Crystalline forms of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo [3, 4-d] pyrimidin-1-yl] piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl) piperazin-1-yl] pent-2-enitrile

Abstract

Provided herein are 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl) pyrazolo [3, 4-d] pyrimidin-1-yl] piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl) piperazin-1-yl] pent-2-enenitrile (identified herein as Compound (I), as well as, for example, 2-(4-fluoro-4-(2-fluoro-4-phenoxy-phenyl) pyrazolo [3, 4-d] pyrimidin-1-yl) piperidine-1-carbonyl)-4-methyl-4-[4-(oxetan-3-yl) The present invention relates to a substantially crystalline solid form of a pharmaceutically acceptable salt selected from the group consisting of HCl, oxalate and / or maleate, or alternatively as a pharmaceutically acceptable co-crystal of methyl parahydroxybenzoate, and pharmaceutical compositions comprising said substantially crystalline form. # imgabs0 #

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]pent-2-enenitrile (identified herein as Compound (I) and also referred to as PRN 1008 or rilzabrutinib), which are potent inhibitors of Bruton's tyrosine kinase ("BTK") useful for treating cancer and other conditions including autoimmune diseases. The present disclosure further relates to pharmaceutical compositions comprising said forms. Background Art

[0002] 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 the development and activation of B cells. BTK activity is involved in the pathogenesis of several disorders and conditions, including B cell-related blood cancers (such as non-Hodgkin's 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 antibody autoimmune hemolytic anemia, asthma and other acute respiratory distress and chronic spontaneous urticaria).

[0003] Therefore, pharmaceutical compositions comprising a therapeutically effective amount of a BTK inhibitor may be used to treat certain cancers and autoimmune diseases.

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

[0005] Furthermore, a common problem in large-scale production of pharmaceutical compounds is that the active substance has a crystalline form to ensure consistent processing parameters and drug quality. In this regard, making a pharmaceutical composition solid to improve its physical and chemical stability can give significant advantages over less stable forms of the same drug.

[0006] When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism." Each crystalline form is a "polymorph." Although polymorphs of a given substance have the same chemical composition, they may differ from one another with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal form, compaction behavior, flow characteristics, and / or solid-state stability. Therefore, different polymorphs may present significant advantages or disadvantages in the preparation of a pharmaceutical composition.

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

[0008] wherein *C is a stereochemical center. Compound (I) is preferably present substantially as the (R)-enantiomer, said compound also known as PRN 1008 or alternatively as rizabrutinib.

[0009] Compound (I) is disclosed and claimed in U.S. Pat. No. 9,266,895 (Example 31 thereof) (corresponding to WO 2014 / 039899). The procedure described in US 9,266,895 provides Compound (I) as a white amorphous solid after solvent extraction, wherein the level of residual solvent present is above the limit suitable for the preparation of pharmaceutical compositions.

[0010] Alternative procedures for producing compound (I) and its solid form are disclosed in WO 2015 / 127310 and U.S. Publication No. 2021 / 0198264. The '264 Publication discloses a method for preparing compound (I) that produces an amorphous form of the compound with a pharmaceutically acceptable level of residual solvent (e.g., methanol, isopropyl acetate, and heptane). In some embodiments described in the '264 Publication, no detectable level of such residual solvent remains in the final product.

[0011] Certain crystalline forms of Compound (I) are disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), including crystalline forms represented therein as Form A, Form B and Form C.

[0012] However, the production of pharmaceutical compositions for the effective treatment of disease also requires that compounds can be produced in a form that is shelf-stable and easily formulated into compositions that can be easily absorbed by the human body not only via immediate absorption but also with modified and extended release formulations. The pharmaceutically active substances used in preparation for treatment should be as pure as possible and maintain their stability in long-term storage under various environmental conditions. These properties can be used to prevent the formation of degradation products in the pharmaceutical composition, which may be potentially toxic or simply lead to a reduction in the effectiveness of the composition.

[0013] If an unstable crystalline form is used, the crystal morphology may change during manufacture and / or storage, leading to quality control problems and formulation irregularities. Such changes may affect the reproducibility of the manufacturing process and thus result in the final formulation not meeting the high quality and stringent requirements imposed on the formulation of the pharmaceutical composition.

[0014] Thus, there remains a need for crystalline forms of Compound (I) that possess sufficient stability and bioabsorption to be suitable for the preparation of effective pharmaceutical formulations and treatments, including compositions designed for prolonged and modified release. Summary of the invention

[0015] The present disclosure relates to a new solid form of compound (I), which provides some significantly improved solubility and stability compared to compound (I) form B disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723), or compared to other solid forms, salt forms or crystalline forms of compound (I) previously disclosed.

[0016] Disclosed herein is a substantially crystalline form of Compound (I), the substantially crystalline form being selected from the group consisting of an HCl salt form, an oxalate salt form and a maleate salt form.

[0017] Also disclosed herein are co-crystalline forms of Compound (I), optionally, substantially crystalline forms of Compound (I) as co-crystals, said co-crystals comprising substantially crystalline Compound (I) and a coformer, wherein in one embodiment, said coformer is methyl paraben.

[0018] The present disclosure also relates to a pharmaceutical composition comprising a solid form of at least one Compound (I) as described herein and a pharmaceutically acceptable excipient.

[0019] The present disclosure further 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 to provide a solid dosage formulation for administration to a subject in need of treatment, wherein the solid dosage formulation provides improved solubility, stability and / or bioabsorption compared to compound (I) Form B disclosed in US 2021 / 0221818 (corresponding to WO 2021 / 150723).

[0020] The present disclosure still further relates to pharmaceutical compositions comprising a substantially crystalline form of Compound (I) as described herein.

[0021] Also disclosed herein are methods of treating a disease mediated by BTK activity in a subject by administering to the subject a pharmaceutical composition comprising at least one substantially crystalline form of Compound (I) as described herein.

[0022] The accompanying drawings, briefly described below, are incorporated herein and constitute a part of this specification. The drawings illustrate several embodiments of the present disclosure and should be considered in conjunction with the description. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Shown is an overlay of XRPD spectra of two different birefringent crystalline forms of Compound (I):HCl crystalline salt obtained using CuKa radiation.

[0024] Figure 2 Shown is the XRPD spectrum of Compound (I): HCl crystalline salt hydrate obtained using CuKα radiation.

[0025] Figure 3 Shown is the DSC / TGA thermogram of Compound (I): HCl crystalline salt hydrate.

[0026] Figure 4 Shown is the XRPD spectrum of Compound (I):HCl crystalline salt Form A obtained using CuKα radiation.

[0027] Figure 5 An additional XRPD spectrum of Compound (I):HCl crystalline salt Form A obtained using CuKa radiation is shown and the peaks are numbered.

[0028] Figure 6 Shown is the TGA thermogram of Compound (I): HCl crystalline salt Form A.

[0029] Figure 7 Shown is the DSC / TGA thermogram of Compound (I): HCl crystalline salt Form A.

[0030] Figure 8 Shown is the XRPD spectrum of Compound (I): oxalate birefringent crystalline salt hydrate Form A obtained using CuKα radiation.

[0031] Fig. 9 The DSC / TGA thermogram of Compound (I): oxalate birefringent crystalline salt hydrate Form A is shown.

[0032] Fig.10 Shown is the XRPD spectrum of Compound (I): maleate birefringent crystalline salt obtained using CuKα radiation.

[0033] Fig.11 Shown is the DSC / TGA thermogram of compound (I): maleate birefringent crystalline salt.

[0034] Fig.12 Shown is the XRPD spectrum of Compound (I) oxalate crystalline salt Form B obtained using CuKα radiation.

[0035] Fig.13 The DSC / TGA thermogram of Compound (I) oxalate crystalline salt Form B is shown.

[0036] Fig.14 Shown is an overlay of XRPD spectra of Compound (I) oxalate crystalline salt hydrate Form A and Compound (I) oxalate crystalline salt hydrate Form B obtained using CuKa radiation.

[0037] Fig.15A and Fig. 15B DSC thermograms of Compound (I) oxalate crystalline salt Form A (15A) and Form B (15B) are shown.

[0038] Fig.16 Shown is the XRPD spectrum of Compound (I) oxalate crystalline salt hydrate Form A obtained using CuKα radiation.

[0039] Fig.17 An additional XRPD spectrum of Compound (I) oxalate crystalline salt hydrate Form A obtained using CuKa radiation is shown and the peaks are numbered.

[0040] Fig.18 The TGA thermogram of Compound (I) oxalate crystalline salt hydrate Form A is shown.

[0041] Fig.19 The DSC / TGA thermogram of Compound (I) oxalate crystalline salt Form A is shown.

[0042] Fig. 20 Shown is the XRPD spectrum of Compound (I): Maleate Crystalline Salt Form B (MeCN Solvate) obtained using CuKα radiation.

[0043] Fig.21 Shown is the DSC / TGA thermogram of Compound (I): maleate crystalline salt Form B (MeCN solvate).

[0044] Fig. 22 Shown is an overlay of XRPD spectra of compound (I): maleate crystalline salt form A, maleic acid, and compound (I) form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) obtained using CuKα radiation.

[0045] Fig.23 The TGA thermogram of Compound (I): Maleate crystalline salt Form A is shown.

[0046] Figure 24A-24C The HCl crystalline salt of compound (I) is shown Fig.24A ), crystalline compound (I) form B ( disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) Fig. 24B ) and Compound (I) Amorphous Form B ( Fig.24C ) for comparative solubility evaluation data.

[0047] Fig.25 Shown is data in graphical form demonstrating the solubility of Compound (I) oxalate crystalline salt Form A at different pH as a function of time.

[0048] Fig.26 The data are shown in graphical form demonstrating the solubility of Compound (I) maleate crystalline salt at different pH as a function of time.

[0049] Fig. 27 Shown is the XRPD spectrum of Compound (I): methyl p-hydroxybenzoate cocrystal obtained using CuKα radiation.

[0050] Fig.28 Shown is the DSC / TGA thermogram of compound (I): methyl p-hydroxybenzoate cocrystal.

[0051] Fig.29 Shown are XRPD spectra of Compound (I): methyl paraben cocrystal collected before and after milling as described in Example 11 obtained using CuKα radiation.

[0052] Fig.30 Shown are XRPD spectra of Compound (I) Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) collected before and after milling as described in Example 11 obtained using CuKα radiation.

[0053] Fig.31 Shown are XRPD spectra of Compound (I): methyl paraben cocrystal collected before and after compression as described in Example 12 obtained using CuKα radiation.

[0054] Fig.32 Shown are XRPD spectra of Compound (I): methyl paraben cocrystal collected before and after storage as described in Example 13 obtained using CuKα radiation. DETAILED DESCRIPTION

[0055] Reference will now be made in detail to certain embodiments illustrated in the following examples and accompanying drawings. Although the present disclosure provides exemplary embodiments, it should be understood that the embodiments are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents that those skilled in the art may understand from the present disclosure.

[0056] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the intended subject matter in any way. I. Definitions

[0057] Unless otherwise indicated, as used herein, "a" or "an" entity refers to one or more of the entity, for example, "a compound" refers to one or more compounds or at least one compound. Therefore, the terms "a" (or "an"), "one or more", and "at least one" are used interchangeably herein.

[0058] As used herein, "about" before one or more specific numerical values ​​is intended to indicate that a range of values ​​is included within the specific values ​​to the extent that one of ordinary skill in the art would consider the range equivalent to the specific stated values ​​(e.g., having the same function or result). When "about" precedes a list of values ​​or ranges, the term modifies all values ​​or ranges provided in the list.

[0059] For example, "about" when used herein with respect to a peak point of an XRPD spectrum indicates that the value of the peak point may be within ±0.2 of the specific number shown. As will be appreciated by those skilled in the art, a specific XRPD peak is not exact, but may vary in either direction with experimental conditions (including the size and purity of the sample).

[0060] As used herein, "birefringence" refers to a crystal having two refractive indices. Birefringence is also called double refraction, and it occurs in anisotropic crystal forms.

[0061] As used herein, "co-crystal", "co-crystal of Compound (I)" or "Compound (I) co-crystal" means that Compound (I) exists in a crystalline form and is non-covalently bonded to at least one co-former in a stoichiometric ratio in the crystal lattice.

[0062] "Co-former" means one or more compounds other than compound (I) in the crystal lattice comprising the co-crystal. For example, with respect to the co-crystal of compound (I) prepared herein, the co-former is a molecule other than compound (I) in the co-crystal, such as methylparaben. The co-crystal may also contain a stoichiometric amount of water compared to compound (I) and methylparaben, such as a monohydrate or a dihydrate.

[0063] Compound (I) as used herein refers to 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, which has the following structure:

[0064] Compound (I) as used herein refers to all stereoisomers or enantiomers thereof, and all mixtures of stereoisomers and enantiomers. Compound (I) may be referred to herein as a "drug", "active agent", "therapeutically active agent" or "API".

[0065] As used herein, "Form B", "Form B of Compound (I)" or "Compound (I) Form B" refers to a crystalline form of Compound (I) described as Form B in US2021 / 0221818 (corresponding to WO 2021 / 150723), and those skilled in the art will understand that it can be confirmed with characterization data and / or by the procedures disclosed in the reference publication. "Form B" disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) is a crystalline form different from Form B of the oxalate and / or Form B of the maleate disclosed herein.

[0066] "Substantially crystalline" or "substantially crystalline form" means that one or more crystalline forms of one or more compounds in a sample (including mixtures of crystalline compounds) are present in an amount greater than 50% by weight, optionally at least 60% or more, or at least 70% or more by weight, compared to one or more amorphous forms of the compound in the sample, which can be readily measured using analytical tools available to those skilled in the art.

[0067] "Substantially pure" or "substantially pure crystalline" means that a single crystalline form of the compound is present in the sample in an amount of 90% or more by weight compared to all other components in the sample (including all other crystalline or amorphous forms of the compound and / or residual solvents or excipients); optionally, in an amount of 95% or more, and optionally, in an amount of 99% or more, compared to all other components.

[0068] As used herein, "pharmaceutically acceptable excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered to be pharmaceutically acceptable to mammals.

[0069] As used herein, the term "room temperature" or "ambient conditions" refers to room temperature, outdoor and uncontrolled humidity conditions, typically at a temperature ranging from about 15°C to about 30°C.

[0070] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0071] As used herein, the terms "treat," "treating," or "treatment," when used in conjunction with a disorder or condition, include any effect that results in improvement of the disorder or condition, such as alleviation, reduction, modulation, improvement, or elimination. The improvement of any symptom of a disorder or condition, or a reduction in its severity, can be readily assessed according to standard methods and techniques known in the art.

[0072] As used herein, the term "solid form" refers to a physical form of a compound that is not predominantly in a liquid or gaseous state, and includes amorphous and crystalline forms.

[0073] As used herein, the term "amorphous" refers to a solid material that has no long-range order in its molecular positions. Amorphous solids are generally supercooled liquids in which molecules are arranged in a random manner so that there is no clear arrangement (e.g., molecular stacking) and no long-range order. For example, an amorphous material is a solid material that does not have one or more sharp characteristic signals in its X-ray powder diffraction pattern (i.e., it is not crystalline as determined by XRPD). On the contrary, one or more broad peaks (e.g., halos) appear in its diffraction pattern. Broad peaks are characteristic of amorphous solids. See, for example, US2004 / 0006237 for a comparison of diffraction patterns of amorphous materials and crystalline materials.

[0074] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0075] As used herein, the term "TGA" refers to the analytical method of thermogravimetric (also known as thermogravimetric) analysis. II. Implementation Plan

[0076] The present disclosure relates to a new solid form of compound (I), which provides significantly improved solubility and / or stability compared to compound (I) form B disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723), or compared to other solid forms, salt forms or crystalline forms of compound (I) previously disclosed.

[0077] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile selected from its HCl salt, oxalate salt or maleate salt form.

[0078] In some embodiments, the present disclosure comprises a substantially crystalline form of a birefringent crystalline salt of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl. In some embodiments, the birefringent crystalline salt of HCl is characterized by being substantially the same as described herein. Figure 1 The XRPD spectrum in is the same as the XRPD spectrum in.

[0079] 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]pent-2-enenitrile:HCl crystalline salt hydrate. In some embodiments, the HCl crystalline salt hydrate is characterized by at least one of the following: substantially the same as described herein Figure 2 The same XRPD pattern as herein; and / or substantially the same Figure 3 Same DSC / TGA graph.

[0080] 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]pent-2-enenitrile: HCl crystalline salt Form A. In some embodiments, the above HCl crystalline salt Form A is characterized by at least one of the following: substantially the same as Figure 4 The same XRPD pattern; and / or substantially the same Figure 5 The same XRPD pattern; and / or substantially the same Figure 6 The same DSC curve as Figure 7 In some embodiments, the above-mentioned HCl crystalline salt form A is characterized by an XRPD spectrum comprising four or more peaks selected from the following positions expressed in 2θ°: 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.

[0081] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile: oxalate birefringent crystalline salt Form A. In some embodiments, the above-mentioned oxalate birefringent crystalline salt Form A is characterized by at least one of the following: substantially the same as Figure 8 The same XRPD pattern; and / or substantially the same Fig. 9 Same DSC / TGA graph.

[0082] In one embodiment, the present disclosure comprises a substantially crystalline form of a birefringent crystalline maleate salt of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: maleate. In some embodiments, the birefringent maleate salt is characterized by at least one of: being substantially the same as Fig.10 The same XRPD pattern; and / or substantially the same Fig.11 Same DSC / TGA graph.

[0083] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile: oxalate crystalline salt hydrate Form A. In some embodiments, the above crystalline oxalate salt hydrate Form A is characterized by at least one of the following: substantially the same as Fig.14 The same XRPD pattern; and / or substantially the same Fig.15A In some embodiments, the above-mentioned oxalate crystalline salt hydrate form A is characterized by at least one of the following: substantially the same as Fig.16 The same XRPD pattern; and / or substantially the same Fig.17 The same XRPD pattern; and / or substantially the same Fig.18 The same TGA curve; and / or substantially the same Fig.19 In some embodiments, the above-mentioned oxalate crystalline salt hydrate form A is characterized by the following XRPD spectrum, the XRPD spectrum comprising four or more peaks selected from the following positions expressed in 2θ°: 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.

[0084] In one embodiment, the present disclosure comprises 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate crystalline salt hydrate Form B. In some embodiments, the above oxalate crystalline salt hydrate Form B is characterized by at least one of the following: substantially the same as Fig.12 The same XRPD pattern; and / or substantially the same Fig.13 The same DSC / TGA curve; and / or substantially the same Fig. 15B Same DSC graph.

[0085] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile: maleate crystalline salt Form B·MeCN solvate. In some embodiments, the maleate crystalline salt Form B·MeCN solvate is characterized by at least one of the following: substantially the same as Fig. 20The same XRPD pattern; and / or substantially the same Fig.21 Same DSC / TGA graph.

[0086] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile: maleate crystalline salt Form A. In some embodiments, the maleate crystalline salt Form A is characterized by at least one of the following: substantially the same as Fig. 22 The same XRPD pattern; and / or substantially the same Fig.23 In some embodiments, the maleate crystalline salt form A is characterized by an XRPD pattern comprising four or more peaks selected from the following positions expressed in 2θ°: 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.

[0087] In one embodiment, the present disclosure comprises 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]pent-2-enenitrile which is a methyl paraben co-crystal. In some embodiments, the methyl paraben co-crystal of the present disclosure described above is characterized by at least one of the following: substantially the same as Fig. 27 The same XRPD pattern; and / or substantially the same Fig.28In some embodiments, the above-mentioned methyl paraben cocrystal is characterized by an XRPD spectrum comprising four or more peaks selected from the following positions expressed in 2θ°: 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 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]pent-2-enenitrile is selected from the HCl salt, oxalate salt, maleate salt or methylparaben cocrystal that 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.

[0088] Additional embodiments disclosed herein relate to pharmaceutical compositions comprising at least one substantially crystalline form of any one of the alternative embodiments herein, and a pharmaceutically acceptable excipient; optionally, the pharmaceutical composition is formulated for modified or extended release of a salt 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-(oxetane-3-yl)piperazin-1-yl]pent-2-enenitrile to a subject; optionally, for treating a disease mediated by BTK kinase in a subject. Pharmaceutical composition

[0089] The crystalline forms described herein can be used as active pharmaceutical ingredients (APIs), and materials for preparing pharmaceutical compositions that incorporate one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects. In some embodiments, these pharmaceutical compositions will be pharmaceutical products, e.g., solid oral dosage forms, such as tablets and / or capsules.

[0090] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of compound (I) selected from the HCl salt, oxalate, maleate or methyl paraben cocrystal. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of compound (I) as described herein and at least one additional pharmaceutically acceptable excipient. Each excipient must be "pharmaceutically acceptable" in the sense that it is compatible with the subject composition and its components are harmless to the patient. Unless any conventional pharmaceutically acceptable excipient is incompatible with compound (I), such as by producing any undesirable biological effect or otherwise interacting with any one or more other components of the pharmaceutically acceptable composition in a harmful manner, the use of the excipient is expected to be within the scope of the present disclosure.

[0091] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one crystalline form of Compound (I) selected from the HCl salt, oxalate salt, maleate salt or methylparaben cocrystal, formulated together with one or more excipients for use in providing extended release or modified release dosing to a subject.

[0092] Some non-limiting examples of materials that can be used 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 carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (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 starch, and cellulose acetate. oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, 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) ethanol; (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. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York (the contents of which are incorporated herein by reference) also disclose other non-limiting examples of pharmaceutically acceptable excipients, as well as known techniques for their preparation and use.

[0093] The pharmaceutical compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by implanted reservoirs. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the pharmaceutical compositions of the present disclosure can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are routinely used as solvents or suspending media.

[0094] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants that are commonly used to prepare pharmaceutically acceptable dosage forms (including emulsions and suspensions). For the purpose of preparation, other conventional surfactants can also be used, such as Tween, Span and other emulsifiers or bioavailability enhancers, which are commonly used to make pharmaceutically acceptable solids, liquids or other dosage forms.

[0095] The pharmaceutical compositions disclosed herein can also be orally administered in any oral 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 an emulsifier and / or a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0096] In some embodiments, pharmaceutical compositions comprising the crystalline salt forms disclosed herein can be used as inhibitors of Bruton's tyrosine kinase (BTK) and for treating diseases mediated by BTK in mammals in need thereof. Such diseases and methods of treating with the crystals disclosed herein can be selected from acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune retinopathy, axonal and neuronal neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating neuropathy, 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, strabismic 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, dysautonomia, age-related macular degeneration (wet and dry), corneal transplant, 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, Sjogren's disease, Sjogren's alba dry eye), non-Sjögren's leukoderma, psoriasis, pemphigus, urticaria (e.g., chronic spontaneous urticaria), asthma, disorders 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 / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, 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's lymphoma / leukemia, and lymphomatoid granulomatosis. Example

[0097] As used in the following examples or elsewhere herein, the abbreviations in the following table may be used. abbreviation AceT Ethyl acetate Al aluminum CI Counter ions DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIEA Diethylamine DIPEA Diisopropylethylamine DMC Dimethyl carbonate DMF / DMA Dimethylformamide / dimethylacetamide DSC Differential Scanning Calorimetry EtOAc Ethyl acetate EtOH Ethanol Eq. or equiv. equivalent EV evaporation FEV Rapid evaporation FT Fourier Transform <![CDATA[ 1 H NMR]]> Proton NMR HPLC High performance liquid chromatography hr Hour IPE Isopropyl ether i Isopropyl acetate MeCN Acetonitrile MeOH Methanol MIBK 4-Methyl-2-pentanone min minute mM mmol MTBE Methyl tert-butyl ether PLM Polarized light microscopy Pt platinum RC Rapid cooling RT Room temperature (or ambient temperature) T3P Propylphosphonic anhydride TA Texas Analytics TC Temperature Cycle TG Thermogravimetry TGA Thermogravimetric analysis vol. volume Wt. weight XRPD X-ray powder diffraction instrument

[0098] The following instruments and procedures were used to collect the data described in the examples herein. Those skilled in the art will appreciate that alternative instruments and procedures, as available and known to the skilled artisan, may optionally be used to collect characterization data, such as NMR, PLM, XRPD, TGA, and DSC / TGA data. Option A Instrument

[0099] XRPD. Ni-filtered Cu Ka (45 kV / 40 mA) radiation and 0.02° 2θ step size and X'celerator TM XRPD data were collected with a PANalytical X'Pert Pro diffractometer using an RTMS (Real Time Multibanding) detector. Configuration on the incident beam side: fixed divergence slit (0.25°), 0.04 Radsoller slit, anti-scatter slit (0.25°), and 10 mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25°) and 0.04 Radsoller slit. Samples were flat mounted on zero background silicon wafers.

[0100] DSC. Data were collected using a TA Instruments Q100 or Q2000 differential scanning calorimeter equipped with an autosampler and refrigerated cooling system under a 40 mL / min N2 purge. DSC thermograms of samples were obtained at 10°C / min in a crimped Al pan.

[0101] TGA. Data were collected on a TA Instruments Q50 thermogravimetric analyzer in a Pt or Al pan under a 40 mL / min N2 purge. TGA thermograms of samples were obtained at 10°C / min. Option B Instrument

[0102] Alternatively, Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automatic sample positioning and XRPD data were collected using a Bruker AXS C2 General Area Detector Diffraction System (GADDS) diffractometer. The X-ray optics consisted of a 2D surface detector coupled to a 0.3 mm pinhole collimator. The X-ray beam was composed of a multilayer mirror. The beam divergence, i.e. the effective size of the X-ray beam on the sample, was about 4 mm. The θ-θ continuous scanning mode was adopted, and the sample-detector distance was 20 cm, which gave an effective 2θ range of 1.5°-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 DiffracPlus EVA for Win7 / XP, respectively. The samples run under ambient conditions were prepared as flat specimens using the powder as received without grinding. The samples were prepared and analyzed on a glass slide by gently pressing the powder to obtain a flat surface for analysis.

[0103] DSC. Alternatively, data were collected on a TA Instruments Discovery DSC equipped with a 50 position autosampler. Typically, 0.5-3 mg of each sample in a pinhole aluminum pan was heated from 25°C to around 230°C at 10°C / min. A 50 ml / min dry nitrogen purge was maintained over the sample. The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0104] TGA. TGA data were collected on a TA Instruments Discovery TGA equipped with a 25 position autosampler. Typically, 5-10 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated from ambient 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 were analyzed using TRIOS or Universal Analysis.

[0105] PLM. Samples were analyzed on a Leica LM / DM polarized light microscope with a digital camera for image capture. A small amount of each sample was placed on a slide with or without immersion oil and covered with a glass slide. The samples were viewed at appropriate magnification and partially polarized light, coupled with a lambda false-color filter. Images were captured using StudioCapture or Image ProPlus software.

[0106] NMR. Spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. 1H NMR spectra. Samples were usually prepared in DMSO-d6 solvent. Standard Bruker loading experiments (1H) were used and automated experiments were obtained using the ICON-NMR configuration in Topspin software. Offline analysis was performed using ACD Spectrus Processo. Starting Materials - Exemplary Synthesis of Compound (I) Form B

[0107] Form B of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) is used as a starting material in each of the procedures described in Examples 1 to 9 below, and as a comparative sample in Examples 10 to 14. Form B of compound (I) can be prepared according to the procedure described in Examples 2 to 4 (optionally, according to Example 4 therein) of US2021 / 0221818 (corresponding to WO 2021 / 150723), which is incorporated herein by reference.

[0108] The following preparation of compound (I) Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) is provided to enable those skilled in the art to prepare BTK inhibitor compounds. The synthetic route should not be considered to limit the scope of the present disclosure, but is merely illustrative and representative of the present disclosure.

[0109] In an alternative, 96 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-(oxetanes-3-yl)piperazine-1-yl]pent-2-enenitrile was dissolved in 0.3 mL of ethyl acetate. The obtained solution was seeded with NaCl and stirred at room temperature. After stirring overnight, a turbid solution was obtained and treated with ultrasound for 5 minutes. After two additional days of stirring, a suspension was obtained and filtered (centrifugal unit filter, PTFE, 0.22 μm) to obtain crystalline Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723).

[0110] In another alternative, 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]pent-2-enenitrile (Compound (I)) Form C is combined with ethanol (4.1 L) at about 15 ° C to form a slurry. Then, Form B seeds (to about 5 wt.%) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) are added, and the slurry is stirred for about two days. The slurry is filtered and heated to dry under vacuum to obtain about 300 g of crystalline Form B (74% yield) of Compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723).

[0111] Form C can also be prepared according to the procedures described in Examples 5 to 8 of US2021 / 0221818 (corresponding to WO 2021 / 150723) (e.g., as described in Example 5 therein), which are incorporated herein by reference. 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-(oxetanes-3-yl)piperazine-1-yl]pent-2-enenitrile was combined with acetonitrile (0.5 mL). The solution was seeded with a crystalline form B of compound (I) disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) and stirred at room temperature for 48 h. At approximately 48 h, a thick white free-flowing slurry was obtained and identified as crystalline Form C (estimated yield >50%). Example 1 - Solubility and Solvent Evaluation

[0112] The solubility of Form B crystals of compound (I) disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) in various solvents was evaluated to facilitate the selection of solvent systems and corresponding feeding strategies for the subsequent screening experiments of Example 2. The solubility in 12 common solvents was visually estimated at room temperature. Form B crystals (about 20 mg) disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) were weighed into each of 12 vials, and then 200 μL of solvent was added at room temperature and observed for 15 min. If the solid was not dissolved in 200 μL at room temperature, a second aliquot of 800 μL of solvent was added at room temperature and the dissolution was visually checked. The results are shown in Table 1. Table 1 - Visual Solubility of Form B Crystals of Compound (I) # Solvents Solubility at room temperature [mg / mL] 1 acetone >100 2 Dichloromethane (DCM) >100 3 Tetrahydrofuran (THF) >100 4 Acetonitrile (MeCN) 20-100 5 Ethyl acetate (EtOAc) 20-100 6 Dimethyl carbonate (DMC) 20-100 7 Cyclohexanone 20-100 8 4-Methyl-2-pentanone (MIBK) 20-100 9 Toluene <20 10 Tert-Butyl Methyl Ether (MTBE) <20 11 Isopropyl ether (IPE) <20 12 Cyclohexane <20 Example 2 - Compound (I): HCl birefringent crystalline salt 2.1. HCl crystal screening.

[0113] Twelve (12) experiments were conducted using Form B crystals of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), focusing on the HCl salt. The experiments were designed to generate data on whether and under what conditions HCl crystalline salts can be obtained in different solvent systems and experimental conditions, as well as the properties of the resulting products. This experiment was conducted using the solution / gel / suspension produced from the solubility experiment in Example 1 as the starting material. One equivalent of 4M HCl / 1,4-dioxane was incorporated into 12 samples produced in 12 aprotic solvents (MeCN, acetone, DCM, MIBK, EtOAc, THF, IPE, toluene, cyclohexane, DMC, MTBE, cyclohexanone) during the evaluation (Example 1), and then a five-step crystallization procedure was used. The experiment was conducted as follows: 1. One equivalent of HCl / 1,4-dioxane was added to the solution / gel / suspension obtained from the 12 solubility experiments of Example 1; 2. The solution / gel / suspension was stirred while the temperature was cycled between 25°C and 5°C for two days (TC1 crystallization); 3. The solvent was quickly evaporated under reduced pressure via GeneVac and 200 μL of solvent was redistributed (FEV); 4. Stir the solution / gel / suspension while the temperature is cycled between 25°C and 5°C for five days (TC2 crystallization); 5. Stir the solution / gel at 25°C for one hour, cool to 4°C and keep at 4°C for two days (RC); 6. The solvent was evaporated in a N2 bleed chamber at room temperature for five days (EV).

[0114] PLM and XRPD analysis were performed in situ on each of the 12 samples under each crystallization mode (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 refraction") crystals were obtained only in the following two cases: (1) after TC2 (step 4) using MeCN as solvent, and (2) after EV (step 5) using DMC as solvent. The remaining experiments produced Form B crystals disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) or an amorphous form of Compound (I). XRPD spectra of the two birefringent samples were obtained and reported in Figure 1 As indicated by the XRPD spectra, the two samples have essentially the same form. Thermal analysis also showed that they contain hydrated forms. Table 2 - Results from crystal screening experiments with HCl Sample No. Solvents Crystallization method result 1 MeCN TCI, FEV, TC2 Birefringent Crystals 2 acetone TCI, FEV, TC2, RC, EV Amorphous 3 DCM TCI, FEV, TC2, RC, EV Amorphous 4 MIBK TCI Amorphous 5 EtOAc TCI Amorphous 6 THF TCI, FEV, TC2, RC, EV Amorphous 7 IPE TCI Form B 8 Toluene TCI Amorphous 9 Cyclohexane TCI Amorphous 10 DMC TCI, FEV, TC2, RC, EV Birefringent Crystals 11 MTBE TC1 Form B 12 Cyclohexanone TCI, FEV, TC2, RC, EV Amorphous 2.2. Scale-up and characterization of Compound (I): HCl crystalline salt Form A.

[0115] The birefringent crystalline HCl salt product obtained from Example 2.1 was scaled up to 100 mg and 1.4 g and further characterized. For the 100 mg scale, about 100.6 mg of compound (I) Form B crystals disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) were mixed in MeCN (1 mL) at room temperature to form a slurry. 4M HCl / 1,4-dioxane solution (1 eq) was added to the slurry. The resulting solution was inoculated with the birefringent HCl crystalline salt product (1 mg) obtained from Example 2.1; seeds persisted. The slurry was stirred at room temperature for 2 days. The solid was filtered and air dried for 2 h to produce 78 mg of compound (I) HCl crystalline salt Form A. 2.3. Preparation and characterization of compound (I): HCl crystalline salt hydrate.

[0116] About 1.6 g of compound (I) Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) was mixed in MeCN (16 mL) at room temperature. 4M HCl / 1,4-dioxane (1 eq) was added to the slurry. The solution was inoculated with compound (I) HCl crystalline salt Form A (70 mg); the seeds persisted. The slurry was stirred at room temperature for 3 days. The solid was filtered and air dried for 16 h to produce 1.4 g of product (90% yield) containing compound (I) mono-HCl crystalline salt (1.9 equivalents) as a hydrate. The XRPD of the sample is shown in Figure 2The results of DSC and TGA thermograms are shown in Figure 3 DSC showed a broad endotherm between 25°C and 140°C and an endotherm starting at 160.8°C. TGA showed a 4.6% weight loss of water (1.9 eq.) between 25°C and 140°C. HPLC purity was 99.4% of the E-isomer. Example 3-Compound (I) HCl Crystalline Salt Form A Preparation and Characterization.

[0117] About 10g of compound (I) Form B free base disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) was stirred in acetonitrile (about 100mL) to obtain a suspension. A saturated HCl solution (about 3mL) in isopropanol was added. After about 3min, a suspension was formed. The slurry was stirred for about 3 days, then filtered and washed with acetonitrile. The resulting crystals were dried under vacuum at 30°C to provide 7.8g of compound (I) HCl crystalline salt Form A as an anhydrous white solid, wherein the purity of the E-isomer of compound (I) was 99.7% and the purity of the combined E and Z isomers was 99.8%. 3.1. XRPD of Example 3 (Compound (I) HCl Crystalline Salt Form A).

[0118] The XRPD diffraction pattern of Compound (I): HCl crystalline salt Form A was obtained using the instrumentation and procedures described in the previous Instrumentation section (Option A). Figure 4 and Figure 5 The XRPD spectra shown in were obtained in duplicate experiments, where Figure 5 Displays the peak number. Figure 5 Peaks identified in include those listed in Table 3A and Table 3B below; optionally, the peaks reported in Table 3B may be considered representative. Table 3A - XRPD data of Example 3 (Compound (I) HCl Crystalline Salt Form A) Table 3B - XRPD data of Example 3 (Compound (I) HCl Crystalline Salt Form A) 3.2. TGA curve of Example 3 (Compound (I) HCl crystalline salt form A).

[0119] The TGA thermogram of Example 3 (Compound (I) HCl Crystalline Salt Form A) was obtained using the instrumentation and procedures described above in the Instrumentation section (Option A). The results are shown in Figure 6 middle. 3.3. DSC / TGA thermogram of Compound (I): HCl crystalline salt form A

[0120] DSC was performed on the sample of Example 3 using the instrumentation and procedure described above in the Instrumentation section (Option A). The results are shown in Figure 7 The temperatures of the exothermic and endothermic transitions recorded by DSC analysis are shown as the starting values ​​in Figure 7 middle. Example 4 - Initial Counterion Studies: Oxalate and Maleate Crystalline Salts

[0121] Forty-eight (48) crystallization experiments were performed using Compound (I) crystalline Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) using eight (8) counterions and six (6) solvents. Salt research experiments were performed using a substantially pure E-isomer of Compound (I) crystalline Form B. Compound (I) Form B has two ionizable basic sites with a pK a The calculated values ​​are 5.3 and 3.6. a A total of 8 counterions were used and were added as anhydrous solids (1 eq.) to study salt formation. Table 4 summarizes the counterions and equivalents used. Table 4-48 Counterions used in salt research experiments serial number Counter ions Eq Feeding method <![CDATA[pKa 6 ]]> 1 Pamoic acid 1 Anhydrous solid 2.5、3.1 2 Citric Acid 1 Anhydrous solid 3.1、4.8、6.4 3 (+)-L-Tartaric Acid 1 Anhydrous solid 3.0、4.4 4 L-Glutamic Acid 1 Anhydrous solid 2.2、4.3、9.7(B) 5 Malonic acid 1 Anhydrous solid 2.8、5.7 6 Fumaric Acid 1 Anhydrous solid 3.0、4.4 7 oxalic acid 1 Anhydrous solid 1.3、4.3 8 Maleic acid 1 Anhydrous solid 1.9、6.2

[0122] Taking into account the solubility (Example 1, Table 1), polarity and chemical diversity of compound (I) Form B crystals disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), six aprotic solvents (MeCN, toluene, MIBK, EtOAc, DMC, acetone) were selected for salt research experiments. The five-step procedure described below was used, and the birefringence of the sample was checked in situ by PLM at each step. If the sample is birefringent, the crystals are separated, analyzed, and grouped by XRPD spectra. All XRPD spectra were compared with the XRPD spectra of compound (I) Form B crystals and appropriate counterions disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) for identification: 1. Add one equivalent of the counterion as an anhydrous solid to a 2 mL HPLC vial containing Form B crystals (approximately 20 mg); 2. Dispense 200-300 μL of solvent (selected from MeCN, toluene, MIBK, EtOAc, DMC and acetone) into 2 mL HPLC vials, each vial containing a mixture of Form B and counterion according to step 1; 3. Stir the solution / suspension / gel while the temperature is cycled between 25°C and 5°C for fifteen days (TC); 4. The solution / gel obtained from step 3 was stirred at 25°C for one hour, cooled to 4°C and kept at 4°C for three days (RC); and 5. The solvent was evaporated in a N2-gassing chamber at room temperature for up to 10 days (EV).

[0123] Table 5 shows the results from the salt study. Of the 48 experiments, only two produced new crystalline forms of compound (I), namely vials containing maleic acid and oxalate counterions in acetonitrile as solvent. Thermal analysis revealed that the hit was a hydrated form. Other birefringent products were observed and isolated in 31 experiments; however, they were confirmed via XRPD as compound (I) Form B crystals, crystalline counterions, or a mixture of compound (I) Form B and counterions disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) (named "mixture" in Table 4).

[0124] The remaining experiments produced amorphous products, as shown in Table 5. Table 5-48 Results of Salt Experiments 4.1. Oxalate Birefringent Salt Form A

[0125] The birefringent crystals of compound (I): oxalate produced in acetonitrile are hydrates (2.7% wt. water). The XRPD spectrum is shown in Figure 8 and the DSC and TGA thermograms are shown in Fig. 9 The DSC thermogram showed a broad endotherm between 25°C and 90°C and an endotherm onset at 156.2°C. The HPLC purity was 99.8% of the E-isomer. 4.2. Maleate birefringent salts

[0126] Compound (I): maleate birefringent crystals produced in acetonitrile are poorly crystalline solids, such as by Fig.10 The DSC and TGA thermograms of the maleate salt are shown in Fig.11 The DSC thermogram showed a broad endotherm between 25°C and 100°C and an endotherm starting at 120.9°C. The HPLC purity was 99.8% of the E-isomer. Example 5 - Compound (I) Oxalate Crystalline Salt Forms A and B 5.1. Compound (I) oxalate crystalline salt hydrate Form A

[0127] Scale-up and characterization of the oxalate salt from Example 4.1 produced two forms of crystalline salt product, designated herein as Compound (I) oxalate crystalline salt hydrate Form A and Compound (I) oxalate crystalline salt hydrate Form B.

[0128] The scale-up of 100 mg was carried out by stirring compound (I) Form B (100.4 mg) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) and oxalic acid solid (1 eq.) in MeCN (1 mL) at room temperature. The slurry was inoculated with the oxalate product (1 mg) of Example 4.1; the seeds persisted. The mixture was stirred at room temperature for 2 days. XRPD of the aliquot showed a new compound (I) oxalate crystalline salt Form B, which was converted to Form A after drying at 30 ° C for 7 h. The solid was filtered and air-dried for 4 h to obtain oxalic acid compound (I) oxalate crystalline salt hydrate Form A. The yield was 70% (80 mg). 5.2. Compound (I) oxalate crystalline salt hydrate form B

[0129] Additional preparation and characterization were performed. Form B (1.57 g) of compound (I) disclosed in US 2021 / 0221818 (corresponding to WO 2021 / 150723) and oxalic acid solid (1 eq.) were stirred at room temperature in MeCN (16 mL), and the slurry was inoculated with the oxalate (70 mg) of Example 4.1; the seeds persisted. The mixture was stirred at room temperature for 3 days. XRPD of the aliquot showed compound (I) oxalate crystalline salt hydrate Form B. The solid was filtered and air-dried for 16 hours, still producing compound (I) oxalate crystalline salt Form B (1.52 g; 85% yield), which is also a hydrate (4.8% wt water) and is characterized in that Fig.12 The XRPD spectra shown in . The DSC and TGA thermograms of Compound (I) oxalate crystalline salt hydrate Form B are shown in Fig.13 The superposition of the XRPD spectra of Compound (I) oxalate crystalline salt hydrate forms A and B is shown in Fig.14 The DSC of Compound (I) oxalate crystalline salt hydrate forms A and B are shown in Fig.15A and Fig. 15B middle.

[0130] The DSC thermogram of compound (I) oxalate crystalline salt hydrate form B shows a broad endotherm between 25°C-110°C and an endotherm starting at 158.2°C. HPLC purity is 99.5% E-isomer. Ion chromatography data indicate monooxalate (theoretical value 11.78% wt CI and experimental value 11.42% wt CI). The attempt to prepare compound (I) oxalate crystalline salt form A from oxalate crystalline salt form B (prepared as described in Example 5.2) produced a poorly crystalline solid, which was a mixture of Example 4.1 (oxalate birefringent salt form A), Example 5.2 (oxalate crystalline salt hydrate form B) and an amorphous product by drying the scaled-up product at 30°C with N2 venting for 24h under vacuum (10 inches of mercury (in Hg)). Example 6 - Compound (I) oxalate crystalline salt hydrate Form A

[0131] About 1 g of compound (I) Form B free base disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) was added to acetonitrile (about 10 mL) to form a solution. Oxalic acid (about 135 mg) was added, and the solution was stirred for about 3 days. The resulting crystals were filtered and washed with acetonitrile (about 15 mL), and dried under vacuum at room temperature to provide 627 mg of compound (I) oxalate crystalline salt Form A as a hydrate, with a purity of 99.7% E-isomer (55% yield). 6.1. XRPD of Compound (I) oxalate crystalline salt hydrate Form A.

[0132] The XRPD diffraction pattern of Compound (I) oxalate crystalline salt hydrate Form A was obtained using the instrumentation and procedures described in the Instrumentation section (Option A) above. The XPRD results obtained are as follows: Fig.16 and Fig.17 shown. Fig.16 and Fig.17 Peaks identified in include those listed in Table 6A and Table 6B below; optionally, the peaks reported in Table 6B may be considered representative. Table 6A - XRPD Data of Example 6 (Compound (I) Oxalate Hydrate Form A) Table 6B - Optional XRPD Data for Example 6 (Compound (I) Oxalate Hydrate Form A) 6.2.TGA and DSC / TGA.

[0133] Additional data for the crystalline oxalate salt hydrate Form A of Compound (I) prepared as described herein were obtained using the instrumentation and procedures described above in the Instrumentation section (Option A). The results obtained are reported in Fig.18 (TGA) and Fig.19 (DSC / TGA). Example 7 - Compound (I) maleate crystalline salt form B·MeCN solvate

[0134] Form B (102.7 mg) of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) and maleic acid counterion (17.9 mg, 1 eq.) were stirred in MeCN (1 mL) at room temperature. The resulting solution was seeded with maleate hydrate (1 mg) of Example 4.2; the seeds persisted. The slurry was stirred at room temperature for 2 days. The solid was filtered and air-dried for 4 h to produce a new crystalline form, compound (I) maleate crystalline salt Form B·MeCN solvate, which was confirmed by XRPD analysis (100 mg; 80% yield).

[0135] The additional preparation and characterization of the maleate salt was carried out as follows. Form B (1.3 g) of compound (I) disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) and maleic acid solid (1 eq.) were stirred in MeCN (13 mL) at room temperature. The resulting slurry was inoculated with a crystalline salt form B·MeCN solvate of compound (I) maleate prepared as described herein; the seeds persisted. The mixture was stirred at room temperature for 3 days. The solid was filtered and air dried for 4 h to produce a crystalline salt form B·MeCN solvate of maleate (1.44 g, 94% yield). The XRPD spectrum of compound (I) maleate crystalline form B·MeCN solvate is shown in Fig. 20 Compound (I) maleate crystalline salt form B is a MeCN solvate. The DSC and TGA thermograms of this form are shown in Fig.21 DSC showed an endotherm with an onset of 132.2°C. HPLC purity was 99.5% of the E-isomer. Proton NMR indicated it was the monomaleate salt with MeCN (0.7 eq). Example 8 - Compound (I) maleate crystalline salt form A

[0136] Form B (1.50mmol) of compound (I) disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723) was stirred in 10.0mL (10vol.) acetonitrile at 20°C. Maleic acid (1.50mmol, 1.00eq.) was added to the suspension in a single addition. The resulting mixture was stirred for 72h at 20°C. Then, vacuum filtration was performed to remove the mother liquor. The resulting wet cake was then washed with acetonitrile (3x 5mL, 5vol.). Solid materials were collected and dried in a vacuum at 25°C for 24h. Maleate (1.17mmol, 78% yield) of compound (I) was obtained as a white solid. The material was identified as maleate crystalline salt form A. 8.1. XRPD of Example 8 (Crystalline Maleate Salt of Compound (I) Form A). The XRPD diffraction pattern of Example 8 was collected using the instrument and procedure described in the Instrumentation section (Option B). The obtained XRPD spectrum of the crystalline maleate salt Form A of Example 8 is shown in Fig. 22 , shown is an overlay of the XRPD spectra of maleic acid and compound (I) Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723). Table 7 - XRPD data of Example 8 (Compound (I) Maleate Salt Form A) 8.2.TGA. Additional data for the maleate crystalline salt Form A of Compound (I) were obtained using the procedure described in the instrumental section above. The results obtained are reported in Fig.23 (TGA). Example 9 - Comparative Solubility Analysis of HCl, Oxalate and Maleate Crystalline Salts of Compound (I)

[0137] The above examples show procedures for obtaining novel crystalline salt forms of compound (I), which have enhanced solubility compared to the amorphous form and the previously reported form B of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723). The higher solubility of the crystalline salts of the present invention described herein may be useful in developing sustained-release or modified-release formulations and / or providing improved bioabsorption formulations. This example reports illustrative data on the comparative solubility of crystals. The HPLC chromatogram used in this example was analyzed at 225 nm. 9.1. Calibration.

[0138] To obtain comparative solubility data, a calibration curve was first generated using a stock solution of Form B (20.0 mg) of Compound (I) disclosed in US 2021 / 0221818 (corresponding to WO 2021 / 150723) 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. Table 8 - Dilution series used for calibration curve

[0139] The purity (area %) of Form B disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) was used to correct the area on HPLC by dividing the measured area by the average purity (area %) of 1 mg / mL and 2 mg / mL solutions. Using linear regression, a linear best fit equation was derived that expressed the concentration (mg / mL) of Compound (I) Form B as a function of the area recorded on HPLC. 9.2. Comparative solubility in Milli-Q purified water.

[0140] The following five-step method is then used to compare the solubility of compound (I) form B, amorphous form of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), and HCl, oxalate and maleate of Example 3, Example 6 and Implementation 8 in water purified by a Milli-Q reverse osmosis system. First, a certain amount of test sample is placed in a 2-dram vial equipped with a stirring bar. For each of compound (I) form B, amorphous (I) and HCl crystalline salt disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), 30 mg of test sample is used in the first step; for oxalate, 60 mg of test sample is used; and for maleate, about 100 mg or more of test sample is used. In the second step, Milli-Q water is added to the vial under stirring, and the pH of the resulting suspension / solution is then measured. For each of Form B, amorphous compound (I) and HCl crystalline salt disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), add a sufficient volume of Milli-Q water to dissolve the test sample; For example, for HCl salt, 3mL Milli-Q water is added, and for oxalate, 2mL Milli-Q water is added in the second step, and for maleate, a larger volume of Milli-Q water is added. After stirring for 1h, a sufficient amount of sample is taken out to enable further filtration and characterization (for example, for Form B, amorphous and HCl crystalline salt disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723), 500 μL samples are taken out, and 150 μL are obtained for oxalate). In each case, the sample is filtered through a 0.2 μm filter. The resulting solution is appropriately diluted to fall within the calibration concentration range on HPLC. Sampling is repeated in the same manner after 3h and 24h. After the last sample was taken, the pH value was recorded again. The dissolved sample was determined by converting the area recorded on the HPLC to concentration (mg / mL) using the established calibration equation. 9.3. Comparative solubility in aqueous buffers.

[0141] The procedure described in Example 9.2 was adjusted to determine the comparative solubility of the test sample in aqueous buffers at pH 4.5 and 6.8. As in Section 9.2, in the first step, the test sample (30 mg of Form B, amorphous or HCl salt disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723); 20 mg of oxalate) was placed in a 2-dram vial equipped with a stirring bar. Next, the second step of the modified procedure included adding buffer (5 mL) to the vial under stirring and then measuring the pH of the resulting suspension. If the pH drifted more than 0.1 units from the target pH, the pH was readjusted to the original value using 10 μL aliquots of 1M NaOH (aq.). After stirring for 1 h, a sample (1000 μL of Form B, amorphous or HCl salt disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723); 150 μL of oxalate) was taken out. As in 9.2 above, the sample was filtered through a 0.2 μm filter, and the resulting solution was appropriately diluted to fall within the calibration concentration range on the HPLC. Sampling was repeated in the same manner after 3 h and 24 h, and the pH value was recorded again after the last sample was taken. The dissolved sample was determined by converting the area recorded on the HPLC into a concentration (mg / mL) using an established calibration equation. 9.4. Solubility data.

[0142] Applying the procedures of Examples 9.1-9.3, the solubility data shown in Tables 9-11 were obtained. Figure 24A-24C Data in graphical form are illustrated, which show that the solubility of the HCl crystalline salt form of Compound (I) is significantly enhanced compared to the amorphous solid form and the Compound (I) Form B solid form disclosed in US2021 / 0221818 (corresponding to WO2021 / 150723). Fig.25 and Fig.26 Illustrated are data in graphical form showing the solubility of the oxalate and maleate crystalline salt forms of Compound (I), respectively, as a function of time at different pHs. Table 9-Table 11: Solubility data of the crystalline salt forms of Examples 3, 6 and 8 across solvent systems compared to Compound (I) crystalline Form B and Compound (I) amorphous form Table 9 (in water) Table 10 (in 50 mM acetate) Table 11 (in 100 mM acetate) Example 10-Compound (I) methyl p-hydroxybenzoate cocrystal

[0143] Form B (approximately 1 g) of compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) was weighed into a 100 mL round-bottom flask, and methyl parahydroxybenzoate (1.0 eq., 228.52 mg) was added to form a mixture. The sample and the co-former (methyl parahydroxybenzoate) were then dissolved in 10 vol. acetone (10 mL) with the aid of stirring. 30 volumes of n-heptane (30 mL) were added to the formed clear solution to obtain a light suspension. The suspension began to dissolve, and an additional 20 vol (20 mL) of n-heptane was added. The sample was still a turbid solution with a brown double layer at the bottom of the flask. It was kept stirring overnight. The white solid formed overnight was filtered and air dried, and then analyzed by XRPD. The sample was confirmed to be a methyl parahydroxybenzoate cocrystal of compound (I). The material was allowed to dry in an oven at 25°C under vacuum for 4 h to provide 80.7% yield and 97.5% purity by HPLC. The DSC thermogram showed an onset at 133.5°C with a heat enthalpy of 42 J / g; the TGA thermogram showed a 2.6% weight loss between 25°C and 250°C.

[0144] After further analysis, it was found that the methylparaben cocrystal was hygroscopic, absorbing 2.3% w / w of water between 0 and 90% RH. After GVS analysis, static storage conditions, grinding and compression studies, and after kinetic solubility analysis, the material also maintained the same XRPD spectrum. In general, as shown by the comparative grinding studies, compression studies, and static storage analyses described in Examples 11, 12, and 13 herein, the solid-state properties of the methylparaben cocrystal form of compound (I) are very positive compared to the Form B crystalline form of compound (I) disclosed in US 2021 / 0221818 (corresponding to WO 2021 / 150723). The cocrystal is also easily prepared by anti-solvent addition and produces a good yield. 10.1.XRPD.

[0145] Obtain the XRPD diffraction pattern using the instrumentation and procedure described in the Instrumentation section (Option B). The XRPD spectrum of the methyl paraben cocrystal is shown in Fig. 27 middle. Fig. 27 Peaks identified in include those listed in Table 12A and Table 12B below; optionally, the peaks reported in Table 12B are considered representative. Table 12A - XRPD Peaks of Example 10 (Methylparaben Cocrystal) strength% angle d value 96 2-θ° Angstrom 93.2 4.6 19.068 19.9 9.3 9.488 18.7 13.1 6.751 30.1 14.4 6.131 20.0 15.4 5.735 40.8 16.6 5.346 32.8 17.7 5.010 55.4 18.3 4.837 100.0 19.3 4.584 33.1 20.2 4.401 25.7 21.0 4.229 33.5 21.6 4.114 49.8 22.5 3.941 24.3 25.5 3.486 20.3 26.0 3.418 19.7 26.9 3.314 20.7 27.4 3.249 18.3 28.0 3.187 16.1 29.2 3.053 39.4 10.8 8.183 27.4 11.2 7.922 15.4 14.0 6.314 20.3 16.2 5.482 16.6 16.9 5.232 25.7 17.3 5.134 32.0 22.2 3.997 20.0 23.3 3.811 26.0 23.7 3.754 22.9 23.9 3.714 14.3 25.3 3.517 Table 12B: XRPD Peaks of Example 10 (Methylparaben Cocrystal) 10.2.DSC / TGA.

[0146] Additional data for the methyl paraben co-crystallized salt form of Compound (I) were obtained using the procedure described in the Instrumental section (Option B) above. The results obtained are reported in Fig.28 (DSC / TGA thermogram). Example 11 - Comparative Grinding Study of Compound (I) Form B and Compound (I): Methylparaben Cocrystal

[0147] For the study, 40 mg of Form B crystalline form of Compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) and 40 mg of methylparaben cocrystal of Example 10 were weighed into separate steel containers, and steel ball bearings of equal size were added to each container. The samples were each ground at 30 Hz for 30 min and then reanalyzed by XRPD. XRPD analysis demonstrated that the methylparaben cocrystal retained its cocrystal structural pattern, with only a limited decrease in overall crystallinity observed, which can be seen in Fig.29 middle, Fig.29 XRPD spectra of methyl paraben before and after grinding are shown. In contrast, a sample comprising the Form B crystalline form of Compound (I) disclosed in US2021 / 0221818 (corresponding to WO 2021 / 150723) becomes amorphous after grinding, which can be seen in Fig.30 ( Fig.30 XRPD spectra of Compound (I) Form B before and after milling are shown). Example 12 - Compression Study of Methylparaben Cocrystal of Example 10

[0148] After drying in a vacuum oven, the methyl paraben co-crystalline form of Compound (I) was compressed into a 6 mm concave disk at 100 kg pressure for 2 min. The disk surface was analyzed by XRPD, which yielded the following: Fig.31 As can be seen, after drying and compression, the methylparaben cocrystals retained their cocrystal structural pattern, with only a limited decrease in overall crystallinity being observed. Example 13 - Compound (I): Static Storage Analysis of Methyl p-Hydroxybenzoate Cocrystal

[0149] A sample of the methyl paraben co-crystalline form of Compound (I) (Example 10) was stored at 25°C and 40°C for one week after drying in a vacuum oven. After storage, XPRD analysis was performed, which yielded Fig.32 The results in , indicate that the methylparaben co-crystalline form of Compound (I) retains its crystalline structure after storage and elevated temperature. Example 14 - Solubility of Methylparaben Cocrystal

[0150] The solubility of the methyl paraben cocrystal of Example 10 was also checked at time intervals of 1h, 3h and 24h using buffer solutions of pH 4.5 and 6.8. The sample was suspended in 1.5mL culture medium to achieve the maximum expected concentration of the free form of compound (I) of about 30mg / mL. The resulting suspension was then vibrated at 25°C / 750rpm for 24h. After 1h, 3h and 24h of equilibrium, 0.5mL of the sample was aliquoted, the appearance was recorded, and the pH of the saturated solution was measured. The sample was then centrifuged at 13,400rpm for 2min. The supernatant was used for HPLC analysis. The sample suspended in pH 4.5 buffer was diluted with pH 4.5 buffer at 1:1 (1h and 3h samples) and 1:8 (24h samples). The sample suspended in pH 6.8 buffer was analyzed without dilution. Quantification was performed by HPLC with reference to a standard solution of about 0.15mg / mL. Different volumes of standard dilution and undiluted sample solutions were injected. Solubility was calculated using the peak area determined by integration of the peak found at the same retention time as the major peak in the standard injection.

[0151] The methylparaben cocrystal showed a solubility that increased over time at pH 4.5, starting from 0.65 mg / mL at the 1 h time point and increasing to 3.9 mg / mL at the 24 h time point. The total solubility at pH 6.8 remained the same at 0.04 mg / mL at all three time points. The data obtained from this solubility assessment are shown in Table 13, Table 14, and Table 15 below. The XRPD analysis reflects no change in the pattern analyzed after dissolution (e.g., with respect to the peaks described in Table 12A and / or Table 12B). Table 13: 1-hour solubility results of methyl paraben eutectic Table 14: 3-hour solubility results of methyl paraben eutectic Table 15: 24-hour solubility results of methyl paraben cocrystal

[0152] The enhanced solubility of crystalline forms of Compound (I) as shown in Examples 9 and 14 enables their use in formulating modified release and / or extended release dosage forms of Compound (I). Equivalent content

[0153] The foregoing written description is considered sufficient to enable one skilled in the art to implement the present embodiment. The foregoing description and examples detail certain embodiments and describe the best mode contemplated by the inventors. However, it should be understood that no matter how detailed the foregoing appears in the text, the embodiments can still be implemented in many ways and should be interpreted 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-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, the substantially crystalline form being selected from the HCl salt, oxalate salt or maleate salt form thereof.

2. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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]pent-2-enenitrile:HCl birefringent crystalline salt.

3. The substantially crystalline form of claim 2, wherein the birefringent crystalline salt of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl is characterized by an XRPD pattern substantially identical to the XRPD pattern in Figure 1.

4. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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]pent-2-enenitrile:HCl crystalline salt hydrate.

5. The substantially crystalline form of claim 4, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl crystalline salt hydrate is characterized by at least one of the following: XRPD pattern substantially the same as that of Figure 2; Essentially the same DSC / TGA graph as Figure 3.

6. The basic crystalline form according to claim 1, which 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-(oxetane-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl crystalline salt form A.

7. The substantially crystalline form of claim 6, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl crystalline salt Form A is characterized by at least one of the following: XRPD pattern substantially the same as that of Figure 4; XRPD pattern substantially the same as that of Figure 5; DSC graph substantially the same as FIG6 ; Essentially the same TGA graph as Figure 7.

8. The substantially crystalline form of claim 6 or 7, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:HCl crystalline salt Form A is characterized by an XRPD pattern comprising four or more peaks expressed in 2θ° selected from the group consisting of peaks at 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 29.3±0.

3.

9. The basic crystalline form according to claim 1, which 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-(oxetane-3-yl)piperazin-1-yl]pent-2-enenitrile: oxalate birefringent crystalline salt form A.

10. The substantially crystalline form of claim 9, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:oxalate birefringent crystalline salt Form A is characterized by at least one of the following: XRPD pattern substantially the same as that of FIG8 ; Essentially the same DSC / TGA graph as Figure 9.

11. The substantially crystalline form of claim 1, wherein the substantially crystalline form is a birefringent crystalline salt of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate.

12. The substantially crystalline form of claim 11, wherein the birefringent crystalline salt of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate is characterized by at least one of the following: XRPD pattern substantially the same as that of Figure 10; Essentially the same DSC / TGA graph as FIG. 11 .

13. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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]pent-2-enenitrile:oxalate crystalline salt hydrate Form A.

14. The substantially crystalline form of claim 13, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:oxalate crystalline salt hydrate Form A is characterized by at least one of the following: XRPD pattern substantially the same as that of FIG. 14 ; A DSC graph substantially the same as FIG. 15A ; XRPD pattern substantially the same as that of FIG. 16 ; XRPD pattern substantially the same as that of FIG. 17 ; TGA graph substantially the same as FIG18 ; Essentially the same DCS / TGA graph as FIG. 19 .

15. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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]pent-2-enenitrile:oxalate crystalline salt hydrate Form B.

16. The substantially crystalline form of claim 15, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:oxalate crystalline salt hydrate Form B is characterized by at least one of the following: XRPD pattern substantially the same as that of FIG. 12 ; DSC / TGA graph substantially the same as FIG13 ; Essentially the same DSC graph as Figure 15B.

17. The substantially crystalline form of claim 13 or 14, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:oxalate crystalline salt hydrate Form A is characterized by an XRPD pattern comprising four or more peaks expressed in 2θ° selected from the group consisting of peaks at 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.

18. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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]pent-2-enenitrile:maleate crystalline salt Form B·MeCN solvate.

19. The substantially crystalline form of claim 18, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate crystalline salt Form B·MeCN solvate is characterized by at least one of the following: XRPD pattern substantially the same as FIG. 20 ; Essentially the same DSC / TGA graph as Figure 21.

20. The substantially crystalline form of claim 1, wherein the substantially crystalline form 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-(oxetane-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate crystalline salt form A.

21. The substantially crystalline form of claim 20, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate crystalline salt Form A is characterized by at least one of the following: An XRPD pattern substantially the same as that shown in FIG22 ; Essentially the same TGA graph as Figure 23.

22. The substantially crystalline form of claim 20 or 21, wherein the crystalline salt Form A of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:maleate is characterized by an XRPD pattern comprising four or more peaks expressed in 2θ° selected from the group consisting of peaks at 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.

23. 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]pent-2-enenitrile, the substantially crystalline form being a methyl para-hydroxybenzoate cocrystal.

24. The substantially crystalline form of claim 23, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:methyl paraben cocrystal is characterized by at least one of the following: XRPD pattern substantially the same as that of Figure 27; Essentially the same DCS / TGA graph as FIG. 28 .

25. The substantially crystalline form of claim 23 or 24, wherein the 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile:methyl paraben cocrystal is characterized by an XRPD pattern comprising four or more peaks expressed in 2θ° selected from the group consisting 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.

26. The substantially crystalline form according to any one of claims 1 to 25, 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.

27. A pharmaceutical composition comprising at least one substantially crystalline form according to any one of the preceding claims and a pharmaceutically acceptable excipient.

28. A method of treating a disease mediated by BTK activity in a subject in need of treatment, the method comprising administering to the subject a 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]pent-2-enenitrile according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 27.

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