XRPD patterns were compared with the XRPD patterns of Compound (I) form B crystals and appropriate counterions as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) for identification: 1. One equivalent of counterion as an anhydrous solid was added to a 2-mL HPLC vial containing Form B crystals (approx. 20 mg); 2. 200 - 300 μL of a solvent (selected from MeCN, toluene, MIBK, EtOAc, DMC, and acetone) was dispensed into a 2-mL HPLC vial containing a mixture of Form B and the counterion according to Step 1, respectively; 3. The solution / suspension / gum was stirred while cycling the temperature between 25 °C and 5 °C for 15 days (TC); 4. The solution / gum obtained from Step 3 was stirred at 25 °C for 1 hour, cooled to 4 °C, and maintained at 4 °C for 3 days (RC); and 5. The solvent was evaporated at room temperature for up to 10 days in an N2 bleed chamber (EV).

[0098] Table 5 shows the results of this salt test. Of the 48 experiments, only two vials, namely those containing maleic acid and oxalic acid counterions together with acetonitrile as the solvent, produced new crystal forms of Compound (I). Thermal analysis revealed that the successful ones were hydrate forms. Other birefringent products were observed and isolated in 31 experiments; however, they were confirmed by XRPD to be Form B crystals of Compound (I), crystalline counterions, or a mixture of Form B of Compound (I) and the counterion (shown as "mixture" in Table 4) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet).

[0099] The remaining experiments produced amorphous products as shown in Table 5.

[0100]

Table 8

[0101] 4.1 Oxalic Acid Birefringent Salt Form A The compound (I) formed in acetonitrile: the oxalate birefringent crystal was a hydrate (2.7 wt% water). The XRPD pattern is shown in Figure 8, and the DSC and TGA thermograms are shown in Figure 9. The DSC thermogram showed a broad endotherm between 25 °C and 90 °C and an endotherm with an onset at 156.2 °C. The HPLC purity was 99.8% of the E-isomer.

[0102] 4.2 Maleic acid birefringent salt The compound (I) formed in acetonitrile: the maleate birefringent crystal was a poorly crystalline solid as reflected in the XRPD pattern shown in Figure 10. The DSC and TGA thermograms of the maleate are shown in Figure 11. The DSC thermogram showed a broad endotherm between 25 °C and 100 °C and an endotherm with an onset at 120.9 °C. The HPLC purity was 99.8% of the E-isomer.

[0103] Example 5 - Compound (I) oxalate crystal forms A and B 5.1 Compound (I) oxalate crystal hydrate form A By scaling up and characterizing the oxalate of Example 4.1, two forms of crystal salt products, namely Compound (I) oxalate crystal hydrate form A and Compound (I) oxalate crystal hydrate form B, were obtained herein.

[0104] The 100 mg scale-up was carried out by stirring Compound (I) form B (100.4 mg) and oxalic acid solid (1 equivalent) in MeCN (1 mL) at room temperature, as disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet). The slurry was seeded with the oxalate product of Example 4.1 (1 mg); the seed crystals persisted. The mixture was stirred at room temperature for 2 days. XRPD of an aliquot sample showed the new Compound (I) oxalate crystal form B, which converted to form A after drying at 30 °C for 7 hours. The solid was filtered and air-dried for 4 hours to obtain Compound (I) oxalate crystal hydrate form A. The yield was 70% (80 mg).

[0105] 5.2 Compound (I) Oxalic Acid Crystal Salt Hydrate Form B Additional preparation and characterization were carried out. Form B (1.57 g) of compound (I) and oxalic acid solid (1 equivalent) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were stirred in MeCN (16 mL) at room temperature, and the slurry was seeded with the oxalate of Example 4.1 (70 mg); the seed crystals continued to exist. The mixture was stirred at room temperature for 3 days. XRPD of an aliquot sample showed compound (I) oxalic acid crystal salt hydrate form B. The solid was filtered and air-dried for 16 hours to obtain compound (I) oxalic acid crystal salt form B (1.52 g; yield 85%), which was also a hydrate (4.8 wt% water) and was characterized by the XRPD pattern shown in Figure 12. The DSC and TGA thermograms of compound (I) oxalic acid crystal salt hydrate form B are shown in Figure 13. An overlay of the XRPD patterns of compound (I) oxalic acid crystal salt hydrate forms A and B is shown in Figure 14. The DSCs of compound (I) oxalic acid crystal salt hydrate forms A and B are shown in Figures 15A and 15B, respectively.

[0106] The DSC thermogram of compound (I) oxalic acid crystal salt hydrate form B showed a broad endotherm between 25 °C and 110 °C and an endotherm with an onset at 158.2 °C. The HPLC purity was 99.5% of the E-isomer. Ion chromatography data showed a mono-oxalate (11.42 wt% Cl experimentally vs. 11.78 wt% Cl theoretical). Attempts to produce compound (I) oxalic acid crystal salt form A from oxalic acid crystal salt form B (prepared as described in Example 5.2) by drying the scaled-up product under vacuum (10-in Hg) at 30 °C with N2 bleed for 24 hours produced a poorly crystalline solid that was a mixture of Example 4.1 (oxalic acid birefringent salt form A), Example 5.2 (oxalic acid crystal salt hydrate form B), and an amorphous product.

[0107] Example 6 - Compound (I) Oxalic Acid Crystal Salt Hydrate Form A The approximately 1 g of Compound (I) in Form B free base, as disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), was added to acetonitrile (approximately 10 mL) to form a solution. Oxalic acid (approximately 135 mg) was added, and the solution was stirred for approximately 3 days. The resulting crystals were filtered, washed with acetonitrile (approximately 15 mL), and dried under vacuum at room temperature to obtain 627 mg of Compound (I) oxalic acid crystal salt Form A as a hydrate with a purity of 99.7% of the E-isomer (yield 55%).

[0108] 6.1 XRPD of Compound (I) oxalic acid crystal salt hydrate Form A. The XRPD diffractogram of Compound (I) oxalic acid crystal salt hydrate Form A was obtained by the instrument and procedure described above in the Instrument section (Option A). The XPRD results were obtained as shown in Figures 16 and 17. The peaks identified in Figures 16 and 17 include those listed in Tables 6A and 6B below; optionally, the peaks reported in Table 6B may be considered representative.

[0109] [Table 9]

[0110] [Table 10]

[0111] 6.2. TGA and DSC / TGA. Additional data on Compound (I) oxalic acid crystal salt hydrate Form A prepared as described herein were obtained using the instrument and procedure described above in the Instrument section (Option A). The results obtained are reported in Figures 18 (TGA) and 19 (DSC / TGA).

[0112] Example 7 - Compound (I) maleic acid crystal salt Form B·MeCN solvate Form B (102.7 mg) of compound (I) and maleic acid counterion (17.9 mg, 1 equivalent) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were stirred in MeCN (1 mL) at room temperature. The resulting solution was seeded with the maleate hydrate (1 mg) of Example 4.2; the seed crystals persisted. The slurry was stirred at room temperature for 2 days. The solid was filtered and air-dried for 4 hours to give a new crystal form - compound (I) maleic acid crystal salt form B·MeCN solvate, which was confirmed by XRPD analysis (100 mg; yield 80%).

[0113] Additional preparation and characterization of the maleate were carried out as follows. Form B (1.3 g) of compound (I) and maleic acid solid (1 equivalent) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) were stirred in MeCN (13 mL) at room temperature. The resulting slurry was seeded with the compound (I) maleic acid crystal salt form B·MeCN solvate prepared as described herein; the seed crystals persisted. The mixture was stirred at room temperature for 3 days. The solid was filtered and air-dried for 4 hours to give the maleic acid crystal salt form B·MeCN solvate (1.44 g, yield 94%). The XRPD pattern of the compound (I) maleate crystal form B·MeCN solvate is shown in Figure 20. The compound (I) maleic acid crystal form B is a MeCN solvate. The DSC and TGA thermograms of this form are shown in Figure 21. DSC showed an endotherm with an onset at 132.2 °C. The HPLC purity was 99.5% of the E-isomer. Proton NMR showed that it is a monomaleate containing MeCN (0.7 equivalent).

[0114] Example 8 - Compound (I) Maleic Acid Crystal Salt Form A Form B (1.50 mmol) of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) was stirred at 20 °C in 10.0 mL (10 volumes) of acetonitrile. Maleic acid (1.50 mmol, 1.00 equivalent) was added to the suspension in one portion. The resulting mixture was stirred at 20 °C for 72 hours. Next, vacuum filtration was carried out to remove the mother liquor. Then, the resulting wet cake was washed with acetonitrile (3 × 5 mL, 5 volumes). The solid material was collected and dried in vacuo at 25 °C for 24 hours. The maleate salt of compound (I) was obtained as a white solid (1.17 mmol, 78% yield). This material was identified as maleic acid crystal salt form A.

[0115] 8.1 XRPD of Example 8 (maleic acid crystal salt of compound (I) form A). The XRPD diffractogram of Example 8 was collected by the instrument and procedure described in the Instrument section (Option B). The obtained XRPD pattern of maleic acid crystal salt form A of Example 8 is shown in Figure 22 as an overlay with the XRPD patterns of maleic acid and form B of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet).

[0116]

Table 11

[0117] 8.2. TGA. Additional data on maleic acid crystal salt form A of compound (I) were obtained using the procedure described above in the Instrument section. The results obtained are reported in Figure 23 (TGA).

[0118] Example 9 - Relative solubility analysis of HCl, oxalic acid, and maleic acid crystal salts of compound (I) The above examples show procedures for obtaining novel crystalline salt forms of compound (I) having increased solubility compared to amorphous and previously reported form B of compound (I) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet). The higher solubility of the crystalline salts of the invention described herein may be useful for developing sustained release or modified release formulations and / or multiple formulations that provide improved bioabsorption. This example reports exemplary data regarding the relative solubility of the crystals. The HPLC chromatograms used in this example were analyzed at 225 nm.

[0119] 9.1. Calibration. To obtain relative solubility data, a calibration curve was first generated using a stock solution of form B (20.0 mg) of compound (I) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) in methanol (10 mL) prepared in a volumetric flask. Using the stock solution, a dilution series for HPLC quantification purposes was generated according to Table 8 below.

[0120] [Table 12]

[0121] Using the purity (area %) of form B disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet), the measured areas of the 1 and 2 mg / mL solutions were divided by the average purity to correct the HPLC area (area %). By using linear regression, a linear best-fit equation was derived, and the concentration of compound (I) form B was expressed in mg / mL as a function of the area recorded by HPLC.

[0122] 9.2. Relative Solubility in Milli-Q Purified Water. Next, using the following 5-step process, the solubilities of Compound (I) Form B, the amorphous form of Compound (I), and the HCl, oxalic acid, and maleate salts of Examples 3, 6, and 8 in water purified by a Milli-Q reverse osmosis system were compared. First, an amount of the test sample was placed in a 2-drum vial equipped with a stir bar. For each of Compound (I) Form B, the amorphous Compound (I), and the HCl crystal salt disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), 30 mg of the test sample was used in this first step; for the oxalate salt, 60 mg of the test sample was used; and for the maleate salt, more than about 100 mg of the test sample was used. In the second step, Milli-Q water was added to the vial with stirring, and then the pH of the resulting suspension / solution was measured. For each of Form B, the amorphous Compound (I), and the HCl crystal salt disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), a sufficient amount of Milli-Q water was added to dissolve the test sample; for example, for the HCl salt, 3 mL of Milli-Q water was added, for the oxalate salt, 2 mL of Milli-Q water was added in the second step, and for the maleate salt, a greater amount of Milli-Q water was added. After 1 hour of stirring, the sample was withdrawn in an amount sufficient to allow further filtration and characterization (e.g., for Form B, the amorphous, and the HCl crystal salt disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet), 500 μL of the sample was withdrawn, and for the oxalate salt, 150 μL was obtained). In each case, the sample was filtered through a 0.2 μm filter. The resulting solution was appropriately diluted to fall within the calibrated concentration range on HPLC. Sampling was repeated in the same manner after 3 hours and 24 hours. After the last sample was taken, the pH was recorded again. The dissolved sample was determined by converting the recorded area on HPLC to a concentration in mg / mL using the established calibration formula.

[0123] 9.3 Relative solubility in aqueous buffer The procedure described in Example 9.2 was modified to determine the relative solubility of the test samples in aqueous buffers at pH 4.5 and 6.8. As in Section 9.2, in the first step, the test samples (30 mg of Form B, amorphous, or HCl salt as disclosed in US Patent Application Publication No. 2021 / 0221818 corresponding to International Publication No. 2021 / 150723 pamphlet; 20 mg of oxalate) were placed in a 2-drum vial equipped with a stir bar. Next, the second step of this modified procedure involved adding the buffer (5 mL) to the vial with stirring, followed by measuring the pH of the resulting suspension. If the pH deviated by more than 0.1 unit from the target pH, 10 μL aliquots of 1 M NaOH (aqueous solution) were used to readjust the pH to the original value. After 1 hour of stirring, samples were withdrawn (1000 μL of Form B, amorphous, or HCl salt as disclosed in US Patent Application Publication No. 2021 / 0221818 corresponding to International Publication No. 2021 / 150723 pamphlet; 150 μL for oxalate). As in 9.2 above, the samples were filtered through a 0.2 μm filter and the resulting solution was appropriately diluted to fall within the calibrated concentration range on HPLC. Sampling was repeated at 3 hours and 24 hours in the same manner, and after the last sample was taken, the pH was recorded again. The dissolved samples were determined by converting the recorded area on HPLC to concentration in mg / mL using the established calibration formula.

[0124] 9.4 Solubility data Applying the procedures of Examples 9.1 - 9.3, solubility data was obtained as described in Tables 9 - 11. Figures 24A - C represent graphical data showing the significantly increased solubility of the HCl crystal salt form of Compound (I) compared to the amorphous and solid form of Compound (I) Form B as disclosed in US Patent Application Publication No. 2021 / 0221818 corresponding to International Publication No. 2021 / 150723 pamphlet. Figures 25 and 26 represent graphical data showing the solubility of the oxalate and maleate crystal salt forms of Compound (I) over time at various pHs, respectively.

[0125]

Table 13

[0126]

Table 14

[0127]

Table 15

[0128] Example 10 - Compound (I) Methylparaben Cocrystal Approximately 1 g of Form B of Compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 Pamphlet) was weighed into a 100 mL round-bottom flask, and methylparaben (1.0 equivalent, 228.52 mg) was added to form a mixture. Subsequently, the sample and the coformer (methylparaben) were dissolved in 10 volumes of acetone (10 mL) with the aid of stirring. A clear solution was formed, to which 30 volumes of n-heptane (30 mL) was added to obtain a pale suspension. The suspension began to dissolve, and an additional 20 volumes (20 mL) of n-heptane was added. The sample remained a turbid solution, and a brown bilayer was at the bottom of the flask. This was left stirring overnight. A white solid formed overnight, which was filtered, air-dried, and then analyzed by XRPD. The sample was confirmed to be the methylparaben cocrystal of Compound (I). When the material was dried in an oven under vacuum at 25 °C for 4 hours, the yield was 80.7% and the purity by HPLC was 97.5%. The DSC thermogram showed an onset at 133.5 °C with an enthalpy heat of 42 J / g; the TGA thermogram showed a weight loss of 2.6% between 25 °C and 250 °C.

[0129] Further analysis revealed that the methylparaben cocrystal is hygroscopic and absorbs 2.3% w / w water between 0% and 90% RH. The material remained in the same XRPD pattern after GVS analysis, static storage conditions, milling and compression tests, and after kinetic solubility analysis. Overall, the solid state properties of the methylparaben cocrystal form of compound (I) are surprisingly good compared to the form B crystal form of compound (I) disclosed in US Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet), as shown by the comparative milling tests, compression tests, and static storage analysis described in Examples 11, 12, and 13 herein. The cocrystal can also be easily prepared by addition of a poor solvent, producing good yields.

[0130] 10.1. XRPD. XRPD diffractograms were obtained by the instrument and procedure described in the instrument section (Option B). The XRPD pattern of the methylparaben cocrystal is shown in Figure 27. The peaks identified in Figure 27 include those listed in Tables 12A and 12B below; optionally, the peaks reported in Table 12B may be considered representative.

[0131]

Table 16

[0132]

Table 17

[0133] 10.2. DSC / TGA. Additional data on the methylparaben cocrystal salt form of compound (I) were obtained using the procedure described above in the instrument section (Option B). The results obtained are reported in Figure 28 (DSC / TGA thermogram).

[0134] Example 11 - Comparative Milling Tests of Compound (I) Form B and Compound (I): Methylparaben Cocrystal For testing, the form B crystalline form of 40 mg of compound (I) and the methylparaben co-crystal of 40 mg of Example 10, disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet), were weighed into separate steel containers, and steel ball bearings of equal size were added to each of the containers. The samples were each milled at 30 Hz for 30 minutes and then re-analyzed by XRPD. The XRPD analysis demonstrated that the methylparaben co-crystal retained its co-crystal structure pattern and only a limited decrease in overall crystallinity was observed, which can be seen in Figure 29 showing the XRPD patterns of methylparaben before and after milling. In comparison, a sample containing the form B crystalline form of compound (I) disclosed in U.S. Patent Application Publication No. 2021 / 0221818 (corresponding to International Publication No. 2021 / 150723 pamphlet) became amorphous after milling, which can be seen in Figure 30 (showing the XRPD patterns of form B of compound (I) before and after milling).

[0135] Example 12 - Compression Test with Methylparaben Co-crystal of Example 10 The methylparaben co-crystalline form of compound (I) after drying in a vacuum oven was compressed at a pressure of 100 kg for 2 minutes to form a recess disk with a 6 mm indentation. Analysis of the disk surface by XRPD produced the results shown in Figure 31. As can be seen, after drying and compression, the methylparaben co-crystal retained its co-crystal structure pattern and only a limited decrease in overall crystallinity was observed.

[0136] Example 13 - Static Storage Analysis of Compound (I): Methylparaben Co-crystal Samples of the methylparaben co-crystalline form of compound (I) (Example 10) after drying in a vacuum oven were stored at 25 °C and 40 °C for 1 week. After storage, XPRD analysis was performed, producing the results in Figure 32, indicating that the methylparaben co-crystalline form of compound (I) retained its crystal structure after storage and at high temperature.

[0137] Solubility of 4-Methylparaben Cocrystal - Example 14 The solubility of the 4-methylparaben cocrystal of Example 10 was investigated at time intervals of 1 hour, 3 hours, and 24 hours using buffer solutions at pH 4.5 and 6.8. Samples were suspended in 1.5 mL of the medium at an approximate maximum predicted concentration of about 30 mg / mL of the free form of Compound (I). The resulting suspensions were then shaken at 25 °C / 750 rpm for 24 hours. After equilibration at 1 hour, 3 hours, and 24 hours, 0.5 mL of the samples were aliquoted, the appearance was recorded, and the pH of the saturated solutions was measured. The samples were then centrifuged at 13,400 rpm for 2 minutes. The supernatants were used for HPLC analysis. Samples suspended in pH 4.5 buffer were diluted 1:1 (for 1- and 3-hour samples) and 1:8 (for 24-hour samples) with pH 4.5 buffer. Samples suspended in pH 6.8 buffer were analyzed without dilution. Quantification was by HPLC using a standard solution of approximately 0.15 mg / mL as a reference. Different volumes of standard dilutions and undiluted sample solutions were injected. Solubility was calculated using the peak areas determined by integration of peaks found at the same retention time as the major peak in a standard injection.

[0138] The 4-methylparaben cocrystal showed an increasing solubility with time at pH 4.5, starting at 0.65 mg / mL at the 1-hour time point and increasing to 3.9 mg / mL at the 24-hour time point. The overall solubility at pH 6.8 remained the same at 0.04 mg / mL at all three time points. The data obtained from this solubility evaluation are shown in Tables 13, 14, and 15 below. XRPD analysis did not show any change in the pattern after solubility analysis (e.g., with respect to the peaks described in Table 12A and / or 12B).

[0139] [Table 18]

[0140] [Table 19]

[0141] [Table 20]

[0142] The increased solubility of the crystalline forms of the compound (I) shown in Examples 9 and 14 enables their use in modified release and / or extended release dosage forms of the compound (I).

[0143] Equivalents The written specification above is considered to be sufficient for one of ordinary skill in the art to practice the embodiments. The above description and examples detail particular embodiments and describe the best mode contemplated by the inventors. However, it will be recognized that, however detailed the above may appear in the text, the embodiments may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

Claims

1. A substantially crystalline 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]penta-2-ennitrile, selected from its HCl salt, oxalate, or maleate form.

2. A substantially crystalline form according to claim 1, comprising a birefringent crystalline salt 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]penta-2-ennitrile:HCl, optionally characterized by substantially the same XRPD pattern as that shown in Figure 1.

3. 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]penta-2-ennitrile:HCl crystalline salt hydrate, optionally, The XRPD pattern is substantially the same as that in Figure 2, and / or The DSC / TGA profile is essentially the same as in Figure 3. A substantially crystalline form according to claim 1, characterized by at least one of the above.

4. 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]penta-2-ennitrile:HCl crystalline salt form A, which can be optionally selected. The XRPD pattern is substantially the same as that in Figure 4, and / or The XRPD pattern is substantially the same as that in Figure 5, and / or The DSC profile is substantially the same as that in Figure 6, and / or A TGA profile substantially the same as that in Figure 7, and / or Approximately 9.7±0.2, 14.9±0.2, and 17.6±0.2, using 2-theta degrees as the unit. XRPD pattern containing four or more peaks selected from the peaks of 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 29.3±0.

3. A substantially crystalline form according to claim 1, characterized by at least one of the above.

5. 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]penta-2-ennitrile:oxalic acid birefringent crystalline salt form A, which is optionally, The XRPD pattern is substantially the same as that in Figure 8, and / or The DSC / TGA profile is essentially the same as Figure 9. A substantially crystalline form according to claim 1, characterized by at least one of the above.

6. 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]penta-2-ennitrile: a birefringent crystalline salt of maleic acid, which can be optionally selected. The XRPD pattern is substantially the same as that of Figure 10, and / or The DSC / TGA profile is essentially the same as Figure 11. A substantially crystalline form according to claim 1, characterized by at least one of the above.

7. The above is 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]penta-2-ennitrile:oxalic acid crystalline salt hydrate form A, which is optionally, The XRPD pattern is substantially the same as that in Figure 14, and / or A DSC profile substantially the same as Figure 15A, and / or The XRPD pattern is substantially the same as that in Figure 16, and / or The XRPD pattern is substantially the same as that in Figure 17, and / or A TGA profile substantially the same as that in Figure 18, and / or The DCS / TGA profile is essentially the same as that in Figure 19. A substantially crystalline form according to claim 1, characterized by at least one of the above.

8. 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]penta-2-ennitrile:oxalic acid crystalline salt hydrate form B, which is optionally, The XRPD pattern is substantially the same as that in Figure 12, and / or A DSC / TGA profile substantially the same as that in Figure 13, and / or A DSC profile substantially the same as Figure 15B, and / or An XRPD pattern containing four or more peaks selected from peaks with values ​​of approximately 4.8±0.2, 9.3±0.2, 14.0±0.2, 14.2±0.2, 17.0±0.2, 18.7±0.2, 19.6±0.2, and 22.6±0.2, with 2-theta degrees as the unit. A substantially crystalline form according to claim 1, characterized by at least one of the above.

9. 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]penta-2-ennitrile:maleic acid crystalline salt form B・MeCN solvate, optionally, The XRPD pattern is substantially the same as that in Figure 20, and / or The DSC / TGA profile is essentially the same as Figure 21. A substantially crystalline form according to claim 1, characterized by at least one of the above.

10. The above is the 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]penta-2-ennitrile:maleic acid crystalline salt A form, which can be optionally selected Substantially the same XRPD pattern as shown in Figure 22, and / or The TGA profile is substantially the same as that of Figure 23, and / or An XRPD pattern containing four or more peaks selected from peaks with values ​​of approximately 9.7±0.2, 14.9±0.2, 17.6±0.2, 19.0±0.2, 19.6±0.2, 21.6±0.2, 22.3±0.2, and 22.8±0.2, with 2-theta degrees as the unit. A substantially crystalline form according to claim 1, characterized by at least one of the above.

11. It is a methylparaben cocrystal, and can be selectively used. The XRPD pattern is substantially the same as that in Figure 27, and / or A DCS / TGA profile substantially the same as that in Figure 28, and / or An XRPD pattern containing four or more peaks selected from peaks with values ​​of approximately 4.6±0.2, 10.8±0.2, 16.6±0.2, 18.3±0.2, 19.3±0.2, 20.2±0.2, 21.6±0.2, and 22.5±0.2, with 2-theta degrees as the unit. A substantially crystalline 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]penta-2-ennitrile, characterized by at least one of the following.

12. A substantially crystalline form according to any one of claims 1 to 11, which is at least 50% crystalline, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.

13. A pharmaceutical composition comprising at least one substantially crystalline form and a pharmaceutically acceptable excipient as described in any one of claims 1 to 12.

14. In the manufacture of a drug for treating a disease mediated by the activity of a target BTK, use of a crystalline 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]penta-2-ennitrile or the pharmaceutical composition according to claim 13.

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