crystallization

Abstract

To provide an active pharmaceutical ingredient having an advantageous physical form. The present invention provides a stoichiometric hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the following formula I: The molar ratio of water to formula I is 4.5:1 or less. JPEG2022104995000043.jpg4763

Description

Technical Field

[0001] This application claims priority based on U.S. Provisional Application No. 62 / 336,549, filed on May 13, 2016, and U.S. Provisional Application No. 62 / 336,652, filed on May 13, 2016, the entire contents of both of which are incorporated by reference herein in their entirety.

[0002] Crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (also known as 5-chloro-2-phosphonooxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide), compositions containing the same, and methods for producing and using such crystals are provided.

Background Art

[0003] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is described in International Publication No. 2013 / 169939 (a U.S. national stage application published as U.S. Patent Publication No. 2015 / 0133405). This compound can be used, for example, for the prevention, treatment and control of aquaporin-mediated conditions such as diseases of water imbalance, such as cerebral edema resulting from head trauma and ischemic stroke.

[0004] Active pharmaceutical ingredients can exist in various physical forms (e.g., liquid or solid in various crystalline, amorphous, hydrate, or solvate forms), and the processability, stability, solubility, bioavailability, or pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) and / or the biological equivalence of the active pharmaceutical ingredient and the pharmaceutical composition containing it may vary.

[0005] Therefore, it is necessary to identify active pharmaceutical ingredients having advantageous physical forms (e.g., solid, liquid, crystalline, hydrate, solvate or amorphous forms).

Summary of the Invention

[0006] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is represented by the following formula I. [ka]

[0007] In cases of stroke or other serious debilitating illnesses or conditions, such as when the patient is unconscious or unable to swallow, intravenous infusion or rapid intravenous injection may be preferable. Furthermore, when a patient has a stroke or traumatic brain injury or spinal cord injury, rapidly achieving a therapeutically effective dose of the therapeutic agent may be crucial for successful treatment outcomes. In hospital settings, particularly in acute care settings for stroke, traumatic brain injury, and myocardial infarction, best practice is to administer drugs intravenously. However, therapeutic agents with limited solubility in water and / or physiological media and / or limited stability may make non-enteral administration of the therapeutic agent, such as intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral administration, difficult. N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide is an aquaporin inhibitor, but its solubility in water is 3 μg / ml. The alanine and di-alanine prodrugs of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide are insoluble in water and water at pH 7.4. The prodrug salt forms of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide show improved solubility, particularly the solubility of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphate disodium salt in water at pH 8.5, which is 20 mg / ml. However, the prodrug salt forms of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide may revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide even in solid form.For example, 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl hydrogen phosphate monosodium salt ("monosodium salt"), 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate bissodium salt ("bissodium salt"), and 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl phosphate bisethanolamine salt ("bisethanolamine salt") all exhibit 1% hydrolysis per day in solid state. Therefore, a stable pharmaceutical composition is needed that allows for the rapid achievement of therapeutically effective doses of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.

[0008] International Publication No. 2015 / 069956, incorporated herein in whole by reference, describes formulations of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate that can enable rapid achievement of therapeutically effective doses of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. For example, International Publication No. 2015 / 069956 describes a composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in which the composition is solid.

[0009] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form I) has been found to be highly likely to exist in multiple polymorphic / solvate forms, e.g., ethyl acetate solvate (Form A), hydrate (Form N), and anhydrous / non-solvate form (Form B). Interconversions of Forms A, B, and N are shown in Figure 30. These forms differ from one another in their physical properties, spectral data, stability, and manufacturing methods. The manufacturing of Form A allows for final filtration, which is also sterile. However, ethyl acetate makes the form pharmaceutically undesirable, and Form A exhibits significant hygroscopicity (approximately 6% weight gain at 5-95% RH). Furthermore, in larger-scale synthesis of Form A, extraction with ethyl acetate was found to fail to remove trifluoroacetic acid and acetic acid impurities. Due to the lack of solvent contents and low hygroscopicity (approximately 0.6% weight gain at 5-95% RH), Form B is pharmaceutically more desirable compared to Form A. Form N is pharmaceutically more preferable to Form A because it exhibits low hygroscopicity (approximately 3% weight increase at 5-95% RH) due to the absence of organic solvent contents and DVS.

[0010] A crystalline form of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), which can be used in a pharmaceutical composition, method, or kit described in International Publication No. 2015 / 069956, is provided herein.

[0011] Therefore, hemi solvates of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., hemiethyl acetate, hemiacetonitrile, hemi-p-dioxane, or hemimethanol solvates), such as those described in the following crystal formulas 1 to 4, are provided.

[0012] moreover, [ka] The ethyl acetate solvate (crystalline form 1, also referred to herein as form A) is provided. Crystalline form 1 is provided as follows. 1.1 Crystal morphology 1, where the molar ratio of ethyl acetate to formula I is a maximum of 0.5 moles of ethyl acetate per 1 mole of formula I (i.e., up to 0.5 moles of ethyl acetate), for example, 0.4 to 0.5 moles of ethyl acetate per 1 mole of formula I. 1.2 A crystalline form of 1 or 1.1 in which the molar ratio of ethyl acetate to formula I is 0.5:1. 1.3 An ethyl acetate solvate with an indeterminate crystalline form, in any of the crystalline forms listed below. 1.4 Hemiethyl acetate solvate, i.e., any of the crystalline forms from 1 onwards, in which the asymmetric unit contains formula I and one molecule of ethyl acetate. 1.5 Crystallized in a monoclinic crystal system, belonging to the C2 / c space group, and having any of the following unit cell parameters: a=26.2223(3)Å, b=9.10581(10)Å, c=34.9080(4)Å, β=97.3256(11)°, α=γ=90°.

[0013] 1.6 V=8267.13(16)Å 3 Crystal morphology 1.5 having a calculated volume. 1.7 The crystal structure is approximately 0.563 x 0.089 x 0.039 mm 3 A crystal with a volume of approximately 0.563 x 0.089 x 0.039 mm 3 A crystalline form of 1.5 or 1.6 obtained using a colorless needle-shaped crystal having a volume of . 1.8 A crystal structure obtained using CuKα irradiation, for example, CuKα irradiation with λ = 1.54184 Å, one of the crystal forms from 1.5 to 1.7. 1.9 A crystal structure obtained at 150K, for example, 150.00(10)K, one of the crystal forms from 1.5 to 1.8. 1.10 Any of the crystal forms from 1 onwards having the calculated XRPD pattern shown in Figure 8.

[0014] 1.11 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 5.1, 6.6, 8.0, 13.8, 14.5, 16.1, 16.5, 17.4, 19.3, 20.9, 21.2, 22.0, 23.2, and 23.8, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.12 An XRPD pattern containing a 2θ(°) value selected from the group consisting of 5.1, 6.6, 8.0, 13.8, 14.5, 16.1, 16.5, 17.4, 19.3, 20.9, 21.2, 22.0, 23.2, and 23.8, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards. 1.13 A crystal morphology exhibiting an XRPD pattern including at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 5.07, 6.61, 7.99, 13.80, 14.46, 16.05, 16.52, 17.40, 19.29, 20.93, 21.18, 21.99, 23.17, and 23.82, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.14 A crystal morphology exhibiting an XRPD pattern containing a 2θ(°) value selected from the group consisting of 5.07, 6.61, 7.99, 13.80, 14.46, 16.05, 16.52, 17.40, 19.29, 20.93, 21.18, 21.99, 23.17, and 23.82, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.15 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table A below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 1]

[0015] 1.16 Crystal morphology: Any of the crystal morphologies listed in Table A of 1.15, where the 2θ(°) value is shown, and the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.17 5.1, 6.6, 8.0, 8.7, 10.2, 11.3, 11.5, 12.6, 13.3, 13.8, 14.2, 14.5, 14.6, 15.4, 16.1, 16.5, 17.2, 17.4, 17.7, 18.3, 19.3, 20.0, 20.2, 20.7, 20.9, 21.2, 21.7, 22.0, 23.2, 23.8, 24.3, 24.7, 25.0, 25.2, 25.9, 26.2, 26.8, 27.0, 27.5, 27.9, 28.2, 28.6 and 29. The XRPD pattern exhibits an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 4, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.18 2θ(°) values ​​less than or equal to: 5.1, 6.6, 8.0, 8.7, 10.2, 11.3, 11.5, 12.6, 13.3, 13.8, 14.2, 14.5, 14.6, 15.4, 16.1, 16.5, 17.2, 17.4, 17.7, 18.3, 19.3, 20.0, 20.2, 20.7, 20.9, 21.2, 21.7, 22.0, 23.2, 23.8, 24.3, 24.7, 25.0, 25.2, 25.9, 26.2, 26.8, 27.0, 27.5, 27.9, 28.2, 28.6 and 29.4 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.19 5.07, 6.61, 7.99, 8.67, 10.15, 11.25, 11.49, 12.58, 13.27, 13.80, 14.21, 14.46, 14.58, 15.39, 16.05, 16.52, 17.16, 17.40, 17.68, 18.26, 19.29, 19.96, 20.18, 20.65, 20.93, 21.18, 21.65, 21.99, 23.17, 23.82, 24.28, 24.70, 24.95, 25.23, 25.93, 26.21, 26.79, 26.98, 27.46, 27 The XRPD pattern exhibits at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 0.86, 28.22, 28.63, and 29.43, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.20 2θ(°) values ​​less than or equal to: 5.07, 6.61, 7.99, 8.67, 10.15, 11.25, 11.49, 12.58, 13.27, 13.80, 14.21, 14.46, 14.58, 15.39, 16.05, 16.52, 17.16, 17.40, 17.68, 18.26, 19.29, 19.96 , 20.18, 20.65, 20.93, 21.18, 21.65, 21.99, 23.17, 23.82, 24.28, 24.70, 24.95, 25.23, 25.93, 26.21, 26.79, 26.98, 27.46, 27.86, 28.22, 28.63 and 29.43 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

[0016] 1.21 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table A below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 2] 1.22 Crystal morphology: Any of the crystal morphologies listed above, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table B of 1.21, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.23 Any of the following crystal morphologies exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 17.4, 13.4, 11.1, 6.4, 6.1, 5.5, 5.4, 5.1, 4.6, 4.2, 4.0, 3.8, and 3.7. 1.24 d interval (Å) values ​​less than: 17.4, 13.4, 11.1, 6.4, 6.1, 5.5, 5.4, 5.1, 4.6, 4.2, 4.0, 3.8, and 3.7 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the following crystal morphologies exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 1.25, 17.43, 13.36, 11.06, 6.41, 6.12, 5.52, 5.36, 5.09, 4.60, 4.24, 4.19, 4.04, 3.84, and 3.73.

[0017] 1.26 d interval (Å) values ​​less than or equal to: 17.43, 13.36, 11.06, 6.41, 6.12, 5.52, 5.36, 5.09, 4.60, 4.24, 4.19, 4.04, 3.84, and 3.73 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the following crystal morphologies exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 1.27, 17.430, 13.364, 11.055, 6.410, 6.121, 5.518, 5.363, 5.093, 4.597, 4.241, 4.192, 4.039, 3.835, and 3.732. 1.28 d interval (Å) values ​​less than or equal to: 17.430, 13.364, 11.055, 6.410, 6.121, 5.518, 5.363, 5.093, 4.597, 4.241, 4.192, 4.039, 3.835, and 3.732 Any of the crystal forms from 1 onwards that exhibit the XRPD pattern. 1.29 Any of the crystal morphologies from 1 onwards that exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the d-interval (Å) values ​​shown in Table A of 1.15. 1.30 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the d-interval (Å) values ​​shown in Table A of 1.15.

[0018] 1.31 Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 17.4, 13.4, 11.1, 10.2, 8.7, 7.9, 7.7, 7.0, 6.7, 6.4, 6.2, 6.1, 5.8, 5.5, 5.4, 5.2, 5.1, 5.0, 4.9, 4.6, 4.4, 4.3, 4.2, 4.1, 4.0, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0, including at least 30 d-interval (Å) values. 1.32 d interval (Å) values ​​less than: Any of the crystal forms from 1 onwards exhibiting an XRPD pattern having 17.4, 13.4, 11.1, 10.2, 8.7, 7.9, 7.7, 7.0, 6.7, 6.4, 6.2, 6.1, 5.8, 5.5, 5.4, 5.2, 5.1, 5.0, 4.9, 4.6, 4.4, 4.3, 4.2, 4.1, 4.0, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0. 1.33 17.43, 13.36, 11.06, 10.19, 8.71, 7.86, 7.70, 7.03, 6.67, 6.41, 6.23, 6.12, 6.07, 5.75, 5.52, 5.36, 5.16, 5.09, 5.01, 4.86, 4.60, 4.44, 4.40, 4.30, 4.24, 4.19, 4.10, 4.04, 3.84, 3.73, 3.66, 3.60, 3.57, 3.53, 3.43, 3.40, 3. Any of the crystal morphologies 1 or later exhibiting an XRPD pattern with an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 33, 3.30, 3.25, 3.20, 3.16, 3.12, and 3.03, and including at least 3. 1.34 d interval (Å) values ​​less than: 17.43, 13.36, 11.06, 10.19, 8.71, 7.86, 7.70, 7.03, 6.67, 6.41, 6.23, 6.12, 6.07, 5.75, 5.52, 5.36, 5.16, 5.09, 5.01, 4.86, 4.60, 4.44, 4.40, 4.30, 4.24, 4.19, 4.10, 4.04, 3.84, 3.73, 3.66, 3.60, 3.57, 3.53, 3.43, 3.40, 3.33, 3.30, 3.25, 3.20, 3.16, 3.12, and 3.03 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics. 1.35 17.430, 13.364, 11.055, 10.190, 8.705, 7.862, 7.695, 7.029, 6.669, 6.410, 6.228, 6.121, 6.070, 5.753, 5.518, 5.363, 5.162, 5.093, 5.013, 4.856, 4.597, 4.444, 4.397, 4.298, 4.241, 4.192, 4.101, 4.039, 3.835, 3.732, 3.663, 3.601, 3.566, 3.527 , any of the crystal morphologies from 1 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 3.433, 3.397, 3.325, 3.302, 3.246, 3.199, 3.160, 3.115 and 3.033, and an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 3.433, 3.397, 3.325, 3.302, 3.246, 3.199, 3.160, 3.115 and 3.033.

[0019] 1.36 d interval (Å) values ​​less than: 17.430, 13.364, 11.055, 10.190, 8.705, 7.862, 7.695, 7.029, 6.669, 6.410, 6.228, 6.121, 6.070, 5.753, 5.518, 5.363, 5.162, 5.093, 5.013, 4.856, 4.597, 4 .444, 4.397, 4.298, 4.241, 4.192, 4.101, 4.039, 3.835, 3.732, 3.663, 3.601, 3.566, 3.527, 3.433, 3.397, 3.325, 3.302, 3.246, 3.199, 3.160, 3.115 and 3.033 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics. 1.37 Any of the crystal morphologies from 1 onwards that exhibit an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table B of Crystal Morphology 1.21. 1.38 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern with the d-interval (Å) values ​​shown in Table B of 1.21. 1.39 A crystal morphology exhibiting an XRPD pattern including at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 5.1, 6.7, 14.6, 16.6, 19.3, 21.2, 22.1, 23.2, and 23.9, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. The XRPD pattern shows 2θ(°) values ​​of 1.40, 5.1, 6.7, 14.6, 16.6, 19.3, 21.2, 22.1, 23.2, and 23.9, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards.

[0020] 1.41 The crystal morphology exhibits an XRPD pattern including at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 5.10, 6.65, 14.60, 16.56, 19.29, 21.19, 22.07, 23.23, and 23.94, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. The XRPD pattern exhibits an XRPD with a 2θ(°) value selected from the group consisting of 1.42, 5.10, 6.65, 14.60, 16.56, 19.29, 21.19, 22.07, 23.23, and 23.94, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.43 A crystal morphology exhibiting an XRPD pattern containing at least 3, e.g., at least 5, 2θ(°) values ​​as shown in Table AA below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 3] 1.44 Crystal morphology: Any of the following crystal morphologies, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table AA of 1.43, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.45 5.1, 6.7, 8.1, 8.7, 10.2, 10.4, 11.3, 11.5, 12.6, 14.0, 14.3, 14.6, 16.3, 16.6, 16.9, 17.2, 17.4, 17.7, 18.3, 18.5, 19.3, 19.7, 20.1, 20.5, 20.7, 21.0, 21.2, 21.7, 22.1, 22.2, 23.2, 23.9, 24.3, 24.8, 25.2, 25.4, 25.7, 26.0, 26.2, 26.5, 27.1, 27.6, 28.4, 28.8 The XRPD pattern exhibits an XRPD with a 2θ(°) value selected from the group consisting of 29.5 and at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards.

[0021] 1.46 2θ(°) values ​​less than: 5.1, 6.7, 8.1, 8.7, 10.2, 10.4, 11.3, 11.5, 12.6, 14.0, 14.3, 14.6, 16.3, 16.6, 16.9, 17.2, 17.4, 17.7, 18.3, 18.5, 19.3, 19.7, 20.1, 20.5, 20.7, 21.0, 21.2, 21.7, 22.1, 22.2, 23.2, 23.9, 24.3, 24.8, 25.2, 25.4, 25.7, 26.0, 26.2, 26.5, 27.1, 27.6, 28.4, 28.8 and 29.5 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.47 5.10, 6.65, 8.11, 8.68, 10.23, 10.43, 11.30, 11.49, 12.60, 13.98, 14.29, 14.60, 16.29, 16.56, 16.88, 17.20, 17.40, 17.69, 18.29, 18.46, 19.29, 19.72, 20.09, 20.51, 20.65, 20.96, 21.19, 21.69, 22.07, 22.24, 23.23, 23.94, 24.30, 24.78, 25.15, 25.38, 25.71, 25.96, 26.22, 26.51, 27 The XRPD pattern exhibits at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 0.11, 27.60, 28.35, 28.81, and 29.48, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.48 2θ(°) values ​​less than or equal to: 5.10, 6.65, 8.11, 8.68, 10.23, 10.43, 11.30, 11.49, 12.60, 13.98, 14.29, 14.60, 16.29, 16.56, 16.88, 17.20, 17.40, 17.69, 18.29, 18.46, 19.29, 19.72, 20.09 , 20.51, 20.65, 20.96, 21.19, 21.69, 22.07, 22.24, 23.23, 23.94, 24.30, 24.78, 25.15, 25.38, 25.71, 25.96, 26.22, 26.51, 27.11, 27.60, 28.35, 28.81 and 29.48 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.49 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table BB below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 4] 1.50 Crystal morphology 1.49 The crystal morphology exhibits an XRPD pattern with the 2θ(°) value shown in Table BB, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 1 onwards.

[0022] 1.51 Any of the crystal morphologies from 1 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 17.3, 13.3, 6.1, 5.3, 4.6, 4.2, 4.0, 3.8, and 3.7. 1.52 d interval (Å) values ​​less than: 17.3, 13.3, 6.1, 5.3, 4.6, 4.2, 4.0, 3.8, and 3.7 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the following crystal morphologies, 1 or later, exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 1.53, 17.30, 13.28, 6.06, 5.35, 4.60, 4.19, 4.02, 3.83, and 3.71. 1.54 The crystal has the following d-interval (Å) values: 17.30, 13.28, 6.06, 5.35, 4.60, 4.19, 4.02, 3.83, and 3.71 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the following crystal morphologies, 1 or later, exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 1.55, 17.299, 13.276, 6.064, 5.348, 4.597, 4.189, 4.024, 3.827, and 3.714.

[0023] 1.56 d interval (Å) values ​​less than: 17.299, 13.276, 6.064, 5.348, 4.597, 4.189, 4.024, 3.827, and 3.714 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. 1.57 Any of the crystal morphologies from 1 onwards that exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the d-interval (Å) values ​​shown in Table AA of 1.43. 1.58 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the d-interval (Å) values ​​shown in Table AA of Crystal Form 1.43. 1.59 Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 17.3, 13.3, 10.9, 10.2, 8.6, 8.5, 7.8, 7.7, 7.0, 6.3, 6.2, 6.1, 5.4, 5.3, 5.2, 5.1, 5.0, 4.8, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0, including at least 30 d-interval (Å) values. 1. d interval (Å) values ​​less than or equal to 1.60: 17.3, 13.3, 10.9, 10.2, 8.6, 8.5, 7.8, 7.7, 7.0, 6.3, 6.2, 6.1, 5.4, 5.3, 5.2, 5.1, 5.0, 4.8, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 and 3.0 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics.

[0024] 1.61 17.30, 13.28, 10.89, 10.18, 8.64, 8.47, 7.83, 7.70, 7.02, 6.33, 6.19, 6.06, 5.44, 5.35, 5.25, 5.15, 5.09, 5.01, 4.85, 4.80, 4.60, 4.50, 4.42, 4.33, 4.30, 4.23, 4.19, 4.09, 4.02, 4.00, 3.83, 3.71, 3.66, 3.59, 3.54, 3.51, 3.46, 3 Any crystal morphology of 1 or later exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 0.43, 3.40, 3.36, 3.29, 3.23, 3.15, 3.10, and 3.03, and an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 0.43, 3.40, 3.36, 3.29, 3.23, 3.15, 3.10, and 3.03. 1. d interval (Å) values ​​less than or equal to 1.62: 17.30, 13.28, 10.89, 10.18, 8.64, 8.47, 7.83, 7.70, 7.02, 6.33, 6.19, 6.06, 5.44, 5.35, 5.25, 5.15, 5.09, 5.01, 4.85, 4.80, 4.60, 4.50, 4.42, 4.33, 4.30, 4.23, 4.19, 4.09, 4.02, 4.00, 3.83, 3.71, 3.66, 3.59, 3.54, 3.51, 3.46, 3.43, 3.40, 3.36, 3.29, 3.23, 3.15, 3.10 and 3.03 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics. 1.63 17.299, 13.276, 10.892, 10.183, 8.640, 8.472, 7.827, 7.698, 7.020, 6.330, 6.194, 6.064, 5.438, 5.348, 5.249, 5.152, 5.091, 5.009, 4.847, 4.801, 4.597, 4.498, 4.417, 4.327, 4.298, 4.234, 4.189, 4.093, 4.024, 3.995, 3.827, 3.714, 3.660, 3.591, 3.538 , any of the crystal morphologies 1 or later exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 3.507, 3.463, 3.430, 3.396, 3.359, 3.287, 3.229, 3.146, 3.096, and 3.028, and an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 3.507, 3.463, 3.430, 3.396, 3.359, 3.287, 3.229, 3.146, 3.096, and 3.028. 1. d interval (Å) values ​​less than or equal to 1.64: 17.299, 13.276, 10.892, 10.183, 8.640, 8.472, 7.827, 7.698, 7.020, 6.330, 6.194, 6.064, 5.438, 5.348, 5.249, 5.152, 5.091, 5.009, 4.847, 4.801, 4.597, 4.498, 4.417, 4.327, 4.29 Any of the crystal forms from 1 onwards exhibiting an XRPD pattern having 8, 4.234, 4.189, 4.093, 4.024, 3.995, 3.827, 3.714, 3.660, 3.591, 3.538, 3.507, 3.463, 3.430, 3.396, 3.359, 3.287, 3.229, 3.146, 3.096 and 3.028. 1.65 A crystal morphology comprising at least 3, e.g., at least 5, e.g., at least 9, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table BB.

[0025] 1.66 The crystal morphology of 1.49, showing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table BB. 1.67 A crystal morphology exhibiting an XRPD pattern including at least 3, e.g., at least 5, e.g., at least 10, 2θ(°) values ​​selected from the group consisting of 5.1, 6.6, 8.0, 11.5, 13.9, 14.5, 16.2, 16.5, 17.4, 19.3, 20.9, 21.1, 22.0, 23.2, and 23.9, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.68 The XRPD pattern shows 2θ(°) values ​​including 5.1, 6.6, 8.0, 11.5, 13.9, 14.5, 16.2, 16.5, 17.4, 19.3, 20.9, 21.1, 22.0, 23.2 and 23.9, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards. The crystal morphology exhibits an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10 2θ(°) values ​​selected from the group consisting of 1.69, 5.08, 6.62, 8.03, 11.47, 13.86, 14.53, 16.15, 16.53, 17.36, 19.26, 20.93, 21.13, 22.03, 23.17, and 23.88, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. The XRPD pattern shows 1.70, 5.08, 6.62, 8.03, 11.47, 13.86, 14.53, 16.15, 16.53, 17.36, 19.26, 20.93, 21.13, 22.03, 23.17, and 23.88, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards.

[0026] 1.71 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table CC below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 5] 1.72 An XRPD pattern having the 2θ(°) values ​​shown in Table CC, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards. 1.73 An XRPD pattern exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.74 2θ(°) values ​​less than: 5.1, 6.6, 8.0, 8.6, 10.2, 11.3, 11.5, 12.6, 13.9, 14.5, 16.2, 16.5, 17.4, 17.7, 18.3, 19.3, 20.0, 20.6, 20.9, 21.1, 22.0, 23.2, 23.9, 24.2, 24.7, 25.3, 26.0 and 26.2 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. Is the group consisting of 1.75, 5.08, 6.62, 8.03, 8.64, 10.18, 11.28, 11.47, 12.58, 13.86, 14.53, 16.15, 16.53, 17.36, 17.67, 18.32, 19.26, 19.97, 20.58, 20.93, 21.13, 22.03, 23.17, 23.88, 24.24, 24.74, 25.28, 25.95, and 26.17? The selected 2θ(°) values ​​include an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards.

[0027] 1.76 2θ(°) values ​​less than or equal to: 5.08, 6.62, 8.03, 8.64, 10.18, 11.28, 11.47, 12.58, 13.86, 14.53, 16.15, 16.53, 17.36, 17.67, 18.32, 19.26, 19.97, 20.58, 20.93, 21.13, 22.03, 23.17, 23.88, 24.24, 24.74, 25.28, 25.95 and 26.17 The XRPD pattern exhibits any of the following crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.77 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table DD below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. [Table 6] 1.78 Crystal morphology: An XRPD pattern having the 2θ(°) values ​​shown in Table DD of 1.77, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 1 onwards. 1.79 Any of the crystal morphologies from 1 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, d-interval (Å) values ​​selected from the group consisting of 17.4, 13.3, 11.0, 7.7, 6.4, 6.1, 5.5, 5.4, 5.1, 4.6, 4.2, 4.0, 3.8, and 3.7. 1. d interval (Å) values ​​less than or equal to 1.80: 17.4, 13.3, 11.0, 7.7, 6.4, 6.1, 5.5, 5.4, 5.1, 4.6, 4.2, 4.0, 3.8, and 3.7 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern.

[0028] Any of the following crystal morphologies exhibit an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10 d-interval (Å) values ​​selected from the group consisting of 1.81, 17.37, 13.35, 11.00, 7.71, 6.39, 6.09, 5.48, 5.36, 5.10, 4.61, 4.24, 4.20, 4.03, 3.84, and 3.72. 1.82 d interval (Å) values ​​less than or equal to: 17.37, 13.35, 11.00, 7.71, 6.39, 6.09, 5.48, 5.36, 5.10, 4.61, 4.24, 4.20, 4.03, 3.84, and 3.72 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10 d-interval (Å) values ​​selected from the group consisting of 1.83, 17.372, 13.349, 10.998, 7.710, 6.385, 6.091, 5.483, 5.359, 5.103, 4.606, 4.240, 4.201, 4.031, 3.835, and 3.723. 1.84 d interval (Å) values ​​less than or equal to: 17.372, 13.349, 10.998, 7.710, 6.385, 6.091, 5.483, 5.359, 5.103, 4.606, 4.240, 4.201, 4.031, 3.835 and 3.723 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern including the XRPD pattern. 1.85 A crystal morphology exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the d-interval (Å) values ​​shown in Table CC, as described in 1.71.

[0029] 1.86 Crystal morphology of 1.71, showing an XRPD pattern including the d-interval (Å) values ​​shown in Table CC. 1.87 Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing an XRPD pattern with at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20 d-interval (Å) values ​​selected from the group consisting of 17.4, 13.3, 11.0, 10.2, 8.7, 7.8, 7.7, 7.0, 6.4, 6.1, 5.5, 5.4, 5.1, 5.0, 4.8, 4.6, 4.4, 4.3, 4.2, 4.0, 3.8, 3.7, 3.6, 3.5, and 3.4. 1.88 d interval (Å) values ​​less than or equal to: 17.4, 13.3, 11.0, 10.2, 8.7, 7.8, 7.7, 7.0, 6.4, 6.1, 5.5, 5.4, 5.1, 5.0, 4.8, 4.6, 4.4, 4.3, 4.2, 4.0, 3.8, 3.7, 3.6, 3.5, and 3.4 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics. Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25 d-interval (Å) values ​​selected from the group consisting of 1.89, 17.37, 13.35, 11.00, 10.22, 8.68, 7.84, 7.71, 7.03, 6.39, 6.09, 5.48, 5.36, 5.10, 5.02, 4.84, 4.61, 4.44, 4.31, 4.24, 4.20, 4.03, 3.84, 3.72, 3.67, 3.60, 3.52, 3.43, and 3.40, and including an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25. 1. d interval (Å) values ​​less than or equal to 1.90: 17.37, 13.35, 11.00, 10.22, 8.68, 7.84, 7.71, 7.03, 6.39, 6.09, 5.48, 5.36, 5.10, 5.02, 4.84, 4.61, 4.44, 4.31, 4.24, 4.20, 4.03, 3.84, 3.72, 3.67, 3.60, 3.52, 3.43 and 3.40 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics.

[0030] Any crystal morphology from 1 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25 d-interval (Å) values ​​selected from the group consisting of 1.91, 17.372, 13.349, 10.998, 10.223, 8.682, 7.837, 7.710, 7.029, 6.385, 6.091, 5.483, 5.359, 5.103, 5.015, 4.839, 4.606, 4.442, 4.311, 4.240, 4.201, 4.031, 3.835, 3.723, 3.669, 3.596, 3.521, 3.430, and 3.402, wherein the d-interval (Å) values ​​are selected from the group consisting of at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25. 1.92 d interval (Å) values ​​less than: 17.372, 13.349, 10.998, 10.223, 8.682, 7.837, 7.710, 7.029, 6.385, 6.091, 5.483, 5.359, 5.103, 5.015, 4.839, 4.606, 4.442, 4.311, 4.240, 4.201, 4.031, 3.835, 3.723, 3.669, 3.596, 3.521, 3.430 and 3.402 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern having the following characteristics. 1.93 A crystal morphology of 1.77 exhibiting an XRPD pattern that includes at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the d-interval (Å) values ​​shown in Table DD. 1.94 Any of the crystal forms from 1 onwards that exhibit an XRPD pattern with d-interval (Å) values ​​shown in Table D of Crystal Form 1.77. 1.95 An XRPD pattern showing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks, and the XRPD is measured using CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal forms from 1 onwards.

[0031] 1.96 An XRPD pattern including characteristic peaks of the XRPD pattern shown in Figure 10, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.97 An XRPD pattern including a representative peak of the XRPD pattern shown in Figure 10, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards. 1.98 The XRPD pattern shown in Figure 10, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.99 An XRPD pattern showing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., an XRPD pattern showing all peaks, where the XRPD is measured using CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 1 onwards. 1.100 An XRPD pattern including the characteristic peaks of the XRPD shown in Figure 11, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards.

[0032] 1.101 An XRPD pattern including a representative peak of the XRPD pattern shown in Figure 11, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 1 onwards. 1.102 The XRPD pattern shown in Figure 11, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 1 onwards. 1.103 An XRPD pattern showing at least five peaks of the XRPD pattern shown in Figure 12a, for example, an XRPD pattern including all peaks, and the XRPD is obtained using a copper source, for example, by CuKα irradiation, and any of the crystal forms from 1 onwards. 1.104 Any of the crystal forms from 1 onwards, which include the characteristic peaks of the XRPD pattern shown in Figure 12a, and in which the XRPD is obtained using a copper source, for example, by CuKα irradiation. 1.105 Any of the crystal forms from 1 onwards, which include a representative peak in the XRPD pattern shown in Figure 12a, and in which the XRPD is obtained using a copper source, for example, by CuKα irradiation.

[0033] 1.106 Any of the crystal forms from 1 onwards, showing the XRPD pattern shown in Figure 12a, obtained using a copper source, for example, by CuKα irradiation. 1.107 An XRPD pattern showing at least five peaks of the XRPD pattern shown in Figure 12a, for example, an XRPD pattern including all peaks, and any of the crystal forms from 1 onwards, obtained using a copper source, for example, by CuKα irradiation. 1.108 Any of the crystal forms from 1 onwards, which include the characteristic peaks of the XRPD pattern shown in Figure 12b, and in which the XRPD is obtained using a copper source, for example, by CuKα irradiation. 1.109 Any of the crystal forms from 1 onwards, which include a representative peak in the XRPD pattern shown in Figure 12b, and in which the XRPD is obtained using a copper source, for example, by CuKα irradiation. 1.110 Any of the crystal forms from 1 onwards, showing the XRPD pattern shown in Figure 12b, obtained using a copper source, for example, by CuKα irradiation.

[0034] 1.111 Any crystal morphology from 1 onwards that exhibits an XRPD pattern including at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks of the XRPD shown in Figures 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58, or 59. 1.112 Any of the crystal morphologies from 1 onwards, including characteristic peaks in the XRPD pattern shown in Figures 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, for example, Figure 10 or 11 or 12a or 12b or 31 or 32 or 33 or 35 or 36 or 38 or 39 or 58 or 59, wherein the XRPD is measured using CuKα irradiation, for example, by irradiation at a wavelength of 1.54059 Å. 1.113 Any of the crystal morphologies from 1 onwards, including representative peaks of the XRPD pattern shown in Figures 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, for example, Figure 10 or 11 or 12a or 12b or 31 or 32 or 33 or 35 or 36 or 38 or 39 or 58 or 59, wherein the XRPD is measured using CuKα irradiation, for example, by irradiation at a wavelength of 1.54059 Å. 1.114 Any of the crystal morphologies from 1 onwards, substantially as shown in Figures 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, for example, substantially as shown in Figures 10 or 11 or 12a or 12b or 31 or 32 or 33 or 35 or 36 or 38 or 39 or 58 or 59, for example, showing an XRPD pattern shown in any of the XRPDs for any of the crystal morphologies A shown herein, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.115 Any of the following crystalline forms, including, for example, a weight loss of 6–9% by weight, for example, 7–9% by weight, for example, 7–8% by weight, or for example, 7.8% by weight, between 90°C and 165°C.

[0035] 1.116 The thermogravimetric analysis (TGA) thermogram shown in Figure 25, one of the crystal forms from 1 onwards. 1.117 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 113°C, showing any of the crystal forms from 1 onwards. 1.118 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 123°C, showing any of the crystal forms from 1 onwards. 1.119 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 131°C, showing any of the crystal forms from 1 onwards. 1.120 Any of the crystal forms from 1 onwards, showing a differential scanning calorimetry (DSC) thermogram including endothermic heating at 176°C, for example, endothermic heating at 176°C with an initiation at 170°C.

[0036] 1.121 A differential scanning calorimetry (DSC) thermogram shown in Figure 25, representing any of the crystal forms from 1 onwards. 1.122 Any of the crystal forms from 1 onwards that exhibit dynamic (water) vapor adsorption (DVS) isotherms, including a weight increase of 7% or less with increasing relative humidity (RH) from 5% to 95%, e.g., a weight increase of 6.5% or less, e.g., a weight increase of 6-7%, e.g., a weight increase of 2% or less at 5% to 75% relative humidity, and a weight increase of 5% or less at 75% to 95% relative humidity, e.g., a weight increase of 1-2% at 5% to 75% relative humidity and a weight increase of 4-5% at 75% to 95% relative humidity. 1.123 Any of the crystal forms shown in Figure 34, representing the dynamic (water) vapor adsorption (DVS) isotherm, from 1 onwards. 1.124 Any of the crystal forms from 1 onwards, wherein the purification of the crystals comprises acidifying an aqueous solution containing one or more 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphates, two {[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl hydrogen phosphate monoanions and 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphate dianions to, for example, pH less than 2, for example less than 1, or for example pH 1, using, for example hydrochloric acid. 1.125 A crystalline form of 1.124, further comprising extracting 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with an organic solvent, such as ethyl acetate, to form an aqueous fraction and an organic fraction.

[0037] 1.126 A crystalline form of 1.125, further comprising the separation of organic fractions. 1.127 A crystalline form of 1.126, further comprising drying the organic fraction with, for example, sodium sulfate. 1.128 A crystalline form of 1.127, including evaporation of an organic solvent. 1.129 Any of the crystal forms of 1.124-1.128, further comprising isolating the crystal. 1.130 A crystalline form of any of 1.124 to 1.128, further comprising concentrating an organic solvent under reduced pressure to provide an oily substance.

[0038] 1.131 The crystalline form of 1.130, further comprising optionally stirring and dissolving an oily substance in an organic solvent (e.g., ethyl acetate). 1.132 The crystalline form of 1.131, further comprising, depending on the circumstances, adding a poor solvent, such as an organic poor solvent (e.g., n-heptane), for example, an excess of the poor solvent, for example, a poor solvent in a ratio of 2.5:1 to an organic solvent, a poor solvent in a ratio of 5:1 or more to an organic solvent, for example, a poor solvent in a ratio of 12:1 or more to an organic solvent, for example, a poor solvent in a ratio of 2.5:1 to 12:1 to an organic solvent. 1.133 The crystalline form of 1.132, further comprising isolating the solid, for example, by filtration. 1.134 The crystalline form of 1.133, further comprising washing the solid with a poor solvent, such as an organic poor solvent (e.g., n-heptane). 1.135 A crystalline form of 1.134, further comprising drying the solid under vacuum.

[0039] 1.136 Any of the crystal forms of 1.124-1.135, further including the isolation of the crystal. 1.137 Any of the crystalline forms from 1 onwards, wherein the preparation of the crystals comprises dissolving 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in an organic solvent (e.g., ethyl acetate or a mixture containing ethyl acetate), optionally at room temperature and / or optionally with stirring. 1.138 The crystalline form of 1.137, further comprising, depending on the circumstances, adding a poor solvent, such as an organic poor solvent (e.g., n-heptane), for example, an excess of the poor solvent, for example, a poor solvent in a ratio of 2.5:1 to an organic solvent, a poor solvent in a ratio of 5:1 or more to an organic solvent, for example, a poor solvent in a ratio of 12:1 or more to an organic solvent, for example, a poor solvent in a ratio of 2.5:1 to 12:1 to an organic solvent. 1.139 The crystalline form of 1.138, further comprising isolating the solid, for example, by filtration. 1.140 The crystalline form of 1.139, further comprising washing the solid with a poor solvent, such as an organic poor solvent (e.g., n-heptane).

[0040] 1.141 A crystalline form of 1.140, further comprising drying the solid under vacuum. 1.142 Any of the crystal forms from 1.124 to 1.141, further including the isolation of the crystal. 1.143 Any of the crystal forms listed above, produced by the steps following Method 1 (see below). 1.144 Any of the crystal forms one or later, which are produced as described in any of the examples for purifying form A. 1.145 Any of the crystal forms from 1 onwards, in which the XRPD pattern has an acceptable deviation of ±0.2°.

[0041] [ka] Hemi-sodium salt crystals (crystal form 2a) are further provided.

[0042] [ka] The acetonitrile solvate (crystalline form 2b) is further provided.

[0043] Crystal forms 2a and 2b are further provided as follows. 2.1 Crystal form is hemisodium hemiacetonitrile solvate, for example, crystal form 2a or crystal form 2b, in which the asymmetric unit comprises four molecules of formula I (two neutral molecules of formula I and two monodeprotonated molecules of formula I), two sodium cations and two acetonitrile molecules. Na substitutes one proton on the PO4 group of the half-molecule. 2.2 A crystalline form of any of 2a, 2b, or 2.1, in which the molar ratio of acetonitrile to formula I is 0.5:1. 2.3 A crystal form of 2a, 2b, or any of 2.1-2.2, in which the molar ratio of sodium to Equation I is 0.5:1. 2.4 Crystal morphology of 2a, 2b, or any of 2.1-2.3, where the ratio of acetonitrile:sodium:formula I is 0.5:0.5:1. 2.5 The crystal morphology is one of 2a, 2b, or 2.1-2.4, where the crystal morphology is monoclinic, belongs to the P21 space group, and has the following unit cell parameters: a=9.0319(2)Å, b=15.4685(4)Å, c=27.7447(5)Å, β=96.9157, α=γ=90°.

[0044] 2.6 V=3848.01(15)Å 3 A crystal form of 2.5 having a calculated volume. 2.7 The crystal structure is approximately 0.25 x 0.10 x 0.09 mm 3 A crystal with a volume of approximately 0.25 x 0.10 x 0.09 mm. 3 A crystal form according to 2.5 or 2.6, obtained using a rod-shaped crystal having the volume of . 2.8 Crystal morphologies of 2.5 to 2.7 obtained by using CuKα irradiation, for example, CuKα irradiation with γ = 1.54178 Å. 2.9 Crystal morphologies of 2.5 to 2.8 obtained at 100K, for example, 100(2)K. 2.10 Any of the two or later crystal forms having the calculated XRPD shown in Figure 20.

[0045] 2.11 Any of the crystal forms from 2 onwards, in which the crystal is manufactured as described in Example 5. 2.12 Any of the two or later crystal forms produced by the steps following Method 1 (see below). 2.13 Any of the two or later crystal forms in which the 2θ(°) value of the XRPD pattern has an allowable deviation of ±0.2°.

[0046] [ka] The p-dioxane solvate (crystal form 3, also referred to herein as formula I) is further provided. Crystal form 3 is further provided as follows:

[0047] 3.1 Crystal form 3, where the crystal form is hemi-p-dioxane solvate, i.e., the molar ratio of p-dioxane to formula I is 0.5:1. 3.2 Exhibiting an XRPD pattern containing at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 6.4, 8.5, 16.3, 17.1, 19.3, 20.1, 21.6, and 23.7, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and the crystal morphology is 3 or 3.1. 3.3 An XRPD pattern containing a 2θ(°) value selected from the group consisting of 6.4, 8.5, 16.3, 17.1, 19.3, 20.1, 21.6 and 23.7, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 3 onwards. 3.4 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 6.37, 8.49, 16.33, 17.06, 19.28, 20.14, 21.61, and 23.65, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the 3 or later crystal forms. 3.5 An XRPD pattern containing a 2θ(°) value selected from the group consisting of 6.37, 8.49, 16.33, 17.06, 19.28, 20.14, 21.61 and 23.65, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 3 onwards.

[0048] 3.6 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table E below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the 3 or later crystal forms. [Table 7] 3.7 The crystal morphology exhibits an XRPD pattern with the 2θ(°) values ​​shown in Table E of the crystal morphologies in 3.6, and the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the crystal morphologies from 3 onwards. 3.8 Is this a group consisting of 6.4, 8.5, 10.7, 12.2, 12.8, 13.6, 14.1, 16.1, 16.3, 17.1, 17.6, 19.3, 19.7, 20.1, 21.0, 21.6, 21.9, 22.2, 22.5, 22.7, 23.7, 24.1, 24.6, 25.2, 25.4, 26.5, 27.5, 28.0, 28.4, 29.0, 29.2, 29.4, 29.9 and 30.2? The selected 2θ(°) values ​​include an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and the crystal morphology is 3 or higher. 3.9 2θ(°) values ​​below: 6.4, 8.5, 10.7, 12.2, 12.8, 13.6, 14.1, 16.1, 16.3, 17.1, 17.6, 19.3, 19.7, 20.1, 21.0, 21.6, 21.9, 22.2, 22.5, 22.7, 23.7, 24.1, 24.6, 25.2, 25.4, 26.5, 27.5, 28.0, 28.4, 29.0, 29.2, 29.4, 29.9 and 30.2 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the crystal morphologies from 3 onwards. 3.10 6.37, 8.49, 10.70, 12.22, 12.77, 13.63, 14.07, 16.10, 16.33, 17.06, 17.58, 19.28, 19.73, 20.14, 21.04, 21.61, 21.92, 22.19, 22.47, 22.72, 23.65, 24.13, 24.61, 25.15, 25.40, 26.53, 27.47, 28.04, 28.35, 28.95, 29.17, 29.44, 29.88 The XRPD pattern exhibits an XRPD with at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 2θ(°) values ​​selected from the group consisting of 30.19, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the three or later crystal forms.

[0049] 3.11 The following 2θ(°) values: 6.37, 8.49, 10.70, 12.22, 12.77, 13.63, 14.07, 16.10, 16.33, 17.06, 17.58, 19.28, 19.73, 20.14, 21.04, 21.61, 21.92, 22.19, 22.47, 22.72, 23.65, 24.13, 24.61, 25.15, 25.40, 26.53, 27.47, 28.04, 28.35, 28.95, 29.17, 29.44, 29.88 and 30.19 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the crystal morphologies from 3 onwards. 3.12 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table F below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 3 onwards. [Table 8] 3.13 Crystal morphology: An XRPD pattern having the 2θ(°) values ​​shown in Table F of 3.12, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 3 onwards. 3.14 Any of the three or later crystal morphologies exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 13.9, 10.4, 5.4, 5.2, 4.6, 4.4, 4.1, and 3.8. 3.15 d interval (Å) values ​​below: 13.9, 10.4, 5.4, 5.2, 4.6, 4.4, 4.1, and 3.8 Any of the three or later crystal forms that exhibit an XRPD pattern including the XRPD pattern.

[0050] 3.16 Any of the three or later crystal morphologies exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 13.87, 10.40, 5.42, 5.19, 4.60, 4.41, 4.11, and 3.76. 3.17 The crystal has the following d-interval (Å) values: 13.87, 10.40, 5.42, 5.19, 4.60, 4.41, 4.11, and 3.76 Any of the three or later crystal forms that exhibit an XRPD pattern including the XRPD pattern. 3.18 Any of the three or later crystal morphologies exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 13.870, 10.402, 5.422, 5.194, 4.600, 4.405, 4.108, and 3.758. 3.19 The following d interval (Å) values: 13.870, 10.402, 5.422, 5.194, 4.600, 4.405, 4.108, and 3.758 Any of the three or later crystal forms that exhibit an XRPD pattern including the XRPD pattern. 3.20 Any of the three or later crystal forms that exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​as shown in Table E of 3.6.

[0051] 3.21 Any of the crystal forms from 3 onwards that exhibit an XRPD pattern including the d-interval (Å) values ​​shown in Table E of 3.6. 3.22 Any of the three or later crystal morphologies exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25 d-interval (Å) values ​​selected from the group consisting of 13.9, 10.4, 8.3, 7.2, 6.9, 6.5, 6.3, 5.5 3.23 The following d interval (Å) values: Any of the three or later crystal forms exhibiting an XRPD pattern having 13.9, 10.4, 8.3, 7.2, 6.9, 6.5, 6.3, 5.5, 5.4, 5.2, 5.0, 4.6, 4.5, 4.4, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.2, 3.1, and 3.0. 3.24 A crystal morphology exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 13.87, 10.40, 8.26, 7.24, 6.93, 6.49, 6.29, 5.50, 5.42, 5.19, 5.04, 4.60, 4.50, 4.41, 4.22, 4.11, 4.05, 4.00, 3.95, 3.91, 3.76, 3.69, 3.61, 3.54, 3.50, 3.36, 3.24, 3.18, 3.15, 3.08, 3.06, 3.03, 2.99, and 2.96, including at least 30 d-interval (Å) values. 3.25 d interval (Å) values ​​less than or equal to: Any of the three or later crystal forms exhibiting an XRPD pattern having 13.87, 10.40, 8.26, 7.24, 6.93, 6.49, 6.29, 5.50, 5.42, 5.19, 5.04, 4.60, 4.50, 4.41, 4.22, 4.11, 4.05, 4.00, 3.95, 3.91, 3.76, 3.69, 3.61, 3.54, 3.50, 3.36, 3.24, 3.18, 3.15, 3.08, 3.06, 3.03, 2.99, and 2.96.

[0052] 3.26 13.870, 10.402, 8.263, 7.235, 6.928, 6.489, 6.290, 5.502, 5.422, 5.194, 5.041, 4.600, 4.497, 4.405, 4.219, 4.108, 4.051, 4.003, 3.954, 3.910, 3.758, 3.685, 3.614, 3.539, 3.504, 3.357, 3.244, 3.18 Any of three or more crystalline morphologies exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 d-interval (Å) values ​​selected from the group consisting of 0, 3.145, 3.082, 3.059, 3.031, 2.988, and 2.958. 3.27 The following d-interval (Å) values: 13.870, 10.402, 8.263, 7.235, 6.928, 6.489, 6.290, 5.502, 5.422, 5.194, 5.041, 4.600, 4.497, 4.405, 4.219, 4.108, 4.051, 4.003, 3.954, 3.910, 3.758, 3.685, 3.614, 3.539, 3.504, 3.357, 3.244, 3.180, 3.145, 3.082, 3.059, 3.031, 2.988 and 2.958 Any of the three or later crystal forms exhibiting an XRPD pattern having the following characteristics. 3.28 Any of the three or later crystal morphologies that exhibit an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table F of 3.12, or any of the three or later crystal morphologies. 3.29 Crystal morphology: Any of the three or later crystal morphologies exhibiting an XRPD pattern with the d-interval (Å) values ​​shown in Table F of 3.12. 3.30 An XRPD pattern showing at least 3, e.g., at least 5, e.g., at least 8, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., an XRPD pattern including all peaks, e.g., any of the three or later crystal forms, where the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

[0053] 3.31 Any of the crystal morphologies from 3 onwards, including the characteristic peaks in the XRPD pattern shown in Figure 22, wherein the XRPD is measured using CuKα irradiation, for example, by irradiation at a wavelength of 1.54059 Å. 3.32 Any of the crystal forms from 3 onwards, including a representative peak in the XRPD pattern shown in Figure 22, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 3.33 Any of the three or later crystal forms, including the XRPD pattern shown in Figure 22, wherein the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 3.34 Any of the three and subsequent crystalline forms, wherein the crystal is produced by dissolving formula I in a solvent containing p-dioxane, optionally using ultrasound. 3.35 The crystalline form of 3.34, further comprising isolating the solid, for example, by filtration.

[0054] 3.36 The crystalline form of 3.35, further comprising drying the solid under vacuum. 3.37 Any crystalline form described in 3.34-3.36, further comprising isolating the crystal. 3.38 Any of the three or later crystal forms, wherein the crystal is produced as described in Example 6. 3.39 Any of the three or later crystal forms having a 2θ(°) value of the XRPD pattern with a deviation of ±0.2°. 3.40 Any of the three or later crystal forms produced by the steps following Method 1 (see below).

[0055] [ka] A methanol solvate (crystalline form 4, also referred to herein as form L) is further provided. Crystalline form 4 is further provided as follows:

[0056] 4.1 Crystal form 4 in which the molar ratio of methanol to equation I is a maximum of 0.6 moles of methanol per 1 mole of equation I (i.e., up to 0.6 moles of methanol). 4.2 The crystalline form is a hemisolvate, i.e., the crystalline form of 4 or 4.1, where the molar ratio of methanol:formula I is 0.5:1. 4.3 Any of the crystal morphologies from 4 onwards, showing an XRPD pattern with 2θ(°) values ​​of 19.0, 20.3, 21.8, 22.0 and 26.0, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 4.4 Any of the crystal morphologies from 4 onwards, showing an XRPD pattern with 2θ(°) values ​​of 18.98, 20.27, 21.75, 21.97 and 25.96, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 4.5 The crystal morphology exhibits an XRPD pattern with the 2θ(°) values ​​shown in Table G below, and the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, as described in 4 or later. [Table 9]

[0057] 4.6 From the group consisting of 6.3, 8.8, 9.5, 11.3, 12.6, 14.2, 14.4, 16.4, 17.6, 18.2, 19.0, 20.3, 20.8, 21.8, 22.0, 22.2, 22.7, 23.1, 23.7, 24.0, 24.8, 25.0, 25.2, 26.0, 26.6, 27.0, 27.2, 27.8, 28.6, 29.0, 29.3, 29.7, and 29.9 The selected 2θ(°) values ​​include an XRPD pattern with at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the 4 or later crystal forms. 4.7 The following 2θ(°) values: 6.3, 8.8, 9.5, 11.3, 12.6, 14.2, 14.4, 16.4, 17.6, 18.2, 19.0, 20.3, 20.8, 21.8, 22.0, 22.2, 22.7, 23.1, 23.7, 24.0, 24.8, 25.0, 25.2, 26.0, 26.6, 27.0, 27.2, 27.8, 28.6, 29.0, 29.3, 29.7 and 29.9 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 4 or later crystalline forms. 4.8 6.29, 8.76, 9.45, 11.26, 12.60, 14.15, 14.44, 16.38, 17.57, 18.17, 18.98, 20.27, 20.75, 21.75, 21.97, 22.21, 22.67, 23.08, 23.73, 23.95, 24.81, 24.95, 25.16, 25.96, 26.55, 26.97, 27.19, 27.76, 28.64, 29.00, 29.3 2. A crystal morphology comprising at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 2θ(°) values ​​selected from the group consisting of 2, 29.73 and 29.91, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 4 onwards. 4.9 The following 2θ(°) values: 6.29, 8.76, 9.45, 11.26, 12.60, 14.15, 14.44, 16.38, 17.57, 18.17, 18.98, 20.27, 20.75, 21.75, 21.97, 22.21, 22.67, 23.08, 23.73, 23.95, 24.81, 24.95, 25.16, 25.96, 26.55, 26.97, 27.19, 27.76, 28.64, 29.00, 29.32, 29.73 and 29.91 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 4 or later crystalline forms. 4.10 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table H below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 4 onwards. [Table 10]

[0058] 4.11 Crystal morphology: Any of the crystal morphologies from 4 onwards, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table H of 4.10, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 4.12 The following d interval (Å) values: 4.7, 4.4, 4.1, 4.0, and 3.4 Any of the four or later crystal forms that exhibit an XRPD pattern including the XRPD pattern. 4.13 The crystal has the following d-interval (Å) values: 4.67, 4.38, 4.08, 4.04, and 3.43 Any of the four or later crystal forms that exhibit an XRPD pattern including the XRPD pattern. 4.14 The following d interval (Å) values: 4.671, 4.377, 4.083, 4.042, and 3.429 Any of the four or later crystal forms that exhibit an XRPD pattern including the XRPD pattern. 4.15 Any of the crystal forms from 4 onwards that exhibit an XRPD pattern including the d-interval (Å) values ​​shown in Table G of 4.5.

[0059] 4.16 Any of the 4 or later crystal morphologies exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20 d-interval (Å) values ​​selected from the group consisting of 14.0, 10.1, 9.3, 7.8, 7.0, 6.3, 6.1, 5.4, 5.0, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0, wherein the d-interval (Å) values ​​are selected from the group consisting of at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20. 4.17 The following d interval (Å) values: 14.0, 10.1, 9.3, 7.8, 7.0, 6.3, 6.1, 5.4, 5.0, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 and 3.0 Any of the four or later crystal forms exhibiting an XRPD pattern having the following characteristics. 4.18 Any of the four or later crystal morphologies exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 14.04, 10.08, 9.35, 7.85, 7.02, 6.26, 6.13, 5.41, 5.04, 4.88, 4.67, 4.38, 4.28, 4.08, 4.04, 4.00, 3.92, 3.85, 3.75, 3.71, 3.59, 3.57, 3.54, 3.43, 3.36, 3.30, 3.28, 3.21, 3.11, 3.08, 3.04, 3.00, and 2.99, including at least 30 d-interval (Å) values. 4.19 The following d interval (Å) values: 14.04, 10.08, 9.35, 7.85, 7.02, 6.26, 6.13, 5.41, 5.04, 4.88, 4.67, 4.38, 4.28, 4.08, 4.04, 4.00, 3.92, 3.85, 3.75, 3.71, 3.59, 3.57, 3.54, 3.43, 3.36, 3.30, 3.28, 3.21, 3.11, 3.08, 3.04, 3.00 and 2.99 Any of the four or later crystal forms exhibiting an XRPD pattern having the following characteristics. 4.20 14.039, 10.081, 9.347, 7.848, 7.019, 6.256, 6.131, 5.409, 5.042, 4.877, 4.671, 4.377, 4.276, 4.083, 4.042, 3.998, 3.920, 3.851, 3.747, 3.713, 3.586, 3.566, 3.537, 3.429, 3.355, 3.303, 3. Any of the four or more crystalline morphologies exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 d-interval (Å) values ​​selected from the group consisting of 277, 3.211, 3.114, 3.076, 3.043, 3.002, and 2.985.

[0060] 4.21 The following d interval (Å) values: 14.039, 10.081, 9.347, 7.848, 7.019, 6.256, 6.131, 5.409, 5.042, 4.877, 4.671, 4.377, 4.276, 4.083, 4.042, 3.998, 3.920, 3.851, 3.747, 3.713, 3.586, 3.566, 3.537, 3.429, 3.355, 3.303, 3.277, 3.211, 3.114, 3.076, 3.043, 3.002, and 2.985 Any of the four or later crystal forms exhibiting an XRPD pattern having the following characteristics. 4.22 Any of the four or later crystal morphologies exhibiting an XRPD pattern that includes at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30 d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table H of 4.10. 4.23 Crystal morphology: Any of the crystal morphologies from 4 onwards that exhibit an XRPD pattern with the d-interval (Å) values ​​shown in Table H of 4.10. 4.24 An XRPD pattern showing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., all peaks of the XRPD shown in Figure 23, wherein the XRPD is measured using CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 4 onwards. 4.25 Any of the crystal forms from 4 onwards, including the characteristic XRPD peak shown in Figure 23, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

[0061] 4.26 Any of the crystal forms from 4 onwards, including the representative XRPD peak shown in Figure 23, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 4.27 Any of the crystal forms from 4 onwards, including the XRPD shown in Figure 23, wherein the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 4.28 Any of the crystal forms from 4 onwards, showing a thermogravimetric analysis (TGA) thermogram that includes a gradual weight loss between 90°C and 150°C, e.g., a weight loss of 3–5% by weight, e.g., a weight loss of 4–5% by weight, e.g., a weight loss of 4.2% by weight. 4.29 The thermogravimetric analysis (TGA) thermogram shown in Figure 29, representing one of the crystal forms from 4 onwards. 4.30 Methanol, for example, a mixture containing methanol and water, for example, a solvent mixture with low water activity (a w )(For example a w Any of the four or later crystalline forms, dissolved in a solvent containing a mixture of methanol and water (where the ratio is less than 0.9).

[0062] 4.31 The crystalline form of 4.30, which further includes slowly cooling the solution and, if applicable, allowing the solution to stand at room temperature. 4.32 The crystalline form of 4.30 or 4.31, further comprising storing the solution in a freezer and, if necessary, raising it to room temperature. 4.33 The crystalline form of 4.32, further comprising isolating the solid, for example, by filtration. 4.34 The crystalline form of 4.33, further comprising drying the solid under vacuum. 4.35 Any of the crystal forms described in 4.30–4.34, further including the isolation of the crystal.

[0063] 4.36 Any of the crystal forms from 4 onwards, in which the crystal is produced as described in Example 7. 4.37 Any of the four or later crystal forms in which the 2θ(°) value of the XRPD pattern has an allowable deviation of ±0.2°. 4.38 Any of the crystal forms from 4 onwards, produced by the steps following Method 1 (see below).

[0064] [ka] Hydrates (crystalline form 5, also referred to herein as form N) are further provided. Crystallized form 5 is further provided as follows:

[0065] 5.1 Water: The molar ratio of formula I is 3:1 to 4:1, crystal form 5. 5.2 Crystal morphology 5, where the molar ratio of water to formula I is 4.5:1 or less, for example 4.2:1 or less, for example 4.2:1, and for example water to formula I is 4:1 or less, for example 3:1 or less, for example 2:1 or less, for example 4:1, for example 3:1, for example 2:1. 5.3 Any of the crystal forms listed in section 5 and later, whose crystal form is a stoichiometric hydrate. 5.4 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 8.8, 9.5, 11.1, 15.2, 15.5, 16.4, 20.2, 20.6, 23.6, 24.0, 24.9, and 27.2, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 5 onwards. 5.5 Any crystal morphology from 5 onwards, showing an XRPD pattern with 2θ(°) values ​​of 8.8, 9.5, 11.1, 15.2, 15.5, 16.4, 20.2, 20.6, 23.6, 24.0, 24.9 and 27.2, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å.

[0066] 5.6 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 8.82, 9.49, 11.12, 15.23, 15.53, 16.35, 20.20, 20.62, 23.63, 23.95, 24.89, and 27.16, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 5 onwards. 5.7 XRPD patterns showing 2θ(°) values ​​of 8.82, 9.49, 11.12, 15.23, 15.53, 16.35, 20.20, 20.62, 23.63, 23.95, 24.89 and 27.16, any of the crystal forms from 5 onwards, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 5.8 An XRPD pattern containing at least 5 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table I below, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and the crystal morphology is any of the 5 or later values. [Table 11] 5.9 Crystal morphology: Any of the crystal morphologies from 5 onwards, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table I of 5.8, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 5.10 4.7, 5.4, 5.6, 8.8, 9.5, 9.9, 10.8, 11.1, 13.1, 14.0, 14.9, 15.2, 15.5, 16.4, 16.5, 17.6, 17.7, 18.8, 19.1, 19.3, 19.5, 19.8, 20.0, 20.2, 20.6, 20.9, 21.2, 21.7, 21.9, 22.4, 22.7, 22.8, 23.2, 23.3, 23.6, 24.0, 24.9, 25.5 , any of the 5 or later crystal forms exhibiting an XRPD pattern including at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 25.8, 26.3, 26.5, 27.0, 27.2, and 27.4, e.g., at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 25.8, 26.3, 26.5, 27.0, 27.2, and 27.4.

[0067] 5.11 The following 2θ(°) values: 4.7, 5.4, 5.6, 8.8, 9.5, 9.9, 10.8, 11.1, 13.1, 14.0, 14.9, 15.2, 15.5, 16.4, 16.5, 17.6, 17.7, 18.8, 19.1, 19.3, 19.5, 19.8, 20.0, 20.2, 20.6, 20.9, 21.2, 21.7, 21.9, 22.4, 22.7, 22.8, 23.2, 23.3, 23.6, 24.0, 24.9, 25.5, 25.8, 26.3, 26.5, 27.0, 27.2, and 27.4 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 5 or later morphologies. 5.12 4.73, 5.36, 5.55, 8.82, 9.49, 9.85, 10.77, 11.12, 13.05, 13.99, 14.91, 15.23, 15.53, 16.35, 16.53, 17.59, 17.70, 18.78, 19.07, 19.30, 19.47, 19.75, 19.99, 20.20, 20.62, 20.91, 21.16, 21.65, 21.89, 22.39, 22.68, 22.83, 23.17, 23.31, 23.63, 23.95, 24.89, 25.54, 25.83, 26.32, The XRPD pattern exhibits at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the group consisting of 26.52, 27.00, 27.16, and 27.42, and the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 5 onwards. 5.13 The following 2θ(°) values: 4.73, 5.36, 5.55, 8.82, 9.49, 9.85, 10.77, 11.12, 13.05, 13.99, 14.91, 15.23, 15.53, 16.35, 16.53, 17.59, 17.70, 18.78, 19.07, 19.30, 19.47, 19.75, 19. 99, 20.20, 20.62, 20.91, 21.16, 21.65, 21.89, 22.39, 22.68, 22.83, 23.17, 23.31, 23.63, 23.95, 24.89, 25.54, 25.83, 26.32, 26.52, 27.00, 27.16, and 27.42 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 5 or later morphologies. 5.14 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table J below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 5 onwards. [Table 12] 5.15 Crystal morphology: An XRPD pattern having the 2θ(°) values ​​shown in Table J of 5.14, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 5 onwards.

[0068] 5.16 Any crystal morphology from 5 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 10.0, 9.3, 8.0, 5.8, 5.7, 5.4, 4.4, 4.3, 3.8, 3.7, 3.6, and 3.3. 5.17 The following d interval (Å) values: 10.0, 9.3, 8.0, 5.8, 5.7, 5.4, 4.4, 4.3, 3.8, 3.7, 3.6, and 3.3 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern including the XRPD pattern. 5.18 Any crystal morphology from 5 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 10.02, 9.31, 7.95, 5.81, 5.70, 5.42, 4.39, 4.31, 3.76, 3.71, 3.57, and 3.28. 5.19 The following d interval (Å) values: 10.02, 9.31, 7.95, 5.81, 5.70, 5.42, 4.39, 4.31, 3.76, 3.71, 3.57, and 3.28 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern having the following characteristics. Any crystal morphology from 5 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 5.20, 10.019, 9.311, 7.952, 5.813, 5.700, 5.417, 4.392, 4.305, 3.763, 3.713, 3.574, and 3.280.

[0069] 5.21 The following d interval (Å) values: 10.019, 9.311, 7.952, 5.813, 5.700, 5.417, 4.392, 4.305, 3.763, 3.713, 3.574, and 3.280 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern including the XRPD pattern. 5.22 Any crystal morphology from 5 onwards that exhibits an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​as shown in Table I of 5.8. 5.23 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern including the d-interval (Å) values ​​shown in Table I of 5.8. 5.24 Any crystal morphology from 5 onwards exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 18.7, 16.5, 15.9, 10.0, 9.3, 9.0, 8.2, 8.0, 6.8, 6.3, 5.9, 5.8, 5.7, 5.4, 5.0, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, and 3.3, including at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25. 5.25 d interval (Å) values ​​less than: 18.7, 16.5, 15.9, 10.0, 9.3, 9.0, 8.2, 8.0, 6.8, 6.3, 5.9, 5.8, 5.7, 5.4, 5.0, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, and 3.3 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern having the following characteristics.

[0070] 5.26 18.68, 16.48, 15.92, 10.02, 9.31, 8.97, 8.21, 7.95, 6.78, 6.33, 5.94, 5.81, 5.70, 5.42, 5.36, 5.04, 5.01, 4.72, 4.65, 4.60, 4.56, 4.49, 4.44, 4.39, 4.31, 4.25, 4.19, 4.10, 4.06, 3.97, 3.92, 3.89, 3.84, 3.81, 3.76, 3.71, 3.57 , any of the 5 or later crystal morphologies exhibiting an XRPD pattern including at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d interval (Å) values ​​selected from the group consisting of 3.49, 3.45, 3.38, 3.36, 3.30, 3.28, and 3.25, and an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d interval (Å) values ​​selected from the group consisting of 3.49, 3.45, 3.38, 3.36, 3.30, 3.28, and 3.25. 5.27 The following d interval (Å) values: 18.68, 16.48, 15.92, 10.02, 9.31, 8.97, 8.21, 7.95, 6.78, 6.33, 5.94, 5.81, 5.70, 5.42, 5.36, 5.04, 5.01, 4.72, 4.65, 4.60, 4.56, 4.49, 4.44, 4.39, 4.31, 4.25, 4.19, 4.10, 4.06, 3.97, 3.92, 3.89, 3.84, 3.81, 3.76, 3.71, 3.57, 3.49, 3.45, 3.38, 3.36, 3.30, 3.28 and 3.25 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern having the following characteristics. 5.28 18.682, 16.479, 15.916, 10.019, 9.311, 8.969, 8.206, 7.952, 6.779, 6.327, 5.937, 5.813, 5.700, 5.417, 5.359, 5.038, 5.006, 4.722, 4.649, 4.596, 4.555, 4.492 A crystal morphology of any 5 or later that exhibits an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of 4.438, 4.392, 4.305, 4.245, 4.194, 4.101, 4.056, 3.968, 3.917, 3.892, 3.836, 3.813, 3.763, 3.713, 3.574, 3.485, 3.446, 3.384, 3.358, 3.300, 3.280, and 3.250, and including d-interval (Å) values ​​selected from the group consisting of 4.438, 4.392, 4.305, 4.245, 4.194, 4.101, 4.056, 3.968, 3.917, 3.892, 3.836, 3.813, 3.763, 3.713, 3.574, 3.485, 3.446, 3.384, 3.358, 3.300, 3.280, and 3.250. 5.29 The following d interval (Å) values: 18.682, 16.479, 15.916, 10.019, 9.311, 8.969, 8.206, 7.952, 6.779, 6.327, 5.937, 5.813, 5.700, 5.417, 5.359, 5.038, 5.006, 4.722, 4.649, 4.596, 4.555, 4.49 2, 4.438, 4.392, 4.305, 4.245, 4.194, 4.101, 4.056, 3.968, 3.917, 3.892, 3.836, 3.813, 3.763, 3.713, 3.574, 3.485, 3.446, 3.384, 3.358, 3.300, 3.280 and 3.250 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern having the following characteristics. 5.30 Crystal morphology Any of the crystal morphologies from 5 onwards that exhibit an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40 d-interval (Å) values ​​selected from the group consisting of d-interval (Å) values ​​shown in Table J of 5.14.

[0071] 5.31 Any of the crystal forms from 5 onwards that exhibit an XRPD pattern with the d-interval (Å) values ​​shown in Table J of 5.14. 5.32 An XRPD pattern showing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks, and the XRPD is measured using CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal forms from 5 onwards. 5.33 Any of the crystal forms from 5 onwards, including the characteristic peak of the XRPD shown in Figure 24, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 5.34 Any of the crystal forms from 5 onwards, including the characteristic peak of the XRPD shown in Figure 24, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 5.35 XRPD shown in Figure 24, where XRPD is measured using CuKα irradiation, for example, XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal forms from 5 onwards.

[0072] 5.36 Any of the crystal morphologies from 5 onwards, showing an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 12, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks of the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, e.g.,20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks of the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, e.g. 5.37 Any of the crystal forms from 5 onwards, including the characteristic peaks of the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, for example, the XRPD being measured using CuKα irradiation, for example, the XRPD being measured using irradiation at a wavelength of 1.54059 Å. 5.38 Any of the crystal forms from 5 onwards, including a representative peak of the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, for example, the XRPD being measured using CuKα irradiation, for example, the XRPD being measured using irradiation at a wavelength of 1.54059 Å. 5.39 Any of the crystal forms from 5 onwards, substantially showing the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, for example, the XRPD shown in Figures 24, 44, 45, 46, 48, 50, 51, 52, 54, or 57, and where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 5.40 Any of the crystalline forms from 5 onwards, showing a thermogravimetric analysis (TGA) thermogram including, for example, a weight loss of 3-4 wt%, for example, a weight loss of 3.5 wt%, or for example, a weight loss of 3.7 wt%, between 20°C and 80°C, for example, between 23°C and 70°C.

[0073] 5.41 Any of the crystal forms from 5 onwards, showing a thermogravimetric analysis (TGA) thermogram including, for example, a weight loss of 3-4% by weight, for example, a weight loss of 3.6% by weight, or for example, a weight loss of 3.7% by weight, between 60°C and 110°C, for example, between 70°C and 105°C. 5.42 Crystal morphology 5, showing a thermogravimetric analysis (TGA) thermogram including, for example, a weight loss of 0.1-2 wt%, a weight loss of 0.6 wt%, or a weight loss of 1.3 wt%, between 100°C and 170°C, for example, between 105°C and 160°C. 5.43 Figure 26 shows the thermogravimetric analysis (TGA) thermogram, crystal morphology 5. 5.44 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 85°C, showing any of the crystal forms from 5 onwards. 5.45 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 91°C, representing any of the crystal forms shown from 5 onwards.

[0074] 5.46 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 95°C, representing any of the crystal forms shown from 5 onwards. 5.47 A differential scanning calorimetry (DSC) thermogram showing endothermic effects at 118°C, showing any of the crystal forms from 5 onwards. Any crystalline form after 5, showing a differential scanning calorimetry (DSC) thermogram including an endotherm at 178 °C, for example an endotherm at 178 °C with onset at 169 °C. 5.49 Any crystalline form after 5, showing the differential scanning calorimetry (DSC) thermogram shown in Figure 26 5.50 Any crystalline form after 5, showing a dynamic (water) vapor sorption (DVS) isotherm including a 30% weight loss after equilibration at 5% relative humidity.

[0075] 5.51 Any crystalline form after 5, showing a weight gain of 4% or less, for example 3% or less, for example 3% weight gain, after an increase in relative humidity from 5% to 95%. 5.52 Any crystalline form after 5, showing the dynamic (water) vapor sorption (DVS) isotherm shown in Figure 27 5.53 Any crystalline form after 5, containing 14% water by Karl Fischer (KF) analysis, for example 14.2% water (equivalent to 4.2 moles of water) by Karl Fischer (KF) analysis. 5.54 Any crystalline form after 5, wherein the production of the crystal comprises optionally stirring and mixing water (for example, including mixing only with water or a mixture containing water (for example, the mixture having a high water activity (a w )(for example a w of 0.9 or higher)) and 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate. 5.55 Crystalline form 5.54, further comprising isolating the solid, for example by filtration.

[0076] 5.56 Crystalline form 5.55, further comprising drying the solid under vacuum. 5.57 Any crystalline form of 5.54 - 5.56, further comprising isolating the crystal. <° 5.58 Any crystalline form after 5, wherein the crystal is produced as described in any of the examples for producing Form N. 5.59 Any of the crystal forms from 5 onwards, produced by the steps following Method 1 (see below). 5.60 Any of the crystal forms from 5 onwards, produced by the steps of Method 2 or later, Method 3 or later, or Method 4 or later (see below). 5.61 Any crystal morphology from 5 onwards, in which the 2θ(°) value of the XRPD pattern has an allowable deviation of ±0.2°.

[0077] [ka] (Crystal form 6, also referred to herein as form B). Crystal form 6 is further provided as follows.

[0078] 6.1 A crystal morphology 6 exhibits an XRPD pattern including at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 6.6, 11.0, 12.6, 14.5, 14.6, 18.0, 19.7, 20.1, 21.0, 21.6, 22.0, 22.4, 23.8, 24.5, 24.8, and 27.4, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.2 XRPD pattern exhibiting a 2θ(°) value selected from the group consisting of 6.6, 11.0, 12.6, 14.5, 14.6, 18.0, 19.7, 20.1, 21.0, 21.6, 22.0, 22.4, 23.8, 24.5, 24.8 and 27.4, wherein the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, crystal morphology 6 or 6.1. 6.3 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the group consisting of 6.64, 10.95, 12.55, 14.48, 14.61, 17.99, 19.74, 20.07, 20.97, 21.63, 22.02, 22.40, 23.80, 24.50, 24.78, and 27.42, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 6 onwards. 6.4 Any crystal morphology from crystal morphology 6 onwards, showing an XRPD pattern with 2θ(°) values ​​of 6.64, 10.95, 12.55, 14.48, 14.61, 17.99, 19.74, 20.07, 20.97, 21.63, 22.02, 22.40, 23.80, 24.50, 24.78 and 27.42, where the XRPD is measured using an incident beam of CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.5 An XRPD pattern exhibiting at least 3, e.g., at least 5, 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table C below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal forms from 6 onwards. [Table 13]

[0079] 6.6 Crystal morphology: Any of the crystal morphologies from 6 onwards, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table C of 6.5, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.7 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 16, e.g., at least 20 crystalline morphologies from 6 onwards, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.8 2θ(°) values ​​below: 6.6, 11.0, 11.1, 12.6, 14.5, 14.6, 15.3, 16.4, 17.1, 18.0, 19.7, 20.1, 21.0, 21.4, 21.6, 22.0, 22.4, 22.8, 23.8, 24.5, 24.8, 25.8, 27.4, and 29.0 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 6 or later morphologies. 6.9 A crystal morphology exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 16, e.g., at least 20 2θ(°) values ​​selected from the group consisting of 6.64, 10.95, 11.13, 12.55, 14.48, 14.61, 15.28, 16.35, 17.09, 17.99, 19.74, 20.07, 20.97, 21.36, 21.63, 22.02, 22.40, 22.77, 23.80, 24.50, 24.78, 25.76, 27.42, and 29.01, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal morphologies from 6 onwards. 6.10 2θ(°) values ​​below: 6.64, 10.95, 11.13, 12.55, 14.48, 14.61, 15.28, 16.35, 17.09, 17.99, 19.74, 20.07, 20.97, 21.36, 21.63, 22.02, 22.40, 22.77, 23.80, 24.50, 24.78, 25.76, 27.42 and 29.01 The crystal morphology exhibits an XRPD pattern having the following characteristics, where the XRPD is measured using an incident beam of CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and is one of the 6 or later morphologies.

[0080] 6.11 An XRPD pattern exhibiting at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 16, e.g., at least 20 2θ(°) values ​​selected from the 2θ(°) values ​​shown in Table D below, wherein the XRPD is measured using an incident beam of CuKα irradiation, e.g., the XRPD is measured using irradiation at a wavelength of 1.54059 Å, and any of the crystal morphologies from 6 onwards. [Table 14] 6.12 Crystal morphology: Any of the crystal morphologies from 6 onwards, exhibiting an XRPD pattern with the 2θ(°) values ​​shown in Table D of 6.11, where the XRPD is measured using an incident beam irradiated with CuKα, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.13 Any of the crystal morphologies from 6 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 13.3, 8.1, 7.0, 6.1, 4.9, 4.5, 4.4, 4.2, 4.1, 4.0, 3.7, 3.6, and 3.3. 6.14 The following d interval (Å) values: 13.3, 8.1, 7.0, 6.1, 4.9, 4.5, 4.4, 4.2, 4.1, 4.0, 3.7, 3.6, and 3.3 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the crystal morphologies from 6 onwards exhibiting an XRPD pattern that includes at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 6.15, 13.30, 8.08, 7.05, 6.11, 6.06, 4.93, 4.50, 4.42, 4.23, 4.11, 4.03, 3.97, 3.74, 3.63, 3.59, and 3.25. .

[0081] 6.16 The following d interval (Å) values: 13.30, 8.08, 7.05, 6.11, 6.06, 4.93, 4.50, 4.42, 4.23, 4.11, 4.03, 3.97, 3.74, 3.63, 3.59 and 3.25 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern including the XRPD pattern. Any of the crystal morphologies from 6 onwards exhibiting an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​selected from the group consisting of 6.17 13.298, 8.075, 7.049, 6.110, 6.060, 4.926, 4.495, 4.421, 4.233, 4.106, 4.033, 3.965, 3.735, 3.630, 3.590, and 3.251. 6.18 The following d interval (Å) values: 13.298, 8.075, 7.049, 6.110, 6.060, 4.926, 4.495, 4.421, 4.233, 4.106, 4.033, 3.965, 3.735, 3.630, 3.590, and 3.251 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern including the XRPD pattern. 6.19 Any of the crystal morphologies from 6 onwards that exhibit an XRPD pattern containing at least 3, for example, at least 5, d-interval (Å) values ​​as shown in Table C of 6.5. 6.20 XRPD pattern including d-interval (Å) values ​​shown in Table C of 6.5, from 6 onwards. One of the following crystalline forms.

[0082] 6.21 Any of the crystal morphologies from 6 onwards exhibiting an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 16 d-interval (Å) values ​​selected from the group consisting of 13.3, 8.1, 7.9, 7.0, 6.1, 5.8, 5.4, 5.2, 4.9, 4.5, 4.4, 4.2, 4.1, 4.0, 3.9, 3.7, 3.6, 3.5, 3.3, and 3.1. 6.22 The following d interval (Å) values: 13.3, 8.1, 7.9, 7.0, 6.1, 5.8, 5.4, 5.2, 4.9, 4.5, 4.4, 4.2, 4.1, 4.0, 3.9, 3.7, 3.6, 3.5, 3.3 and 3.1 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern having the following characteristics. Any crystal morphology from 6 onwards exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 6.23, 13.30, 8.08, 7.94, 7.05, 6.11, 6.06, 5.79, 5.42, 5.19, 4.93, 4.50, 4.42, 4.23, 4.16, 4.11, 4.03, 3.97, 3.90, 3.74, 3.63, 3.59, 3.46, 3.25, and 3.08, with at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 15, e.g., at least 16, e.g., at least 20. 6.24 d interval (Å) values ​​below: 13.30, 8.08, 7.94, 7.05, 6.11, 6.06, 5.79, 5.42, 5.19, 4.93, 4.50, 4.42, 4.23, 4.16, 4.11, 4.03, 3.97, 3.90, 3.74, 3.63, 3.59, 3.46, 3.25, and 3.08 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern having the following characteristics. Any crystal morphology from 6 onwards exhibiting an XRPD pattern containing an XRPD pattern with d-interval (Å) values ​​selected from the group consisting of 6.25, 13.298, 8.075, 7.944, 7.049, 6.110, 6.060, 5.793, 5.417, 5.185, 4.926, 4.495, 4.421, 4.233, 4.157, 4.106, 4.033, 3.965, 3.901, 3.735, 3.630, 3.590, 3.456, 3.251, and 3.075, with at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 16, e.g., at least 20.

[0083] 6.26 The following d interval (Å) values: 13.298, 8.075, 7.944, 7.049, 6.110, 6.060, 5.793, 5.417, 5.185, 4.926, 4.495, 4.421, 4.233, 4.157, 4.106, 4.033, 3.965, 3.901, 3.735, 3.630, 3.590, 3.456, 3.251 and 3.075 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern having the following characteristics. 6.27 Any of the six or later crystal morphologies exhibiting an XRPD pattern that includes at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 16, e.g., at least 20 d-interval (Å) values ​​selected from the d-interval (Å) values ​​shown in Table D of 6.11. 6.28 Any of the crystal forms from 6 onwards that exhibit an XRPD pattern with the d-interval (Å) values ​​shown in Table D of 6.11. 6.29 Any of the crystal forms from 6 onwards, showing an XRPD pattern containing at least 3, e.g., at least 5, e.g., at least 10, e.g., at least 14, e.g., at least 15, e.g., at least 20, e.g., at least 25, e.g., at least 30, e.g., at least 35, e.g., at least 40, e.g., all peaks, e.g., XRPD measured using CuKα irradiation, e.g., XRPD measured using irradiation at a wavelength of 1.54059 Å. 6.30 Any of the crystal forms from 6 onwards, in which the XRPD is measured using CuKα irradiation, for example, when the XRPD is measured using irradiation at a wavelength of 1.54059 Å, including the characteristic peak of the XRPD shown in Figure 21.

[0084] 6.31 Any of the crystal forms from 6 onwards, including the typical XRPD peak shown in Figure 21, where the XRPD is measured using CuKα irradiation, for example, where the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.32 XRPD shown in Figure 21, where XRPD is measured using CuKα irradiation, for example, XRPD is measured using irradiation at a wavelength of 1.54059 Å, any of the crystal forms from 6 onwards. 6.33 Any of the crystal morphologies from 6 onwards, showing an XRPD pattern including at least 3, for example at least 5, for example at least 10, for example at least 14, for example at least 15, for example at least 20, for example at least 25, for example at least 30, for example at least 35, for example at least 40, for example all peaks, and the XRPD is measured using CuKα irradiation, for example the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.34 Any of the crystal forms from 6 onwards, including the characteristic peaks of the XRPD shown in Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, for example, Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, wherein the XRPD is measured using CuKα irradiation, for example, by irradiation at a wavelength of 1.54059 Å. 6.35 Any of the crystal forms from 6 onwards, including a representative peak of the XRPD shown in Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, for example, Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, wherein the XRPD is measured using CuKα irradiation, for example, by irradiation at a wavelength of 1.54059 Å.

[0085] 6.36 Any of the crystal forms from 6 onwards, showing the XRPD substantially shown in Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, for example, Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53, or Figure 55, where the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 6.37 Any of the crystal forms listed above that exhibit a dynamic (water) vapor adsorption (DVS) isotherm containing 0.6 wt% water vapor adsorption at relative humidity levels of 5% to 95%. 6.38 Any of the crystal forms from 6 onwards, showing the dynamic (water) vapor adsorption (DVS) isotherm shown in Figure 28. 6.39 Any of the crystal forms from 6 onwards, showing a differential scanning calorimetry (DSC) thermogram including endothermic heating at 177°C, for example, endothermic heating at 177°C with an initiation at 173°C. 6.40 A differential scanning calorimetry (DSC) thermogram shown in Figure 40, representing any of the crystal forms from 6 onwards.

[0086] 6.41 Any of the crystalline forms from 6 onwards, showing a thermogravimetric analysis (TGA) thermogram with a weight loss of 0.1 to 1% by weight, e.g., 0.7% by weight, between 23°C and 150°C. 6.42 The thermogravimetric analysis (TGA) thermogram shown in Figure 40, representing any of the crystal forms from 6 onwards. 6.43 Any crystalline form from 6 onwards, wherein the preparation of the crystals comprises mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with an organic solvent, e.g., halogenated organic solvents, e.g., fluorinated organic solvents (e.g., hexafluoroisopropanol (HFIPA), 2,2,2-trifluoroethanol (TFE), and / or chloroform) and / or toluene, optionally with stirring. 6.44 Further comprising cooling the mixture to obtain a crystalline form 6.43. 6.45 The crystalline form of 6.43 or 6.44, further comprising isolating the solid, for example, by filtration.

[0087] 6.46 Crystalline form, further comprising drying the solid under vacuum. 6.43 6.47 Any crystal form of 6.43-6.46, further including isolation of the crystal. 6.48 Any of the crystal forms listed in 6 or later, produced by the steps following Method 1 (see below). 6.49 Any of the crystal forms from 6 onwards, produced by the steps of Method 5 and later (see below). 6.50 Any of the crystal forms from 6 onwards, wherein the crystal is produced as described in any of the examples for producing form B. 6.51 Any crystal morphology from 6 onwards, in which the 2θ(°) value of the XRPD pattern has an allowable deviation of ±0.2°.

[0088] Further, a method (Method 1) is provided for producing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) in crystalline form, for example, any of the crystalline forms from crystalline form 1 onwards, crystalline forms from crystalline form 2 onwards, crystalline forms from crystalline form 3 onwards, crystalline forms from crystalline form 4 onwards, crystalline forms from crystalline form 5 onwards, and crystalline forms from crystalline form 6 onwards, for example, for producing crystalline form 1. Method 1 is further provided as follows.

[0089] 1.1 Method 1, comprising acidifying an aqueous solution containing 1 or more units of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl hydrogen phosphate monoanion and 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl phosphate dianion, for example, to a pH of less than 2, for example, to a pH of 1, for example, using HCl, for example, to a pH of 1. 1.2 The method of 1.1, further comprising extracting with an organic solvent, for example, ethyl acetate, to produce an aqueous fraction and an organic fraction. 1.3 The method of 1.2, further comprising separating organic fractions. 1.4 The method of 1.3, for example, further comprising drying the organic fraction with sodium sulfate. 1.5 The method of 1.4, further comprising evaporating an organic solvent.

[0090] 1.6 The method of 1.5, further comprising isolating the crystals. 1.7 The method of 1.4, further comprising concentrating an organic solvent under reduced pressure and providing it. 1.8 The method of 1.7, further comprising dissolving the oily substance in an organic solvent (e.g., ethyl acetate) while stirring, if necessary. 1.9 The method of 1.8, further comprising adding a poor solvent, such as an organic poor solvent (e.g., n-heptane), while stirring as appropriate. 1.10 The method of 1.9, further comprising isolating the solid, for example by filtration.

[0091] 1.11 The method of 1.10, further comprising washing the solid with a poor solvent, e.g., an organic poor solvent (e.g., n-heptane). 1.12 The method of 1.11, further comprising drying the solid under vacuum. 1.13 The method of 1.11 or 1.12, further comprising isolating the crystals. 1.14 Any of the methods listed in 1 or later, further comprising dissolving 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in an organic solvent (e.g., ethyl acetate) at room temperature, with stirring if necessary. 1.15 The method of 1.14, further comprising adding a poor solvent, such as an organic poor solvent (e.g., n-heptane), while stirring as appropriate.

[0092] 1.16 The method of 1.15, further comprising isolating the solid, for example, by filtration. 1.17 The method of 1.16, further comprising washing the solid with a poor solvent, such as an organic poor solvent (e.g., n-heptane). 1.18 The method of 1.17, further comprising drying under vacuum. 1.19 The method of 1.17 or 1.18, further comprising isolating the crystals. 1.20 Any of the methods from 1 onward, further comprising mixing Formula I with an organic solvent and optionally a poor solvent, for example, mixing Formula I with one or more of ethyl acetate, heptane, acetonitrile, toluene, methanol, and p-dioxane. The mixture may optionally be stirred and / or cooled. 1.21 Any of the methods from 1 onward, further comprising isolating the crystal. 1.22 Crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, prepared by any of the methods described in 1 or later. 1.23 A crystal form which is any of crystal forms 1 or later, crystal form 2 or later, crystal form 3 or later, crystal form 4 or later, crystal form 5 or later, and crystal form 6 or later, for example any of crystal forms 1 or later, wherein the crystal is produced by any of the methods 1.1 to 1.21.

[0093] Crystals produced by any of the methods described in 1 or later are further provided.

[0094] A method for producing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (Method 2) is further provided, comprising crystallizing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) from an organic solvent (e.g., ethyl acetate, heptane, acetonitrile, methanol, toluene, e.g., one or more of ethyl acetate / heptane) to obtain a solvate, and stirring and / or washing the solvate with water to obtain 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate free from organic solvents. Method 2 is further provided as follows.

[0095] 2.1 Method 2, wherein the organic solvent is one or more of ethyl acetate, heptane, acetonitrile, methanol, and toluene, e.g., ethyl acetate, e.g., ethyl acetate / heptane. 2.2 The method of 2 or 2.1, including stirring the solvate with water, for example, stirring the solvate with water at room temperature, for example, stirring the solvate with water at room temperature for 2 hours. 2.3 The method of 2.2, further including isolating the solid, for example, by filtration. 2.4 The method of 2.3, further including washing the solid with water. 2.5 The method of 2.4, further including drying the solid, for example, drying the solid under vacuum for 1 hour. 2.6 Any method after 2, further including isolating the solid, optionally in crystalline form. 2.7 Any method after 2, wherein the final product is 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, for example, a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, for example, a crystal including any of crystalline forms 5 and after.

[0096] Crystals produced by any method after 2 are further provided.

[0097] A method for producing a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (for example, any of crystalline forms 5 and after), including mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (for example, any of crystalline forms 1 and after, for example, Form A) and water while optionally stirring (Method 3 is provided). Method 3 is further provided as follows.

[0098] 3.1 Method 3, further including mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (for example, any of crystalline forms 1 and after) and water with a poor solvent (for example, toluene) while optionally stirring. 3.2 The method of 3 or 3.1, further including recovering the solid by filtration. The method of 3.2, further comprising vacuum drying the solid. Any method after 3, further comprising isolating the crystals.

[0099] Crystals produced by any method after 3 are further provided.

[0100] A method (Method 4) for producing a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (e.g., any of crystal forms 5 and later), which includes optionally stirring and mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with water, is provided. Method 4 is further provided as follows.

[0101] Method 4, including mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with water and an organic solvent, e.g., a poor solvent, optionally with stirring. 4.2 Mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with a solvent mixture containing water having a high water activity (a w )(e.g., 0.9 or higher), in the method of 4 or 4.1. Any method after 4, further comprising recovering the solid by filtration. Any method after 4, further comprising vacuum drying the solid. Any method after 4, further comprising isolating the solid.

[0102] Crystals produced by any method after 4 are further provided.

[0103] A method (Method 5) for producing a nonsolvated nonhydrate crystalline form of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (e.g., any of crystalline forms 6 onwards) is further provided, comprising mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with an organic solvent (e.g., a halogenated organic solvent, e.g., a fluorinated organic solvent (e.g., hexafluoroisopropanol (HFIPA), 2,2,2-trifluoroethanol (TFE), and / or chloroform) and / or toluene), possibly with stirring. Method 5 is further provided as follows:

[0104] 5.1 Method 5, wherein the organic solvent is a halogenated organic solvent, for example, a fluorinated organic solvent (e.g., hexafluoroisopropanol (HFIPA), 2,2,2-trifluoroethanol (TFE), and / or chloroform). 5.2 The method of 5 or 5.1, wherein the organic solvent is toluene. 5.3 Any of the methods from 5 onward, further comprising cooling the mixture. 5.4 Any method from 5 onward, further comprising isolating the solid, for example, by filtration. 5.5 The method of 5.4, further comprising drying the solid under vacuum. 5.6 Any method from 5 onward, further comprising isolating the crystal.

[0105] A pharmaceutical composition (Composition 1) containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) in a crystalline form, for example, any of the crystalline forms from 1 onwards, any of the crystalline forms from 2 onwards, any of the crystalline forms from 5 onwards, and any of the crystalline forms from 6 onwards, for example, any of the crystalline forms from 1 onwards, for example, any of the crystalline forms from 5 onwards, for example, any of the crystalline forms from 6 onwards, is further provided and incorporated herein by reference to the whole thereof.

[0106] A pharmaceutical composition (Composition 1) is further provided, which includes crystals of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (crystal formula I), for example, any of crystal forms 1 and later, 2 and later, 5 and later, and 6 and later, for example, any of crystal forms 1 and later, for example, any of crystal forms 5 and later. Composition 1 is further provided as follows.

[0107] 1.1 Composition 1 comprising crystalline formula I in an amount of 25-500 mg, for example 25-300 mg or 350 mg, for example 25-200 mg, for example 15 mg, 20 mg, 30 mg, 35 mg, 50 mg or 100-150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, for example 35 mg, for example 350 mg. 1.2 Doses of 0.01 mg / kg or 0.1 mg / kg or 0.5-1 mg / kg or 5 mg / kg or 10 mg / kg or 15 mg / kg, for example, doses of 0.05-1 mg / kg or 5 mg / kg, for example, doses of 0.05-0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg or 20 mg / kg, for example, 0.5-1 mg / A composition according to 1 or 1.1, comprising crystalline formula I in an amount sufficient to provide doses of 1-2 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg, for example, 1-2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, or 50 mg / kg of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. 1.3 A composition according to 1.1~1.2, wherein after dissolving the composition in a solvent, for example an aqueous solution, the composition contains a base having a pH of 7, 7.5 or 8~10.5, for example 7, 7.5 or 8~9.5, for example 7 or 7.5~8, for example 7.5~8.5, for example 7.5, for example 8.5, for example 8~8.5, for example 8.2, for example 6, 7, 8, 9 or 10~11, for example 6, 7, 8 or 9~10, for example 7~9, for example 8~9, where the base is: a) C 1-8 -Alkyl mono, di, or tricarboxylate salts, e.g. succinates, e.g. metal succinates (e.g., alkaline and / or alkaline citrates, e.g. alkaline citrates, e.g. sodium citrate and / or potassium citrate), e.g. tartrates (e.g., metal tartrates, alkaline tartrates, e.g. sodium tartrate), e.g. succinates (e.g., metal succinates, e.g. alkaline succinates, e.g. disodium succinate) and / or e.g. lactates (e.g., metal lactates, e.g. alkaline lactates, e.g. sodium lactate), b) Phosphates, for example, metal phosphates (e.g., alkaline and / or alkaline phosphates, e.g., alkaline phosphates, e.g., sodium phosphate (e.g., NaH2PO4 and / or Na2HPO4) and / or potassium phosphate (e.g., KH2PO4 and / or K2HPO4)), c) Amines and / or salts thereof (e.g., morpholine, piperazine, benetamine, benzathine, trimethylglycine, chloroprocaine, hydravamin, amino acids (e.g., arginine and / or lysine), mono and / or polyhydroxyalkylamines, and / or salts thereof, e.g., (HO) n R 8 NH2, [(HO) n R 8 ]2NH, (HO) n R 8 ]3N, and / or its salts (where each R 8 C is independent 1-8 Alkyl (for example, C 1-6 -alkyl, for example, C 1-4 -Alkyl (e.g., -CH2CH3, e.g., -CH3), where n is 0 or C 1-8 -Alkylene (for example, C 1-6 - Alkylenes, for example, C 1-4 -Alkylenes, e.g., -CH2-CH2-, e.g., -C(CH2)3-, e.g., one R 8 is -CH3, and the other R 8 (where is -(CH2)6-) and each n is independently 1-8 (e.g., 1, 2, 3, 4, 5, or 6), for example tris(hydroxymethyl)aminomethane (also known as Tris base) and / or its salts (e.g., tris(hydroxymethyl)aminomethane acetate (also known as Tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and / or diethanolamine), for example the conjugate acid of an amine and / or its salt having a pKa of 6, 7, 8, 9, or 10-11, for example 6, 7, 8, or 9-10, for example 7-9, for example 8-9, any of the above, d) Acetates, for example, metal acetates (e.g., alkali and / or alkaline acetates, e.g., alkaline acetates, e.g., sodium acetate and / or potassium acetate), e) Hydroxide and / or alkoxide salts, e.g., metal hydroxide and / or metal alkoxide salts (e.g., quaternary ammonium hydroxide, e.g., ammonium hydroxide and / or choline hydroxide, lithium hydroxide, aluminum hydroxide, e.g., alkali and / or alkaline hydroxide salts, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and / or magnesium ethoxide, e.g., sodium hydroxide), f) Carbonates and / or bicarbonates, e.g., metallic carbon carbonates and / or metallic bicarbonates (e.g., alkalis and / or alkaline carbonates, e.g., alkalis and / or alkaline bicarbonates, e.g., sodium bicarbonate), or g) Borates, for example, metal borates (for example, alkaline borates, for example, sodium borate), or any combination thereof For example, one or more of sodium citrate, Na2HPO4, tris(hydroxymethyl)aminomethane, and tris(hydroxymethyl)aminomethane salt (e.g., trisacetate), for example, sodium citrate, Na2HPO4, and tris(hydroxymethyl)aminomethane, for example, one or more of sodium citrate and Na2HPO4, for example, Na2HPO4, for example, one or more of tris(hydroxymethyl)aminomethane any of the following compositions:

[0108] 1.4 The composition of 1.3, comprising 1 mg or 5 to 200 mg or 500 mg of a base, for example 1 mg or 5 mg or 10 to 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 1000 mg or 1500 mg, for example 15 mg, 20 mg, 30 mg, 50 mg, or 100 to 200 mg, 250 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 1000 mg or 1500 mg of a base. 1.5 The base is an amine and / or its salt (e.g., morpholine), an amino acid (e.g., arginine), a mono and / or polyhydroxyalkylamine and / or its salt, e.g., H2NR 20 HNR 20 R 21 , NR 20 R 21 R 22 and / or salts thereof, where R 20 , R 21 and R 22 C may be independently substituted by one or more -OH groups (for example, 1 to 8 -OH groups, e.g., 1, 2, 3, 4, 5, or 6 -OH groups). 1-8 -alkyl (for example, C 1-6 -alkyl, for example, C 1-4 A composition of 1.3 or 1.4, wherein the conjugate acid and / or salt of an amine, for example, C2-alkyl (e.g., C2-alkyl, for example, -CH3), for example, tris(hydroxymethyl)aminomethane (also known as a Tris base) and / or its salt (e.g., tris(hydroxymethyl)aminomethane acetate (also known as Tris acetate) meglumine and / or diethanolamine), has a pKa of 6, 7, 8, 9 or 10-11, for example, 6, 7, 8 or 9-10, for example, 7-9, for example, 8-9. 1.6 A composition of any of 1.3 to 1.5, wherein the base is a Tris base. 1.7 A composition according to any of 1.3 to 1.6, wherein the conjugate acid of a base, e.g., an amine and / or its salt, has a pKa of 6, 7, 8, 9 or 10-11, e.g., 6, 7, 8, or 9-10, e.g., 7-9, e.g., 8-9. 1.8 A composition of any of 1.3 to 1.7, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the base is at least 1:1, for example, the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to the base is at least 2:1.

[0109] 1.9 A composition of any of 1.3 to 1.7, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to a base is at least 1:2, for example at least 1:2, 1:3, 1:4, or 1:5~1:6, 1:7, 1:8, 1:10, 1:15, 1:20 or 1:30, for example at least 1:2.5~1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20 or 1:30, for example at least 1:2.5, for example at least 1:5, for example at least 1:10. 1.10 A composition comprising, for example, one or more fillers such as mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, arginine, glycine, histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone, polyethylene glycol, and polypropylene glycol, and one or more of mannitol, glucose, sucrose, lactose, trehalose, and dextran (e.g., dextran 40), for example, dextran (e.g., dextran 40). 1.11 Any composition from 1 onwards comprising 5 mg or 10 mg or 50 mg to 2 g or 5 g of filler, for example, 50 mg or 100 to 200 mg, 300 mg, 500 mg or 800 mg, or 1 g, 1.5 g, 2 g, 3 g, 4 g or 5 g of filler. 1.12 Any of the compositions hereinafter, wherein the composition is solid, such as a pharmaceutically acceptable excipient, such as one or more bases are solid. 1.13 Any of the compositions hereinafter, which is suitable for mixing with an aqueous solution in a pharmaceutically acceptable liquid (such as a solution or suspension, such as a solution). 1.14 Any of the compositions hereinafter, for injection, such as subcutaneous, intramuscular, intravenous or intrathecal, such as intramuscular or intravenous, such as subcutaneous, intramuscular, intravenous or intrathecal bolus injection. 1.15 The composition of 1.14, for intravenous injection, such as IV bolus injection and / or IV infusion, such as IV infusion after IV bolus injection. 1.16 The composition of 1.14, for intramuscular injection, such as IM bolus injection and / or IM infusion, such as IM infusion after IM bolus injection. 1.17 Any of the compositions of 1.3 - 1.16, wherein both crystalline form I and the base are in powder form.

[0110] 1.18 Composition 1, comprising 20 - 500 mg, such as 25 - 450 mg, such as 30 - 400 mg, such as 35 - 350 mg of crystalline form I, and one or more bases of the base, such as tris(hydroxymethyl)aminomethane, Na2HPO4, meglumine and sodium citrate, such as 15 - 1000 mg, such as 20 - 600 mg, such as 50 - 200 mg, such as 50 - 150 mg, such as 10 - 1500 mg, such as 15 - 1000 mg, such as 20 - 600 mg, such as 50 - 200 mg, such as 50 - 150 mg of the base. 1.19 The composition of 1.18, comprising 20 - 500 mg, such as 25 - 450 mg, such as 30 - 400 mg, such as 35 - 350 mg of crystalline form I, and tris(hydroxymethyl)aminomethane, such as 10 - 600 mg, such as 20 - 500, such as 40 - 500 mg of tris(hydroxymethyl)aminomethane. 1.20 Stable at room temperature for at least one week, e.g., at least one month, two months, four months, six months, eight months, or twelve months, e.g., <20% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <15% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <10% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <5% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, <2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, 1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, or <1% Any of the compositions from 1 onwards, comprising N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. 1.21 Any of the compositions from 1 onwards, comprising less than 10%, less than 15%, or less than 20% of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, for example less than 5%, less than 4%, less than 3%, or less than 2% of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide for at least one week, for example at least one month, two months, four months, six months, eight months, or twelve months.

[0111] 1.22 Any composition from 1 onwards in which crystal formula I is any of crystal forms 1 onwards. 1.23 Any composition from 1 onwards, wherein crystal formula I is one of crystal forms 2 or later. 1.24 Any composition from 1 onwards, wherein crystal formula I is any of crystal forms 5 or later. 1.25 Any composition from 1 onwards, wherein crystal formula I is any of crystal forms 6 or later. 1.26 Any one of the following compositions for use in any of the methods described herein, for example, for use in either Method 1 or later and Method 2 or later (see below). 1.27 Any of the following compositions, substantially exhibiting an XRPD pattern as shown at the top of Figure 47 (or at the top of Figure 56), wherein the XRPD is measured using CuKα irradiation, for example, the XRPD is measured using irradiation at a wavelength of 1.54059 Å. 1.28 Any composition from 1 onwards, wherein the XRPD pattern of the composition includes any of the 2θ(°) values ​​and / or d-interval (Å) values ​​(e.g., characteristic, representative, and / or principal peaks) shown in any of the crystal morphologies 1 onwards, 2 onwards, 5 onwards, or 6 onwards.

[0112] A method (Method 4) for producing a pharmaceutical composition comprising a monoanion or dianion of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) is further provided, comprising mixing any of the crystal forms 1 or later, 2 or later, 5 or later, or 6 or later with a pharmaceutically acceptable liquid, such as an aqueous solution, such as a sterile solution. Method 4 is further provided as follows:

[0113] 4.1 The monoanion of Equation I is [ka] Method 4. 4.2 The monoanion of Equation I is [ka] Method 4. 4.3 Any of the methods from 4 onwards, comprising mixing any of the compositions from 1 onwards with a liquid, such as an aqueous solution. 4.4 The concentration of the monoanion or dianion is 0.01 mM, 0.02 mM, 0.05 mM, 0.1 mM, 0.5 mM, 1 mM, or 2-250 mM, for example 0.01 mM, 0.1 mM, 0.5-1 mM, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 40 mM, 50 mM, 60 mM, 75 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 1000 mM, for example Any of the following methods: 1-2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 40 mM, 50 mM or 60 mM, for example; 5 mM, 10 mM, 15 mM, 20 mM, 25 mM or 50-100 mM, 200 mM, 250 mM, 300 mM, 400 mM, 500 mM or 1000 mM, for example; 2 mM, 20 mM or 200 mM, for example; 5 mM, 10 mM, 50 mM, 500 mM, 500 mM or 1000 mM. 4.5 Any of the methods described in section 4 or later, wherein a liquid, such as an aqueous solution, contains a base.

[0114] 4.6 The method of 4.5, wherein the base and its amount are as described in any of the above compositions, 1.3 to 1.9, 1.12, 1.18, and 1.19. 4.7 Any of the methods from 4 onward, comprising sterile water for injection, the liquid which may optionally contain a base as in the method of 4.5 or 4.6. 4.8 Any of the methods from 4 onward, wherein the liquid is a sterile solution containing dextrose (e.g., 5% dextrose injection), which may optionally contain a base as described in method 4.5 or 4.6. 4.9 Any of the methods from 4 onward, wherein the liquid is a sterile solution containing sodium chloride (e.g., 0.9% sodium chloride injection), which may optionally contain a base as described in method 4.5 or 4.6. 4.10 Any of the methods from 4 onward, wherein the liquid is a sterile solution containing benzyl alcohol (e.g., bacteriostatic water for injecting benzyl alcohol or sodium chloride for injecting benzyl alcohol), which may optionally contain a base as described in method 4.5 or 4.6.

[0115] 4.11 Any of the methods from 4 onward, wherein the liquid comprises a Ringer's solution of lactate, which may optionally contain a base as described in method 4.5 or 4.6. 4.12 Any of the methods from 4 onwards, which involves mixing 0.5 to 500 mL, e.g., 1 mL or 2 mL to 500 mL, e.g., 1 mL or 2 mL to 5 mL, 10 mL, 25 mL, 30 mL, 35 mL, 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 300 mL, or 500 mL, e.g., 1 mL or 2 mL to 5 mL, 10 mL, 25 mL, 50 mL, 75 mL, 100 mL, or 200 mL, e.g., 3.5 mL or 5 to 10 mL, 25 mL, 50 mL, or 100 mL, e.g., 3.5 mL or 35 mL of liquid, e.g., aqueous solution, e.g., any of the liquids shown in methods 4.5 to 4.11, with crystal formula I. 4.13 Any of the methods from 4 onwards, wherein the pharmaceutical composition has a pH of 7, 7.5, or 8-10.5, for example 7, 7.5, or 8-9.5, for example 7 or 7.5-8, for example 7.5-8.5, for example 7.5, for example 8.5, for example 8-8.5, for example 8.2. 4.14 Any method from 4 onwards for which the pharmaceutical composition is for injection, for example subcutaneous, intramuscular, intravenous or intrathecal, for example intramuscular or intravenous, for example subcutaneous, intramuscular, intravenous or intrathecal bolus injection. 4.15 Any of the methods from 4 onwards, including intravenous injection, e.g., IV bolus injection and / or IV infusion, e.g., for IV infusion after IV bolus injection.

[0116] 4.16 Any method from 4 onwards in which the pharmaceutical composition is for intramuscular injection, IM bolus injection and / or IM infusion, for example, for IM infusion after IM bolus injection. 4.17 Any method of 4.14 to 4.16, further comprising filtering the pharmaceutical composition to remove particles and microorganisms before injection. 4.18 Any of the methods described in 4 or later, wherein crystal formula I is one of the crystal forms 1 or later. 4.19 Any of the methods from 4 onwards, wherein crystal formula I is one of the crystal forms 2 or later. 4.20 Any method from 4 onwards, wherein crystal formula I is one of crystal forms 5 or later.

[0117] 4.21 Any method from 4 onwards, wherein crystal formula I is one of crystal forms 6 or later. 4.22 Any of the methods described in 4 or later for preparing a pharmaceutical composition, for example, by mixing crystalline formula I and a pharmaceutically acceptable liquid immediately before or before administration to a patient requiring administration. 4.23 Any of the methods described in 4 or later, which prepare the pharmaceutical composition within 24 hours, for example, within 12 hours, for example, within 10 hours, for example, within 8 hours, for example, within 2 hours, for example, within 1 hour, for example, within 30 minutes, for example, within 20 minutes, for example, within 15 minutes, for example, within 10 minutes, for example, within 5 minutes, for example, within 3 minutes, for example, within 2 minutes, or for example, within 1 minute, before administration to a patient requiring administration. 4.24 Mixing crystalline formula I and the base (for example, in solid form, for example, both in powder form) before mixing with the liquid, using any of the methods from 4 onwards. 4.25 Mix crystal formula I with a liquid, where the liquid contains a base, using any of the methods described in section 4 or later.

[0118] When dissolved in a pharmaceutically acceptable liquid, the pH of any of the pharmaceutical compositions disclosed herein, for example, any of the compositions from composition 1 onward, can be adjusted to achieve a desired pH by adding a metal hydroxide salt (e.g., NaOH and / or KOH, e.g., NaOH) to the composition.

[0119] A kit is further provided that includes crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (crystal formula I), for example, any of crystal forms 1 onwards, any of crystal forms 2 onwards, any of crystal forms 5 onwards, and any of crystal forms 6 onwards, for example, any of crystal forms 1 onwards, for example, any of crystal forms 5 onwards. Kit 1 is further provided as follows:

[0120] 1.1 Kit 1, containing crystal formula I in amounts ranging from 25 to 500 mg, e.g., 25 to 300 mg or 350 mg, e.g., from 25 to 200 mg, e.g., 15 mg, 20 mg, 30 mg, 35 mg, 50 mg or 100 to 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, e.g., 35 mg, e.g., 350 mg. 1.2 A kit of 1 or 1.1, wherein the composition contains a sufficient amount of crystalline formula I to provide N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide in amounts of 0.01 mg / kg or 0.1 mg / kg or 0.5-1 mg / kg or 5 mg / kg or 5 mg / kg or 10 mg / kg or 15 mg / kg, for example, 0.05-1 mg / kg or 5 mg / kg, 0.05-0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg or 20 mg / kg, for example, 0.5-1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg or 10-20 mg / kg, for example, 1-2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg or 50 mg / kg. 1.3 A kit of 1 or 1.1 further comprising a base, for example, the base and its amount as described in any of the compositions of 1.3 to 1.9, 1.12, 1.18, and 1.19. 1.4 Kit 1.3 contains 1 mg or 5-200 mg or 500 mg of base, for example 1 mg or 5 mg or 10-15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 1000 mg or 1500 mg, for example 15 mg, 20 mg, 30 mg, 50 mg or 100-200 mg, 250 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 1000 mg or 1500 mg. 1.5 The concentration of the base is 0.01 mM, 0.1 mM, 0.5 mM, 1 mM, or 2-250 mM, for example 0.01 mM, 0.1 mM, or 0.5-1, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 40 mM, 50 mM, 60 mM, 75 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 250 mM, or 1000 mM, for example 1-2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 40 mM, 50 mM, or 60 mM, for example 5 Kits 1.3 or 1.4, with concentrations of ~50mM, e.g., 5, 10, 15, 20, 25 or 50~100, 200, 250, 300, 400, 500mM or 1000mM, e.g., 2mM, 20mM or 200mM, e.g., 5mM, 10mM, 50mM, 500mM, 500mM or 1000mM, e.g., 5mM, 10mM, 15mM, 20mM, 25mM or 50~100mM, 200mM, 250mM, 300mM, 400mM, 500mM or 1000mM.

[0121] 1.6 The base is an amine and / or its salt (e.g., morpholine), an amino acid (e.g., arginine), a mono and / or polyhydroxyalkylamine and / or its salt, e.g., H2NR 20 HNR 20 R 21 , NR 20 R 21 R 22 , and / or their salts (where each R 20 , R 21 and R 22 The -OH group may be independently substituted by one or more -OH groups (for example, 1 to 8 -OH groups, for example, 1, 2, 3, 4, 5, or 6 -OH groups). 1-8 -alkyl (for example, C 1-6 -alkyl, for example, C 1-4A kit of any of the above, wherein the conjugate acid and / or salt of an amine, for example, is an alkyl (e.g., C2-alkyl, e.g., -CH3), for example, tris(hydroxymethyl)aminomethane (also known as a Tris base) and / or its salt (e.g., tris(hydroxymethyl)aminomethane acetate (also known as Tris acetate), meglumine and / or diethanolamine), or any of the above, having a pKa of 6, 7, 8, 9 or 10-11, for example, 6, 7, 8 or 9-10, for example, 7-9, for example, 8-9. 1.7 A kit from 1.3 to 1.6 in which one of the bases is a Tris base. 1.8 A kit of 1.3–1.7, where the conjugate acid of the base, e.g., an amine and / or salt thereof, has a pKa of 6, 7, 8, 9 or 10–11, e.g., 6, 7, 8 or 9–10, e.g., 7–9, e.g., 8–9. 1.9 A kit containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in a molar ratio of at least 1:1 relative to a base, for example, 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in a molar ratio of at least 2:1 relative to a base, one of kits from 1.3 to 1.8. 1.10 A kit containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in a molar ratio of at least 1:2 for one or more bases, e.g., at least 1:2, 1:3, 1:4 or 1:5-1:6, 1:7, 1:8-1:10, 1:15, 1:20 or 1:30, e.g., at least 1:2.5-1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20 or 1:30, e.g., at least 1:2.5, e.g., at least 1:5, e.g., at least 1:10, e.g., at least 1:10, e.g., any kit of 1.3 to 1.8.

[0122] 1.11 Any kit from now on comprising, for example, one or more pharmaceutically acceptable excipients, e.g., fillers, e.g., mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, arginine, glycine, histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone, polyethylene glycol, and polypropylene glycol, further comprising, for example, one or more mannitol, glucose, sucrose, lactose, trehalose, and dextran (e.g., dextran 40). Kit 1.11 includes fillers of 5 mg, 10 mg, or 50 mg to 2 g or 5 g, for example, 50 mg, 100-200 mg, 300 mg, 500 mg, or 800 mg, or 1 g, 1.5 g, 2 g, 3 g, 4 g, or 5 g. 1.13 Kit 1 comprising Crystalline Formula I, for example 25-450 mg, for example 30-400 mg, for example 35-350 mg, and one or more bases, for example tris(hydroxymethyl)aminomethane, Na2HPO4, meglumine, and sodium citrate, for example 15-1000 mg of base, for example 20-600 mg, for example 50-200 mg, for example 50-150 mg, for example 10-1500 mg of base, for example 15-1000 mg, for example 20-600 mg, for example 50-200 mg, for example 50-150 mg of base. 1.14 A kit of 1.13 containing 20-500 mg, e.g., 25-450 mg, e.g., 30-400 mg, e.g., 35-350 mg of crystalline formula I and tris(hydroxymethyl)aminomethane, e.g., 10-600 mg, e.g., 20-500 mg, e.g., 40-500 mg of tris(hydroxymethyl)aminomethane. 1.15 Any kit from 1 onwards in which crystal formula I is suitable for mixing an aqueous solution with a pharmaceutically acceptable liquid (e.g., solution or suspension, e.g., a solution).

[0123] 1.16 Any kit from 1 onwards comprising a pharmaceutically acceptable liquid, for example, a sterile solution, which may optionally contain an aqueous solution containing a base, for example, a base and the amount thereof described in any of the compositions of 1.3 to 1.9, 1.12, 1.18 and 1.19, for example, a base and the amount thereof described in any of the kits of 1.3 to 1.10, 1.13 or 1.14. 1.17 A 1.16 kit containing sterile water for injection. 1.18 A kit of 1.16 or 1.17 in which the liquid is a sterile solution containing dextrose (e.g., 5% dextrose injection). 1.19 A kit of any of the types 1.16-1.18 in which the liquid is a sterile solution containing sodium chloride (e.g., 0.9% sodium chloride injection). 1.20 A kit of any of the types 1.16-1.19 in which the liquid is a sterile solution containing benzyl alcohol (e.g., bacteriostatic water for injection containing benzyl alcohol or bacteriostatic sodium chloride for injection containing benzyl alcohol).

[0124] 1.21 A kit from 1.16 to 1.20 in which the liquid contains Ringer's lactate solution. 1.22 A kit containing 0.5 to 500 mL of liquid, e.g., aqueous solution, e.g., 1 mL or 2 mL to 500 mL, e.g., 1 mL or 2 mL to 5 mL, 10 mL, 2 mL, 30 mL, 35 mL, 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 300 mL or 500 mL, e.g., 1 mL or 2 mL to 5 mL, 10 mL, 25 mL, 50 mL, 75 mL, 100 mL or 200 mL, e.g., 3.5 mL or 5 to 10 mL, 25 mL, 50 mL or 100 mL, e.g., 3.5 mL or 35 mL of aqueous solution, as specified in 1.16 to 1.21. 1.23 Any kit from 1 onwards comprising a pharmaceutical composition comprising, for example, any of the compositions from 1 onwards, crystal formula I. 1.24 Any kit from 1 onwards in which the components of the kit are contained in the same container or in one or more different containers. 1.25 A kit of 1.24 in which crystal formula I and the base are present in the same container (container 1), and the liquid is present in a different container (container 2).

[0125] 1.26 A kit of Kit 1.24 in which the liquid and base are present in the same container (container 1), and crystal formula I is present in a different container (container 2). 1.27 A kit of 1.24, in which crystal formula I is present in container (container 1), a different base is present in container (container 2), and a different liquid is present in container (container 3). 1.28 A kit of any of types 1.25 to 1.27, in which a pharmaceutically acceptable excipient is present in container 1. 1.29 A kit from 1.25 to 1.27 in which a pharmaceutically acceptable excipient is present in container 2. 1.30 A kit of 1.27 in which pharmaceutically acceptable excipients are present in container 3.

[0126] 1.31 A kit of 1.24, in which the crystal formula I, base, liquid, and pharmaceutically acceptable excipients are each present in separate containers. 1.32 Any kit from 1 onwards in which crystal formula I is one of the crystal forms from 1 onwards. 1.33 Any kit from 1 onwards in which crystal formula I is one of crystal forms 2 or later. 1.34 Any kit from 1 onwards in which crystal formula I is one of crystal forms 5 or later. 1.35 Any kit from 1 onwards in which crystal formula I is one of crystal forms 6 or later. 1.36 Any kit from 1 onwards includes instructions for using 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to treat or control aquaporin-mediated diseases or conditions (e.g., for the use of any of the methods 1 and later and methods 2 and later (see below) for treating or controlling the diseases or conditions described herein), instructions for administering 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to a patient requiring administration, instructions for mixing crystal formula I with a base and / or liquid, instructions for using the pharmaceutical composition of Kit 1.23 to treat or control aquaporin-mediated diseases or conditions (e.g., for the use of any of the methods 1 and later and methods 2 and later (see below) for treating or controlling the diseases or conditions described herein), instructions for administering the pharmaceutical composition of Kit 1.23 to a patient requiring administration, instructions for manufacturing the pharmaceutical composition of Kit 1.23. 1.37 Any kit one or later for any use described herein, for example, for any use of Method 1 or later and Method 2 or later (see below).

[0127] A method for treating or controlling a disease or condition involving aquaporins, such as water imbalance and other diseases, is further provided (Method 1), which involves providing to a patient requiring administration an effective amount (or an effective amount of a pharmaceutical composition) of crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, for example, any of crystal form 1 onwards, any of crystal form 2 onwards, any of crystal form 5 onwards, and any of crystal form 6 onwards, for example, any of crystal form 1 onwards, for example, any of crystal form 5 onwards. Method 1 is further provided as follows:

[0128] 1.1 Method 1, where the disease or condition is selected from edema, epilepsy, neuromyelitis optica, migraine, hyponatremia, retinal ischemia or other eye diseases associated with abnormal intraocular pressure and / or tissue hydration, excess fluid retention, myocardial ischemia, myocardial infarction, myocardial hypoxia, congestive heart failure, and sepsis. 1.2 The method of 1 or 1.1 in which the disease or condition is edema, e.g., edema of the brain or spinal cord. 1.3 The method of 1.2, wherein the disease or condition is cerebral edema, e.g., cerebral edema due to ischemic stroke, e.g., cytotoxic cerebral edema, e.g., cytotoxic cerebral edema due to ischemic stroke. 1.4 The method of 1.3, where the disease or condition is cerebral edema, e.g., cytotoxic cerebral edema due to trauma (e.g., head injury), stroke (e.g., ischemic stroke), traumatic brain injury, glioma, meningitis, acute altitude sickness, epileptic seizure, infection, metabolic disorder, hypoxia (including generalized hypoxia and hypoxia due to heart attack or other impaired blood perfusion to the brain), water intoxication, hepatic failure, hepatic encephalopathy or diabetic ketoacidosis, e.g., cerebral edema due to head injury, e.g., stroke (e.g., ischemic stroke), e.g., traumatic brain injury, e.g., hypoxia due to heart attack or other impaired blood perfusion to the brain. 1.5 The method of 1.3 if the disease or condition is cytotoxic cerebral edema due to, for example, microgravity exposure, radiation exposure, invasive central nervous system surgery (e.g., neurosurgery, endovascular clot removal, spinal puncture, aneurysm repair or deep brain stimulation), abscess, eclampsia, Creutzfeldt-Jakob disease or lupus encephalitis.

[0129] 1.6 The disease or condition is spinal cord edema, e.g., spinal cord edema due to spinal cord injury, e.g., spinal cord compression. Method 1.2. 1.7 The method of 1.2, wherein the disease or condition is retinal edema, ophthalmic nerve edema due to microgravity or radiation exposure, edema due to hypoxia, or cardiac edema (e.g., cardiac edema due to cardiac ischemia or other obstruction of blood flow to the heart). 1.8 The method of 1 or 1.1, wherein the disease or condition is selected from hyponatremia and fluid retention due to, for example, heart failure, cirrhosis, nephrotic disorder or syndrome of inappropriate antidiuretic hormone secretion (SIADH). 1.9 Method 1, where the disease or condition is selected from glioblastoma, ovarian hyperstimulation syndrome, pulmonary edema, fibromyalgia, and multiple sclerosis. 1.10 A disease or condition described in International Publication No. WO2013 / 169939 (a U.S. national application published as U.S. Patent Publication No. 2015 / 0133405) or International Publication No. WO2015 / 069948 (U.S. national application No. 15 / 034,543), WO2015 / 069956 (U.S. national application No. 15 / 035,006), WO2015 / 069961 (U.S. national application No. 15 / 034,274), or WO2016 / 077787, and each of these is incorporated herein by any method of 1 or 1.1 to 1.9.

[0130] Further methods are provided for treating or preventing graft rejection, inhibiting rejection of transplanted biological material, or preventing, treating, or controlling transplant-induced edema, comprising administering to a patient in need of them crystals (or a pharmaceutical composition containing an effective amount) of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, for example, any of crystal forms 1 or later, 2 or later, 5 or later, and 6 or later, for example, any of crystal forms 1 or later, for example, any of crystal forms 5 or later. Method 2 is further provided as follows:

[0131] 2.1 Method 2, including treatment or prevention of graft rejection. 2.2 Method 2, comprising inhibiting the rejection of transplantable biological material. 2.3 Method 2, including prevention, treatment, or control of transplant-induced edema. 2.4 Rejection or edema, e.g., graft rejection, e.g., edema, resulting from the transplantation of an organ (e.g., kidney, liver, pancreas, lung, heart, thymus, intestine, uterus, e.g., heart) or a part thereof, by any of the methods described in 2 or later. 2.5 Edema, e.g., graft rejection, e.g., edema, resulting from a facial, limb (e.g., hand), eye, trachea, muscle, or esophageal graft, by any of methods 2 or 2.1-2.3. 2.6 Any of the methods described in 2 or later, wherein the graft rejection is hyperacute or accelerated rejection, e.g., hyperacute rejection, e.g., accelerated rejection. 2.7 Graft rejection is acute rejection, by any of the methods described in 2 or 2.1-2.5. 2.8 Graft rejection is chronic rejection, by any of the methods described in 2 or 2.1-2.5. 2.9 Any of the methods described in International Application No. PCT / US2015 / 060731, which is incorporated herein by whole reference, for inhibiting, preventing, treating, or controlling graft rejection, rejection of transplanted biological material, or for preventing, treating, or controlling edema caused by transplantation.

[0132] A method for protecting the heart during cardiac surgery, such as cardiac incision, is further provided, comprising administering a crystal (a pharmaceutical composition containing an effective amount) containing an effective amount of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, for example, any of crystal forms 1 onwards, 2 onwards, 5 onwards, and 6 onwards, for example, any of crystal forms 1 onwards, for example, any of crystal forms 5 onwards, to a patient in need.

[0133] moreover, (i) For use in the methods described herein or in the treatment of any disease or condition, 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), for example any of crystal form 1 or later, crystal form 2 or later, crystal form 5 or later and crystal form 6 or later, for example any of crystal form 1 or later, for example any of crystal form 5 or later, (ii) A crystal (in the manufacture of a pharmaceutical product) for treating any disease or condition described herein, comprising, for example, any of crystal form 1 or later, crystal form 2 or later, crystal form 5 or later, and crystal form 6 or later, for example any of crystal form 1 or later, for example any of crystal form 5 or later, (iii) A pharmaceutical composition comprising, for example, any of the crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate as described herein, for example, any of crystal form 1 or later, crystal form 2 or later, crystal form 5 or later, and crystal form 6 or later, for example any of crystal form 1 or later, for example any of crystal form 5 or later, in combination with or together with a pharmaceutically acceptable diluent or carrier, for example any of composition 1 or later, and (iv) A pharmaceutical composition for use in the treatment of any disease or condition described herein, comprising, for example, any of the crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) as described herein, for example any of crystal forms 1 onwards, crystal forms 2 onwards, crystal forms 5 onwards and crystal forms 6 onwards, for example any of crystal forms 1 onwards, for example crystal form 5 onwards, in combination with or together with a pharmaceutically acceptable diluent or carrier, for example any of the compositions 1 onwards It will be provided. [Brief explanation of the drawing]

[0134] [Figure 1] The atomic displacement ellipse diagram of the asymmetric unit of form A is shown. The atom is represented by an anisotropic thermal vibration ellipse with a 50% probability. [Figure 2] The atomic displacement ellipse diagram for form A is shown. Atoms are represented by anisotropic thermal vibration ellipses with a 50% probability. One of the two molecules of equation I is shown using atomic labels. [Figure 3] The packing diagram of morphology A, viewed parallel to the crystal axis a, is shown. [Figure 4] The packing diagram of morphology A, viewed parallel to the crystal axis b, is shown. [Figure 5]The packing diagram of morphology A, viewed parallel to the crystal axis c, is shown. [Figure 6] This shows the hydrogen bonding environment around the two molecules in the asymmetric unit of morphology A. [Figure 7] This shows hydrogen bond chains parallel to the b-axis in morphology A. [Figure 8] The computational XRPD pattern for form A is shown. [Figure 9] The experimental and computed XRPD patterns for morphology A are shown. The upper XRPD pattern is the experimental XRPD pattern at room temperature. The middle XRPD pattern is the computed XRPD pattern adjusted to room temperature. The XRPD pattern shown is the computed XRPD pattern at 150K. [Figure 10] The XRPD pattern of morphology A recovered using CuKα irradiation is shown. [Figure 11] The XRPD pattern of morphology A recovered using CuKα irradiation is shown. [Figure 12] Figures 12a (top) and 12b (bottom) show the XRPD patterns of morphology A recovered using a copper source. [Figure 13] The atomic displacement ellipse diagram of the hemisodium hemiacetonitrile solvate is shown. The atoms are represented by an anisotropic thermal vibration ellipse with a 50% probability. [Figure 14] The atomic displacement ellipse diagram of the hemisodium hemiacetonitrile solvate is shown. The atoms are represented by an anisotropic thermal vibration ellipse with a 50% probability. [Figure 15] This shows the packing diagram of the hemisodium hemiacetonitrile solvate, viewed parallel to the crystal axis a. [Figure 16] This shows the packing diagram of the hemisodium hemiacetonitrile solvate, viewed parallel to the crystal axis b. [Figure 17] This shows a packing diagram of hemisodium hemiacetonitrile solvate viewed parallel to the crystal axis c. [Figure 18] This shows the interaction between formula I and acetonitrile with hemisodium hemiacetonitrile solvate, parallel to the a-axis. [Figure 19] This shows a hydrogen bond between the phosphate group and the hemisodium hemiacetonitrile solvate. [Figure 20] The calculated XRPD pattern for hemisodium hemiacetonitrile solvate is shown. [Figure 21] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 22] The XRPD patterns of morphology I collected using CuKα irradiation are shown. [Figure 23] The XRPD patterns of morphology L collected using CuKα irradiation are shown. [Figure 24] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 25] The DSC and TGA overlays for morphology A are shown. [Figure 26] The DSC and TGA overlays for morphology N are shown. [Figure 27] The DVS isotherms of morphology N are shown. [Figure 28] DVS isotherms of morphology B are shown. [Figure 29] The TGA thermogram of morphology L is shown. [Figure 30] This shows the interconversion between forms A, B, and N. [Figure 31] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Figure 32] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Figure 33] The overlay of the morphological AXRPD patterns is shown. The upper XRPD pattern is morphological A derived from Example 2A (XRPD patterns shown in Figures 10 and 31). The lower XRPD pattern is morphological A derived from Example 3 (XRPD patterns shown in Figures 11 and 32). [Figure 34] The DVS isotherms of morphology A are shown. [Figure 35] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Figure 36]The overlay of the morphological AXRPD patterns is shown. The upper XRPD pattern is morphological A derived from Example 2B (XRPD pattern shown in Figure 35). The lower XRPD pattern is morphological A derived from Example 2A (XRPD patterns shown in Figures 10 and 31). [Figure 37] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 38] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Figure 39] The XRPD patterns of morphology A (and unknown trace components) collected using CuKα irradiation are shown. [Figure 40] The DSC and TGA overlays for form B are shown. [Figure 41] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 42] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 43] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 44] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 45] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 46] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 47] The XRPD patterns of morphology A + Tris base, morphology A, and Tris base are shown. The upper XRPD pattern is morphology A powdered with Tris base. The middle XRPD pattern is morphology A derived from Example 2A. The lower XRPD pattern is Tris base. [Figure 48] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 49] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 50]The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 51] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 52] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 53] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 54] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 55] The XRPD patterns of morphology B collected using CuKα irradiation are shown. [Figure 56] This shows the XRPD pattern of morphology A+ Tris base. [Figure 57] The XRPD patterns of morphology N collected using CuKα irradiation are shown. [Figure 58] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Figure 59] The XRPD patterns of morphology A collected using CuKα irradiation are shown. [Modes for carrying out the invention]

[0135] Detailed explanation The crystallinity, morphology, and properties of any of the crystals described herein, such as crystal morphology 1 and later, crystal morphology 2 and later, crystal morphology 3 and later, crystal morphology 4 and later, crystal morphology 5 and later, and crystal morphology 6 and later, can be determined by many methods, including, but not limited to, single-crystal X-ray diffraction, X-ray powder diffraction, polar optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic (water) vapor sorption, infrared absorption spectroscopy, and Raman spectroscopy.

[0136] It is understood that the XRPD pattern of a given sample may vary (standard deviation) due to the equipment used, the time of measurement, the temperature of the sample, and standard experimental error. Therefore, the 2θ value (°2θ), d-interval value, height, and relative intensity of the peaks have an acceptable level of deviation. For example, the values ​​may have acceptable deviations of, for example, 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In certain embodiments, the 2θ (°) value or d-interval (Å) value of the crystal morphology XRPD pattern described herein may have an acceptable deviation of 0.2° and / or ±0.2Å. Furthermore, the XRPD patterns of the crystal morphologies described herein may be identified by characteristic peaks recognizable to those skilled in the art. For example, any of the crystal morphologies described herein, e.g., crystal morphologies 1 onwards, 2 onwards, 3 onwards, 4 onwards, or 5 onwards, may be identified, for example, by two characteristic peaks, in some cases three characteristic peaks, or in other cases five characteristic peaks. Therefore, the term “substantially” as shown in a particular figure means any crystal having an XRPD with major and / or characteristic and / or representative peaks recognized by those skilled in the art.

[0137] It is also understood that differential scanning calorimetry and thermogravimetric thermograms of a given sample may vary (standard deviation) depending on the equipment used, the time of measurement, the sample temperature, and standard experimental error. The temperature value itself may deviate by up to ±10°C, preferably ±5°C, and preferably ±3°C from the reference temperature.

[0138] According to USP guidelines, variable hydrates and solvates may exhibit peak dispersion greater than ±0.2°²θ. Therefore, the ±0.2°²θ peak dispersion may not be applicable to these substances.

[0139] If multiple diffraction patterns are available, particle statistics (PS) and / or orientation alignment (PO) can be evaluated. Reproducibility between XRPDs derived from multiple samples analyzed in a single diffractometer indicates good particle statistics. Consistency of relative intensity between XRPD patterns derived from multiple diffractometers indicates good alignment statistics. Alternatively, if available, observed XRPD patterns can be compared to calculated XRPD patterns based on the single-crystal structure. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS / PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the average powder intensity for the sample, and prominent peaks can be identified as "representative peaks." Generally, the more data collected to determine representative peaks, the more certain the classification of those peaks becomes.

[0140] A "characteristic peak," as far as it exists, is a subset of representative peaks and can be used to distinguish one polymorphism from another crystalline polymorphism (a polymorphism that is a crystalline form having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks are present in the crystalline polymorphism of a given compound, within ±0.2°²θ of all known crystalline polymorphism peaks of that compound, if any. A crystalline polymorphism of a compound does not necessarily have at least one characteristic peak.

[0141] As used herein, "XRPD" means X-ray powder diffraction.

[0142] As used herein, the term "patient" includes both human and non-human beings. In one embodiment, the patient is human. In another embodiment, the patient is non-human.

[0143] As used herein, "bolus administration" refers to the administration of a therapeutic agent in a single injection lasting a relatively short period, for example, 60 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, 5 minutes or less, for example, 3 minutes or less, for example, 1 minute or less. Bolus administration rapidly delivers a therapeutically effective amount of the therapeutic agent into the bloodstream.

[0144] As used herein, the term "solvate" refers to a crystal containing stoichiometric or non-stoichiometric amounts of solvent within its crystal structure.

[0145] As used herein, the term "non-solvate" means a crystal that does not contain or substantially contains solvent molecules in its crystalline structure.

[0146] As used herein, the term "hydrate" refers to a crystal containing stoichiometric or non-stoichiometric amounts of water within its crystal structure.

[0147] As used herein, the term "nonhydrate" means a crystal that does not contain or substantially contains water molecules in its crystal structure.

[0148] As used herein, "stoichiometric hydrate" refers to a crystalline substance having a specific water content exceeding an extended relative humidity (RH) range.

[0149] As used herein, "variable hydrate" refers to a crystalline substance that has a variable water content exceeding an extended relative humidity (RH) range, but whose phase remains unchanged.

[0150] As used herein, the term "amorphous" refers to a solid with a disordered arrangement of molecules and lacking a recognizable crystalline lattice.

[0151] As used herein, "poor solvent" means a solvent in which 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) is either soluble or insoluble. For example, poor solvents include solvents in which 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) has a solubility of less than 35 mg / ml, e.g., solubility of 10 to less than 30 mg / ml, e.g., solubility of 1 to less than 10 mg / ml, e.g., solubility of less than 1 mg / ml.

[0152] As used herein, "crystal formula I" means a crystal containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (formula I), for example, any of crystal forms 1 and later, crystal forms 2 and later, crystal forms 5 and later, and crystal forms 6 and later, for example, any of crystal forms 1 and later, for example, any of crystal forms 5 and later.

[0153] In some embodiments, the bases used herein are solids.

[0154] In some embodiments, the term "base" as used herein refers to an inorganic or organic Brønsted base.

[0155] The wavelength used for the calculation interval (Å) value of 1.5405929 Å in this specification is Cu-K. α1 Wavelength (Holzer, G. et al., E. Phys. Rev., 1997, A56 (6), 4554-4568). Variations associated with d-interval predictions at each d-interval are calculated from USP recommendations and provided in representative data tables. [Examples]

[0156] Example 1: General Method Example 1A: General XRPD method XRPD patterns are collected using a PANalytical X'Pert PRO MPD diffractometer with an incident Cu irradiation beam generated using a long, high-precision focused light source. Ellipsoidal multilayer mirrors are used to direct the CuKα X-rays through the sample and focus them on the detector. Before analysis, a silicon sample (NIST SRM 640e) is analyzed to confirm the Si 111 peak position. Sample A is sandwiched between 3 μm thick films and analyzed using transmission geometry. A short anti-scattering extension and anti-scattering knife edge are used to stop the beam and minimize background generated by air. Solar slits are used for the incident and diffracted beams to minimize spreading from axial divergence. Diffraction patterns are collected using a scan position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.2.2b.

[0157] Select peaks within a range of approximately 30°²θ. Using a rounding algorithm based on the instrument used for data acquisition and / or its inherent peak splitting, process each peak to the nearest 0.1°²θ or 0.01°²θ. Peak position changes occur within ±0.2°²θ. Third-party measurements of independently calibrated samples using different instruments may introduce changes greater than ±0.2°²θ.

[0158] Preferably, prominent peaks are selected from the observed peaks by identifying low-angle peaks with strong intensity that do not overlap.

[0159] Example 1B - XRPD indexing In the referenced figure for a given indexed XRPD pattern, the agreement between the acceptable peak positions indicated by bars and the observed peaks indicates a consistent unit cell determination. Unless otherwise specified, successful indexing of the pattern indicates that the sample consists primarily of single-crystal phase. To confirm the transient indexing solution, the molecular packing motifs within the crystalline unit cells must be determined. No attempts at molecular packing have been made.

[0160] Example 1C Differential Scanning Calorimetry (DSC) a.Standard DSC DSC is performed using a TA Instrument 2920 differential scanning calorimeter. Temperature calibration is performed using NIST-traceable indium metal. The sample is placed in an aluminum DSC pan, covered with a lid, and its weight is accurately recorded. The weighed aluminum pan, designated as the sample pan, is placed on the reference side of the cell. The thermogram method code is an abbreviation for the start and yield temperatures as well as the heating rate; for example, (-30)-250-10 means "-30°C to 250°C, 10°C / min". The abbreviation T0C indicates the use of a T-zero crimped pan. b. Modulated DSC Modulated DSC data are obtained using a TA instrument Q2000 differential scanning calorimeter equipped with a refrigerated cooling system (RCS). Temperature calibration is performed using NIST-traceable indium metal. The sample is placed in an aluminum DSC pan, covered with a lid, and its weight is accurately recorded. The gravimetrically measured aluminum pan, set as the sample pan, is placed on the reference side of the cell. Temperatures are obtained from 2 to 200°C using a heating rate of 2°C / min with adjustment ranges of 1.00°C and 60 seconds. The reported glass transition temperature is obtained from the inflection point of the step change in the reversible component of the heat flow relative to the temperature curve.

[0161] Example 1D Dynamic water vapor adsorption (DVS) Dynamic water vapor adsorption (DVS) data are collected using a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP are used as calibration standards. Samples are not dried before analysis. Adsorption and desorption data are collected under nitrogen purge, with a 10% RH increase, in the range of 5% to 95% relative humidity (RH). The equilibrium criterion used for analysis has a maximum equilibrium time of 3 hours and a weight change of less than 0.0100% in 5 minutes. Data are not corrected for the initial moisture content of the sample.

[0162] Example 1E Thermogravimetric Analysis (TGA) TG analysis is performed using a TA Instruments Discovery or Q5000 IR thermogravimetric analyzer. Temperature calibration is performed using nickel and alumel. TM The procedure is carried out using the following method: Place each sample in an aluminum pan. Seal the sample, puncture the lid, and then insert it into the TG heating furnace. Heat the furnace under a nitrogen atmosphere. Collect data at a gradient rate of 10°C / min.

[0163] Example 1F: Energy-dispersive X-ray spectroscopy (EDX) EDX is EDAX with FEI Quanta 200 SEM TM Data is collected using a Sapphire X-ray detector and analyzed using EDAX Genesis software (v.3.5). The detector is calibrated using NIST-traceable aluminum and copper. For analysis, a sample is prepared and a small amount of sample is placed on a carbon-deposited tab supported on an aluminum stage. The analysis time recorded during the detector's effective measurement time is 200 seconds, using a time of 10 microseconds and a beam voltage of 15 kV.

[0164] Example 1G: Karl Fischer coulometric titration (KF) Coulometric Karl Fischer analysis for moisture content measurement is performed using a Mettler Toledo DL39 Karl Fischer titrator with a Stromboli oven attachment. Two sample replicas are placed in a drying oven set at approximately 130-140°C. The drying oven is purged into the titrator with dry nitrogen. The samples are then titrated using a generator electrode that produces iodine by electro-oxidation: 2I- → I2 + 2e-. To check the operation of the coulometer, the NIST tracking water standard (Hydranal Water Standard 10.0) is analyzed.

[0165] Example 1H: Crash Cooling (CC) Prepare a concentrated solution of Formula I in a solvent at an elevated temperature. Filter the solution, if possible while still warm, through a 0.2 μm nylon filter into a warm vial. Cover the vial and place it directly into a freezer for crush cooling. Leave the solution in the freezer for a set period of time to collect any solids present.

[0166] Example 1I: Crush precipitation (CP) Prepare a solution of formula I. Filter the solution through a 0.2 μm nylon filter, if necessary. While stirring, partition aliquots of the poor solvent until a precipitate forms. Isolate the solid.

[0167] Example 1: Rapid Cooling (FC) Prepare a concentrated solution of formula I in a solvent at high temperature. Filter the solution, if necessary, through a 0.2 μm nylon filter into a warm vial while still warm. Cover the vial and allow it to cool rapidly to room temperature by placing it directly on the workbench. Maintain the solution under ambient conditions for a certain period of time and collect any solids present.

[0168] Example 1: Low-speed evaporation (SE) Prepare a solution of formula I. Filter the solution through a 0.2 μm nylon filter, if necessary. Evaporate the solution in a loosely sealed vial or a vial covered with perforated aluminum foil under conditions that result in slow evaporation. Evaporate the solution to dryness unless the method results in partial slow evaporation (solid present with a small amount of residual solvent). Isolate the solid.

[0169] Example 2A: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate (Form A) [ka] Step 1: [ka] Under an N2 atmosphere, 5-chlorosalicylic acid (43.7 g, 300 mmol, 1 equivalent) is dissolved in toluene (1500 mL), then phosphorus trichloride (10.5 mL, 150 mmol, 0.5 equivalent) is added dropwise, followed by the addition of 3,5-bis(trifluoromethyl)aniline (50 g, 228 mmol, 0.87 equivalent). The reaction mixture is stirred under reflux for 12 hours and cooled to room temperature. Another 0.1 equivalent of phosphorus trichloride (2 ml) is added, and the reaction mixture is heated for a further 4 hours. After cooling, 1 L of ethyl acetate is added. The reaction mixture is poured onto a silica gel column, and the silica gel column is eluted with 3 L of ethyl acetate. After evaporation of the solvent, 70 g of the product is obtained. 1 H NMR (400MHz, CDCl3): δ 11.35(bs, 1H), 10.85(bs, 1H), 8.40(s, 2H), 7.80-7.79(m, 2H), 7.50(dd, 1H), 7.00(d, 1H).

[0170] Step 2: [ka] Dissolve N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (40.0 g, 0.1 mol, 1 equivalent) in CH3CN (400 mL), then add DMAP (0.8 g, 0.001 mol, 0.06 equivalents), Hünig base (34 mL, 0.21 mol, 2 equivalents), and CCl4 (82.02 g, 0.52 mol, 5 equivalents) in that order. Cool the solution to 0°C, and add a solution of ((CH3)3SiCH2CH2O)2P(O)H (46 g, 0.16 mol, 1.5 equivalents) in CH3CN (50 mL) dropwise. Stir the reaction mixture at room temperature for 20 hours, then add water (6 L) and extract twice with  (2 L). The combined organic layers are washed with a saturated solution of NaCl, dried over Na2SO4, filtered, and the solvent is concentrated under reduced pressure to obtain a crude substance, which is then used in the next step. 1H NMR (200MHz, CDCl3):δ 10.20(bs, 1H), 8.32(s, 2H), 7.90(s, 1H), 7.62(s, 1H), 7.45-7.40(m, 1H) ), 7.30-7.28(m, 1H), 4.40-4.30(m, 4H), 1.20-1.00(m, 4H), 0.0(s, 18H).

[0171] Step 3: [ka] 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate (64 g, 0.1 mol, 1 equivalent) was dissolved in a TFA:water (5:1, 500 mL) mixture. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was concentrated. The crude oily substance was dissolved in 1 L of water containing 0.4 mol of NaOH (16 g). The turbid solution was extracted twice with 1 L of ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted twice with 1.5 L of ethyl acetate. The combined ethyl acetate fraction was dried over sodium sulfate and evaporated to obtain a grayish-white solid, which was crystalline by XRPD at 24 g. Mass spectrum M+1 = 463.9946, calculated value for C15H10ClF6NO5P = 463.9889. 1 H NMR (400MHz, CD3OD): δ 8.38(s, 2H), 7.78(s, 1H), 7.70(s, 1H), 7.55-7.50(m, 1H), 7.45-7.43(m, 1H). 1 H NMR (600MHz, DMSO d6): δ 11.2(s, 1H), 8.07(s, 2H), 7.8(s, 1H), 7.75(s, 1H), 7.70(d, 1H), 7.4(d, 1H). Elemental analysis: 39.67% C, 2.23% H, 2.87% N, 7.15% Cl, 20.49% F, 6.28% P Ion chromatography (IC) and inductively coupled plasma emission spectrometry (ICP-OES) (Na + Analysis): 0.18% Na by IC + , 0.19% Na by ICP-OES (acid hydrolysis method) +

[0172] The XRPD patterns of the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate prepared as described in this example are shown in Figures 12a and 12b. The XRPDs are obtained using a Bruker D2 phaser with a copper source.

[0173] The XRPD pattern of the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate prepared as described in this example is shown in Figure 10. The XRPD pattern is also shown in Figure 31. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d intervals, and peak intensities of the XRPD patterns shown in Figures 10 and 31 are provided above in Table B of Crystal Morphology 1.21. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°²θ, step size: 0.017°²θ, acquisition time: 717 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0174] The XRPD pattern in Figure 10 (also shown in Figure 31) successfully indexes, indicating that the material consists mainly or exclusively of a single-crystal phase. The unit cell volume obtained from the indexed solution allows for the application of Equation I to up to approximately 0.5 moles of ethyl for every 1 mole of Equation I.

[0175] 1 The 1H NMR spectrum shows 0.4 moles of  per mole of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate.

[0176] Figure 25 shows the overlay of DSC and TGA thermograms (DSC parameters: size: 2.5900 mg, method: (-30)-250-10, T0C, instrument: 2920 MDSC V2.6A, TGA: 12.8974 mg). A weight loss of 0.5 wt% is observed from 23°C to 90°C. A weight loss of 7.8 wt% is observed from 90°C to 165°C. Assuming a small amount of toluene volatilizes during the weight loss, the weight loss is equivalent to 0.4 moles of toluene. Overlapping endothermic phenomena occur with maximum peaks at 113°C, 123°C, and 131°C, which are thought to correspond to desolvation. A sharp endothermic peak is observed at 176°C (around 170°C), which probably corresponds to melting. Decomposition appears to follow melting, as evidenced by the sharp drop in the TGA thermogram.

[0177] The kinetic and thermodynamic hygroscopicity of morphology A is evaluated by DVS and loading at elevated RH, respectively. Loading a morphology A sample at approximately 97% RH for 7 days induces a morphological change to a mixture of a small amount of morphology N (hydrate) component and the raw material.

[0178] The DVS isotherms are shown in Figure 34. Initially, the sample loses 0.76 wt% at equilibrium at 5% RH, which is thought to correspond to the loss of moisture due to environmental preservation and / or adsorption by the bound ₹. The substance exhibits significant hygroscopicity, absorbing 6.07 wt% moisture between 5% and 95% RH (1.65% weight increase at 5% to 75% RH, 4.42% weight increase at 75% to 95% RH). A large amount of water adsorption (4.42%) occurs between 75% and 95% RH. Significant hysteresis is shown in the adsorption isotherms, along with a fixed 8.73% weight loss occurring between 95% and 5% RH. The larger weight loss during desorption indicates a simultaneous phenomenon from the adsorption of bound ₹ and water. The two stages in the experiment reach their maximum equilibrium times: 85% to 95% RH for adsorption and 85% to 75% RH for desorption. If the equilibrium time is longer, the sample may undergo further vapor adsorption or desorption under the corresponding RH conditions.

[0179] XRPD of DVS-posted samples shows a transformation into an unknown substance that causes interference.

[0180] As described in Example 5, a single crystal structure grown using Morph A of this lot is dissolved. The crystal structure is consistent with the hemi-ACN hemi salt of formula I. To investigate whether the single crystal is representative of the entire lot of Morph A, the material is analyzed by elemental analysis (EA), ion chromatography (IC), inductively coupled plasma emission spectrometry (ICP-OES), and energy-dispersive X-ray spectroscopy (EDX), and the results are shown in Table 1, comparing the theoretical composition ratio with the obtained measurements. [Table 15]

[0181] The EA test is relatively comprehensive because the measurements for C, H, N, Cl, F, and P cannot distinguish between hemi-sodium salt and free acid. Analysis by IC, ICP-OES (using acid hydrolysis), and EDX all show very small sodium content, confirming that form A of this lot consists of formula I (free acid). The hemi-sodium salt analyzed by SCXRD may originate from small amounts of Na impurities in the substance crystallized from solution as hemi-sodium salt.

[0182] Crush precipitation of formula I in a à / heptane mixture, reduced slow evaporation, crush cooling, and rapid cooling all result in form A.

[0183] Example 2B: Re-preparation of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A) A solution of a portion of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A was mixed with 1N HCl. A white solid was isolated by evaporation. The 600 MHz NMR spectrum showed approximately 0.28 moles of siRNA. The substance was analyzed by EDX, and the results are shown in Table 2. [Table 16]

[0184] Figure 35 shows the XRPD pattern of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate prepared as described in this example. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d interval, and peak intensities of the XRPD pattern shown in Figure 35 are provided above in Table DD of Crystal Morphology 1.77. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°2θ, step size: 0.017°2θ, acquisition time: 716 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0185] The XRPD pattern shows the sample exhibiting morphology A and potentially small amounts of unknown components.

[0186] Example 3: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is stirred with 1N HCl in HCl and evaporated. The solid is then crushed and precipitated with HCl / heptane and filtered under vacuum.

[0187] Further experimental details regarding the synthesis are given in the following paragraphs. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from Example 2B (28.1 mg) is dissolved in  (0.1 mL) under sonication to produce a clear solution. Aliquots of heptane (4 x 0.1 mL) are added with stirring to produce a precipitate. An opaque white suspension is observed. The resulting solid is isolated by vacuum filtration and air-dried under reduced pressure for 2 minutes.

[0188] The XRPD pattern of the product (2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate) is shown in Figure 11. The XRPD pattern is also shown in Figure 32. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d intervals, and peak intensities of the XRPD patterns shown in Figures 11 and 32 are provided above in Table BB of Crystal Morphology 1.49. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 721 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0189] A peak shift is observed in the XRPD pattern of morphology A, which is thought to be caused by a changeable ԅ content that leads to expansion or contraction of the crystal lattice.

[0190] For comparative purposes, the XRPD pattern in Figure 11 (also shown in Figure 32) is indexed. Although the volume is slightly smaller than that of Form A derived from Example 2A, the unit cell volume for this substance also adapts to a maximum of approximately 0.5 moles of siRNA per mole of Formula I. Figure 33 shows an XRPD overlay illustrating the peak shift observed between the XRPD patterns in Figures 10 and 31 and the XRPD patterns in Figures 11 and 32. The indexing leads to the suggestion that very small differences in siRNA content (and consequently unit cell volume) cause a relatively noticeable peak shift by XRPD.

[0191] Example 4: Preparation of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hemiethyl acetate solvate (Form A) and determination of its single crystal structure. introduction The structure of the single crystal is determined by single-crystal X-ray diffraction. Single-crystal data acquisition, structural analysis, and fine-tuning are carried out in accordance with cGMP specifications.

[0192] Results and Review The monoclinic cell parameters and calculated volume are: a=26.2223(3)Å, b=9.10581(10)Å, c=34.9080(4)Å, β=97.3256(11)° (α=γ=90°), V=8267.13(16)ų. The formula weight of the asymmetric unit in the crystal structure of form A is 10¹⁵.41 gmol, where Z=8. -1 Therefore, it is 1.632 gcm³. -3 The computational density is given. The interval group is determined to be C2 / c(no.15). An overview of the crystal data and crystal data acquisition parameters is provided in Table 3.

[0193] The fitting residual (R) is (3.88%).

[0194] Figure 1 shows the atomic displacement ellipse diagram of the asymmetric unit of form A, and Figure 2 shows the atomic labels.

[0195] The asymmetric unit shown in Figure 1 contains two molecules of formula I and one molecule of ethyl acetate, indicating that form A is hemiethyl acetate solvate.

[0196] Each of the molecules in Equation I is modeled as having one of the -CF3 parts being irregular.

[0197] The packing diagrams viewed parallel to crystal axes a, b, and c are shown in Figures 3-5, respectively. The hydrogen bonding environment around both 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate molecules in the asymmetric unit is shown in Figure 6. Hydrogen bonds occur between the amide nitrogen and amide oxygen of adjacent molecules and between the phosphate portions of adjacent molecules that form a one-dimensional chain below the b axis (Figure 7). The ethyl acetate molecule hydrogen bonds to the alternative phosphate molecule below the chain.

[0198] Figure 8 shows the calculated XRPD pattern of morphology A arising from a single crystal structure. In Figure 9, the experimental XRPD pattern of morphology A is superimposed on the calculated XRPD pattern. All peaks of the experimental pattern are represented in the calculated XRPD pattern.

[0199] Differences in intensity between calculated and experimental powder diffraction patterns are often due to preferred alignment. Preferred alignment tends to cause crystals to be aligned in a straight line at a certain angle. This preferred alignment of a sample can significantly affect peak intensity in the experimental powder diffraction pattern, but not peak position. Furthermore, some shifts in peak position between calculated and experimental powder diffraction patterns can be expected because the experimental powder diffraction pattern is corrected for ambient temperature, while the single-crystal data is corrected at 150K. Lower temperatures are used in single-crystal analysis to improve structural quality, but this causes crystal shrinkage and changes in unit cell parameters reflected in the calculated powder diffraction pattern. These shifts are particularly evident at high diffraction angles. Unit cell parameters derived from XRPD indexing are used to adjust the calculated pattern to room temperature.

[0200] Table 3. Crystal data and data acquisition parameters for morphology A. [Table 17]

[0201] Experimental section manufacturing The single crystals are grown by temperature cycling in heptane / alkyl 81:19 (v / v) solution.

[0202] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate was stirred in HCl with 1N HCl and evaporated. The solid was then slowly cooled from 74°C to room temperature in heptane / SiO2 81:19 (v / v) and allowed to stand at room temperature for 1 day. The solution was reheated to 71°C with occasional stirring (without agitation), slowly cooled from 71°C to room temperature, and allowed to stand at room temperature for 3 days. The solution was reheated to 71°C with shaking, slowly cooled from 71°C to room temperature over 5 hours or more (without shaking), and allowed to stand at room temperature for 1 day. The solution was reheated to 72°C with shaking, slowly cooled from 72°C to room temperature over 5 hours or more (without agitation), and allowed to stand at room temperature for 1 day. Thin needle-shaped crystals were observed.

[0203] Further experimental details regarding the synthesis are described in this paragraph. A solution of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (31.2 mg) derived from Example 2B in heptane / siRNA 81:19 (v / v, 2.35 mL) was heated to 74°C with stirring to obtain a clear solution. The solution was left on a heat block on a hot plate, the heat source was turned off, and the sample was allowed to cool slowly to ambient temperature. After standing at ambient temperature for 1 day, the sample was observed to consist of a clear liquid and a large amount of white solid. The sample was heated to 71°C, stirring occasionally by hand until a small amount of undissolved solid remained. The sample was allowed to cool slowly again to ambient temperature on a heat block on a hot plate without stirring. After standing at ambient temperature for 3 days, a white solid and a clear liquid phase were observed. The sample was reheated to 71°C with shaking using an orbital shaker until a small amount of undissolved solid remained. The orbital shaker is set to cool by 5°C every 30 minutes, and the sample is cooled to ambient temperature without shaking. After standing at ambient temperature for 1 day, a white solid and a transparent liquid phase are observed. The sample is reheated to 72°C while shaking until a small amount of undissolved solid remains, and the orbital shaker is set to the same parameters. After standing at ambient temperature for 1 day, the sample is observed to contain a transparent liquid and a white solid consisting of thin, birefringent needle-shaped crystals. The single crystal is collected and analyzed by single-crystal X-ray diffraction.

[0204] Data collection Approximately 0.563x0.089x0.039mm 3 Colorless needle-shaped crystals of C34H26Cl2F12N2O12P2[2(C15H9ClF6NO5P),C4H8O2] with a volume of 12H26Cl2F12N2O12P2[2(C15H9ClF6NO5P),C4H8O2] are placed on the fiber in a random arrangement. Preliminary tests and data acquisition are performed using a Rigaku SuperNova diffractometer with a copper anode microfocus shielded X-ray tube and a Dectris Pilatus3 R 200K hybrid pixel array detector with CuKα irradiation (λ=1.54184Å). Fine-tuning is performed using SHELXL-2014 (Sheldrick, GM, Acta Cryst., 2008, A64, 112-122). Cell consistency and array matrix for data acquisition are obtained from least-squares fine-tuning using 13054 reflection angle settings in the range of 4°<θ<77°. The spacing group is determined to be (no. 15) by CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). Data are collected at a temperature of 150K and a maximum diffraction angle (2θ) of 154.67°.

[0205] Data organization Frames were integrated using CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). A total of 21801 reflections were collected, of which 8486 were unique. Lorentz and polarization corrections were applied to the data. For CuKα irradiation, the linear absorption coefficient was 3.221 mm². -1 Numerical absorption correction is applied using CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). The transmission coefficient range is 0.424 to 0.888. A second attenuation correction is applied. The final coefficient, finely adjusted using least squares, is 0.000093 (13) (absolute units). Equivalent reflection intensities are averaged. The averaging coincidence coefficient is 2.92% based on intensity.

[0206] Structural analysis and fine-tuning The structure is elucidated using Olex2 (Dolomanov, OV et al., J. Appl. Cryst., 2009, 42, 339-341) and SHELXT (Sheldrick, GM, Acta Cryst., 2015, A71, 3-8) via a direct method. The remaining atoms are located in the subsequent difference Fourier synthesis. Fine-tuning is performed using SHELXL-2014 (Sheldrick, GM, Acta Cryst., 2008, A64, 112-122). Hydrogen atoms located on oxygen or nitrogen are fine-tuned independently. All other hydrogen atoms are included in the fine-tuning, but their presence on the bonding atom is suppressed. Function:

number

[0207] The weight w is

number

[0208] The scattering factors are obtained from "International Tables for Crystallography" (International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.14). For the 8486 reflections used in fine-tuning, F o 2 >2σ(F o 2 Only reflections with ) are used in the calculation of the fitted residual, R. A total of 7442 reflections are used in the calculation. The final cycle of fine-tuning includes 660 variable parameters, unloaded and loaded matching coefficients:

number

[0209] The standard deviation (goodness of fit) of the observed values ​​under unit load is 1.039. The highest peak in the final difference Fourier transform is 0.793 e / Å. 3 This is the height. The smallest negative peak is -0.537 e / Å. 3 It has a height of .

[0210] Computed X-ray powder diffraction (XRPD) patterns Using Mercury (Macrae, CF et al., J. Appl. Cryst., 2006, 39, 453-457), we generate calculated XRPD patterns for Cu irradiation and atomic arrangement, spacing, and unit cell parameters from single-crystal structures. Since the single-crystal data is collected at low temperatures (150K), peak shifts may be evident between the pattern calculated from the low-temperature data and the experimental powder diffraction pattern at room temperature, especially at large diffraction angles. To adjust the calculated XRPD pattern for room temperature, we use the unit cell obtained from XRPD indexing.

[0211] Atomic displacement ellipse diagram and filling diagram Atomic displacement ellipse diagrams are created using Mercury (Macrae, CF et al., J. Appl. Cryst., 2006, 39, 453-457). Atoms are represented by anisotropic thermal vibration ellipses with a 50% probability. Packing diagrams and further diagrams are also created using Mercury. Hydrogen bonds are represented by dashed lines.

[0212] Example 5: Preparation and determination of the single crystal structure of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hemisodium hemiacetonitrile solvate (hemisodium hemiacetonitrile solvate). introduction The structure of the single crystal is determined by single-crystal X-ray diffraction. Single-crystal data acquisition, structural analysis, and fine-tuning are not performed in accordance with cGMP specifications.

[0213] Results and discussion The monoclinic cell parameters and calculated volume are: 9.0319(2) Å, b=15.4685(4) Å, c=27.7447(5) Å, β=96.9157(15)° (α=γ=90°), V=3848.01(15) Å 3 The formula weight of the asymmetric unit in the crystal structure of hemisodium hemiacetonitrile solvate is 990.34 gmol, where Z=4. -1 Therefore, it is 1.709 gcm³. -3 The computational density is given. The interval group is determined to be P21 (no. 4). An overview of the crystal data and crystal data acquisition parameters is provided in Table 4.

[0214] The fitting residual (R) is 0.0509 (5.09%).

[0215] Figure 13 shows the atomic displacement ellipse of the hemisodium hemiacetonitrile solvate, and Figure 14 shows the atomic labels. The asymmetric unit shown in Figure 13 contains two molecules of formula I, two mono-deprotonated anions of formula I, two sodium cations, and two acetonitrile molecules. The packing diagrams viewed parallel to crystal axes a, b, and c are shown in Figures 15-17, respectively. As shown in Figure 18, the sodium atoms are arranged in a 5-array and, in addition to the acetonitrile nitrogen atom, form interactions with two phosphate oxygen atoms and two amide oxygen atoms from four different formula I molecules, forming a chain parallel to the a-axis. As shown in Figure 19, hydrogen bonds occur parallel to the b-axis between adjacent phosphate groups, creating a two-dimensional network.

[0216] Figure 20 shows the calculated XRPD pattern of the hemisodium hemiacetonitrile solvate derived from the single crystal structure.

[0217] Table 4. Crystal data and data acquisition parameters for hemisodium hemiacetonitrile solvate. [Table 18]

[0218] Experimental section manufacturing A 3:8 (v / v) acetonitrile (ACN):toluene solvent mixture is added to 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate while sonicating. The solution is filtered (through a 0.2 μm nylon filter). Crystals are grown from the solution by partial slow evaporation (in a loosely sealed vial). Long, thick needle-shaped crystals are observed.

[0219] Further experimental details regarding the synthesis are described in this paragraph. While sonicating, 28.6 mg of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A was added to acetonitrile / toluene 3:8 (v / v, 8 mL) to obtain a suspension containing undissolved solids. The suspension was filtered through a 0.2 μm nylon filter to obtain a clear solution. The cap of the solution was loosened for slow evaporation under environmental conditions. After partial evaporation over 15 days, the sample was observed to contain a clear liquid phase and a few colorless needle-shaped crystals at the bottom.

[0220] Data collection Approx. 0.25x0.10x0.09mm 3 C having volume 32 H 20 Cl2F 12 N3NaO 10 P2[C 15 H9ClF6NO5P, C 15 Colorless rod-shaped crystals of [H8ClF6NO5P, Na, C2H3N] are placed in a random arrangement on a nylon loop. Preliminary tests and data acquisition are performed using a Rigaku Rapid II diffractometer with confocal optics under CuKα irradiation (λ=1.54184Å). Fine-tuning is performed using SHELXL-2014 (Sheldrick, GM, Acta Cryst., 2015, C71, 3-8).

[0221] Cell consistency and array matrices for data acquisition are obtained from least-squares fine-tuning using 42,984 reflection angle settings in the range of 1° < θ < 72°. The spacing group is determined to be P21 (no. 4) from the following conditions: regular presence of 0k0k = 2n and subsequent least-squares fine-tuning. Data are collected at a minimum diffraction angle (2θ) of 144.28° and a temperature of 100K.

[0222] Data organization Frames were integrated using HKL3000 (Otwinowski, Z. et al., Methods Enzymol., 1997, 276, 307). A total of 42,984 reflections were collected, of which 13,870 were unique. Lorentz and polarization corrections were applied to the data. For CuKα irradiation, the linear absorption coefficient was 3.514 mm². -1 Numerical absorption correction using SCALEPACK (Otwinowski, Z. et al., Methods Enzymol., 1997, 276, 307) is applied. The transmission coefficient range is 0.538 to 0.743. A second attenuation correction is applied. The final coefficient, finely adjusted using least squares, is 0.000093(13) (absolute units). Equivalent reflection intensities are averaged. The averaging coincidence coefficient is 4.71% based on intensity.

[0223] Structural analysis and fine-tuning The structure is elucidated by a direct method using SHELXS-97 (Sheldrick, GM, Acta Cryst., 2015, C71, 3-8). The remaining atoms are positioned by subsequent difference Fourier synthesis. Fine-tuning is performed using SHELXL-2014 (Sheldrick, GM, Acta Cryst., 2008, A64, 112-122). The oxyhydrogen atoms are fine-tuned independently. All other hydrogen atoms are included in the fine-tuning, but their presence on the bonding atoms is suppressed. Function:

number

[0224] The weight w is

number

[0225] The scattering factors are obtained from "International Tables for Crystallography" (International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.14). For the 13870 reflections used in fine-tuning, F o 2 >2σ(F o 2 Only reflections with ) are used in the calculation of the fitted residual, R. A total of 7442 reflections are used in the calculation. The final cycle of fine-tuning includes 265 variable parameters, unloaded and load matching coefficients:

number

[0226] The standard deviation (goodness of fit) of the observed values ​​under unit load is 1.115. The highest peak in the final difference Fourier is 0.662 e / Å. 3 This is the height. The smallest negative peak is -0.452 e / Å. 3 It has a height of .

[0227] Computed X-ray powder diffraction (XRPD) patterns Using Mercury (Macrae, C.F. et al., J. Appl. Cryst., 2006, 39, 453 - 457), a calculated XRPD pattern is generated for the Cu irradiation and the atomic arrangement, space group, and unit cell parameters from the single crystal structure. Since the single crystal data is collected at low temperature (100 K), a peak shift may be evident between the pattern calculated from the low temperature data and the experimental powder diffraction pattern at room temperature, especially at large diffraction angles. To adjust the calculated XRPD pattern for room temperature, the unit cell obtained from XRPD indexing is used.

[0228] Ellipsoid of atomic displacement and packing diagram An ellipsoid of atomic displacement is created using Mercury (Macrae, C.F. et al., J. Appl. Cryst., 2006, 39, 453 - 457). The atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability. Packing diagrams and additional drawings are also created using Mercury. Hydrogen bonds are represented by dashed lines.

[0229] Example 6 2-{[3,5 - Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate p-dioxane solvate (Form I) 2-{[3,5 - Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate p-dioxane solvate is produced by rapid evaporation from p-dioxane.

[0230] Further experimental details for the synthesis are described in this paragraph. While sonicating, 2-{[3,5 - Bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (37.2 mg) from Example 2A is dissolved in p-dioxane (1 mL) to obtain a clear solution. The solution is filtered through a 0.2 μm nylon filter and evaporated to dryness from an open vial under environmental conditions. A slightly waxy white solid is observed.

[0231] 1The 1H NMR spectrum shows 0.5 moles of p-dioxane per mole of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate.

[0232] The XRPD pattern of the product (2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate p-dioxane solvate) is shown in Figure 22. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d interval, and peak intensities for the XRPD pattern shown in Figure 22 are provided above in Table F of Crystal Morphology 3.12. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°2θ, step size: 0.017°2θ, acquisition time: 721 sec, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0233] The XRPD pattern in Figure 22 indicates successful indexing and that the sample consists mainly or exclusively of the single-crystal phase. The unit cell volume obtained from the indexed solution is consistent with that of the hemidioxane solvate (capable of containing up to approximately 0.5 moles of p-dioxane).

[0234] Example 7: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate methanol solvate (Form L) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in MeOH / water 26:74(v / v, a w 0.89) Slowly cool from 63°C to room temperature and let stand at room temperature for 5 days. Store the solution in the freezer for 4 days. Next, equilibrium the solution with room temperature and vacuum filter it.

[0235] Further experimental details regarding the synthesis are described in this paragraph. A solution of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (30.0 mg) derived from Example 2A in MeOH / water 26:74 (v / v, 1.32 ml) was heated to 63°C with stirring to obtain a slightly turbid solution. The solution was filtered into a warm vial using a pre-warmed syringe and a 0.2 μm nylon filter. After filtration, the solution was kept slightly turbid. The solution was left on a heat block on a hot plate, the heat source was turned off, and the sample was allowed to cool slowly to ambient temperature without stirring. After standing at ambient temperature for 5 hours, a translucent jelly-like substance and a clear liquid were observed. The sample was stored in a freezer for 4 days. Upon removal from the freezer, a translucent gel was observed. Due to equilibrium to ambient temperature, the gel in the suspension became a liquid with a white solid. The obtained solid was recovered by vacuum filtration and air-dried on the filter under reduced pressure for 1 minute.

[0236] 1 The 1H NMR spectrum shows 0.6 moles of methanol per mole of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate.

[0237] The XRPD pattern of the product (2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate p-dioxane solvate) is shown in Figure 23. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d interval, and peak intensities for the XRPD pattern shown in Figure 23 are provided above in Table H of Crystal Morphology 4.10. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°2θ, step size: 0.017°2θ, acquisition time: 718 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0238] The XRPD pattern in Figure 23 shows successful indexing, indicating that the sample consists mainly or exclusively of a single-crystal phase. The unit cell volume obtained from the indexed solution is consistent with the presence of up to approximately 0.5 moles of MeOH.

[0239] The TGA thermogram of the product (1.2348 mg) is shown in Figure 29. There is almost no weight loss observed up to 90°C (a 0.5 wt% loss between 60°C and 90°C). A gradual weight loss of 4.2 wt% is observed between 90°C and 150°C, which is thought to correspond to a decrease in the solvent. If we assume that only MeOH volatilized, the weight loss corresponds to 0.6 moles of MeOH.

[0240] Example 8: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hydrate (Form N) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is slurryed in water (pH 5) at room temperature for 5 minutes. Slurrying is continued at room temperature for 24 hours. The solution is filtered by vacuum. The by-sample (part 1), which appears as a grayish-white paste, is removed. The remainder (part 2) is air-dried on a filter for 5 minutes. The pH of the water after slurrying is 1.6.

[0241] Further experimental details regarding the synthesis are described in this paragraph. Using 74.6 mg of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A, a suspension of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is prepared. The suspension is left to stir under ambient conditions. After 5 minutes, a viscous suspension is observed. The slurry is stirred for 24 hours, and a portion of the resulting solid is isolated by vacuum filtration while still moist. It is collected from the filter (Part 1). Another portion of the resulting solid is vacuum filtered and dried on the filter under reduced pressure for 5 minutes (Part 2).

[0242] The XRPD pattern of part 1 is shown in Figure 24. The XRPD pattern is also shown in Figure 44. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d interval and peak intensity for the XRPD pattern shown in Figure 23 are provided above in Table J of Crystal Morphology 5.14. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°2θ, step size: 0.017°2θ, acquisition time: 718 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0243] The XRPD pattern in Figure 24 (also shown in Figure 44) indicates successful indexing, showing that the sample consists mainly or exclusively of a single-crystal phase. The unit cell volume obtained from the indexed solution allows for the application of up to 3 moles of water to equation I for every 1 mole of equation I.

[0244] The XRPD pattern of part 2 also indicates that it is morphology N. The XRPD pattern of part 2 is shown in Figure 45. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 719 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0245] Part 2 DSC and TGA thermograms are obtained (DSC parameters: weight: 1.4620 mg, method: (-30)-250-10, T0C, instrument: 2920 MDSC V2.6A, TGA: 7.61023 mg). The overlay of the DSC and TGA thermograms is shown in Figure 26. The sample shows two separate weight loss stages of 3.5 wt% at 23°C–70°C and 3.6 wt% at 70°C–105°C, which corresponds to a series of overlapping endothermic events at 85°C, 91°C, and 95°C as measured by the DSC. Assuming that only water evaporated, each weight loss corresponds to 1 mole of water per mole of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, indicating that the sample consists of a dihydrate. A 0.6 wt% loss is observed in the TGA thermogram from 105°C–160°C. Following dehydration, a small endothermic reaction was observed at 118°C, which likely corresponds to the crystallization phenomenon. Relatively sharp endothermic reactions began at 169°C and continued until 178°C, which are thought to correspond to incidental melting and decomposition, as evidenced by the sharp drop in the TGA thermogram and the unstable thermal behavior observed in DSCs above 175°C. The possible melting initiation temperature is slightly lower than that for the anhydrous / non-solvated form B (169°C vs. 173°C for form B), suggesting that form N does not convert to form B during dehydration.

[0246] To further confirm the chemical composition of morphology N, the substance was slurryed in hexafluoroisopropanol (HFIPA) for 1 day, and XRPD was performed to induce a conversion to morphology B (containing a trace peak at 23°2θ). The XRPD pattern of the product is shown in Figure 49. The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD were: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°2θ, step size: 0.017°2θ, acquisition time: 718 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0247] Example 9: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hydrate (Form N) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is stirred with 1N HCl in SiO2 and evaporated. The solid is then slurryed in water at room temperature and filtered by vacuum.

[0248] Further experimental details regarding the synthesis are described in this paragraph. A suspension of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is prepared using 127.6 mg of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2B and water (5 mL). The suspension is stirred under ambient conditions to produce an opaque white suspension. The resulting solid is isolated by vacuum filtration and dried on the filter under reduced pressure for 4 minutes.

[0249] The XRPD pattern of the product indicates that it is morphology N. The XRPD pattern of the product is shown in Figure 46. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 721 sec, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0250] The DVS isotherm of the product is shown in Figure 27. The product shows a 30% weight loss at equilibrium with 5% relative humidity, which is thought to indicate a decrease in residual water. The presence of residual water is consistent with the >100 yield obtained from the production of the product. It is unclear whether possible unbound water is also decreasing at this equilibrium stage. As the relative humidity is increased from 5% to 95%, the sample increases by 3 wt%, exhibiting hygroscopicity. All of this weight loss is due to desorption with slight hysteresis observed between 35% and 5% relative humidity. The XRPD of the material after DVS shows no change in morphology. The XRPD of the material after DVS is shown in Figure 54. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 720 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0251] Karl Fischer (KF) analysis reveals that the product contains 14.2% moisture, equivalent to 4.2 moles of water. Some of the measured moisture may be due to residual water in the sample. The percentage moisture content by KF is lower than the percentage weight loss observed in the DVS test at % relative humidity, which is likely due to some drying of the analysis and / or preparation for the KF analysis.

[0252] Example 10: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form B) Hexafluoroisopropanol (HFIPA) is added to 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, the solution is refrigerated for 2 months, and then vacuum filtered.

[0253] Further experimental details regarding the synthesis are described in this paragraph. 29.3 mg of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A is combined with hexafluoroisopropanol (HFIPA) under sonication to obtain a concentrated, opaque suspension. The sample is stored refrigerated for two months, after which the solid is recovered by vacuum filtration, and the suspension is left agitated under ambient conditions to produce an opaque white suspension. The obtained solid is isolated by vacuum filtration and dried on a filter under reduced pressure for 0.5–1 minute.

[0254] The solvent is 1 It was not detected by 1H NMR, indicating that it is a non-solvable substance.

[0255] The XRPD pattern of the product is shown in Figure 21 (morphology B + trace peak at approximately 23°θ). The XRPD pattern is also shown in Figure 37. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The 2θ values, d interval and peak intensity for the XRPD pattern shown in Figure 21 are provided above in Table D of Crystal Morphology 6.11. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°²θ, step size: 0.017°²θ, acquisition time: 718 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0256] The XRPD pattern in Figure 21 (also shown in Figure 37) shows successful indexing, indicating that the sample consists mainly or exclusively of a single-crystal phase. However, a further broad peak at approximately 23°2θ is present in all XRPD patterns of morphology B discussed herein, and the peak position does not coincide with that given by the indexed solution, indicating that the morphology B sample contains further unknown phases. The unit cell volume obtained from the indexed solution is consistent with formula I of the anhydrous / non-solvate.

[0257] Figure 40 shows an overlay of DSC and TGA thermograms (DSC parameters: weight: 1.3670 mg, method: (-30)-250-10, T0C, instrument: 2920 MDSC V2.6A, TGA: 2.86113 mg). The TGA thermogram shows a decrease of 0.7 wt% between 23°C and 150°C. The desolvation endothermy of Broad was not observed by DSC, which is consistent with the anhydrous / non-solvated substance. The DSC thermogram shows a rapid endothermic reaction at 177°C (starting at 173°C), which is thought to correspond to melting and simultaneous decomposition, as evidenced by the unstable thermal behavior by DSC and the rapid weight loss above approximately 150°C by TGA.

[0258] Example 11: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form B) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is stirred with 1N HCl in siRNA and evaporated. Then, acetonitrile is added to the solid while stirring for several minutes. MeOH is added while stirring. Toluene is added while stirring (toluene / acetonitrile / MeOH 24:6:1 v / v / v). Partial evaporation is performed. The liquid phase is filtered and the solid is discarded. Evaporate under N2 for 5 minutes. Hexafluoroisopropanol (HFIPA) is added to the solid. Slurry is allowed to form at room temperature for 1 day, then vacuum filter is performed.

[0259] Further experimental details regarding the synthesis are described in this paragraph. While stirring, 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (86.9 mg) derived from Example 2B is dissolved in acetonitrile to obtain a clear solution. After stirring for several minutes, a precipitate is observed. While stirring, MeOH (0.1 mL) is added to obtain a clear solution. Then, while stirring, toluene (2.4 mL) is added (toluene / acetonitrile / MeOH 24:6:1 v / v / v), and a clear solution is observed. The solution is allowed to stand and partially evaporated for 1 day from a vial covered with perforated aluminum foil to obtain a clear liquid phase with a small amount of solid at the surface and bottom of the solvent. The liquid phase is filtered through a 0.2 μm nylon filter to obtain a clear solution, and the solid is discarded. The filtered solution is connected to a rotary evaporator equipped with a water bath at 60-69°C. After evaporation for 30 minutes, no significant volume decrease is observed. The solution is then evaporated under an N2 stream for 5 minutes until no liquid remains visible in between. The resulting white solid is combined with hexafluoroisopropanol (HFIPA) (2 ml), and an insoluble solid is present. The slurry is stirred at ambient temperature for 1 day to produce an opaque white suspension. The solid is isolated by vacuum filtration and dried on the filter under reduced pressure for 2 minutes.

[0260] The XRPD pattern of the product indicates that it is morphology B (morphology B + a small peak at approximately 23°θ). The XRPD pattern of the product is shown in Figure 41. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 716 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0261] The hygroscopic properties of form B are evaluated by DVS and by the load at increased relative humidity (see Example 12 for the increased relative humidity).

[0262] The DVS isotherm for morphology B is shown in Figure 28. The substance shows a decrease of 0.04 wt% at 5% relative humidity. The substance exhibits relatively low kinetic hygroscopicity, absorbing 0.6 wt% water vapor through absorption between 5% and 95% relative humidity. All of this weight loss is due to desorption with the noted slight hysteresis. XRPD analysis of the substance after DVS shows that its morphology has not changed. The XRPD pattern of the substance after DVS is shown in Figure 55. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°²θ, step size: 0.017°²θ, acquisition time: 719 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0263] Example 12: Form B and Form N 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and hexafluoroisopropanol (HFIPA) are prepared as a slurry at room temperature for 4 days, and then filtered under vacuum.

[0264] The XRPD of the product shows morphology B (morphology B + a small peak at approximately 23°θ). The XRPD pattern of the product is shown in Figure 42. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°²θ, step size: 0.017°²θ, acquisition time: 719 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0265] The product was loaded at 97% relative humidity for 7 days, resulting in partial conversion to form N. The partial conversion after 7 days, as noted, indicates that form B completely transforms into hydrate form N after a longer period.

[0266] The product was converted to morphology N by slurrying with water at room temperature for 7 days, and then vacuum filtered. The XRPD pattern of the product is shown in Figure 50. The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD were: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 715 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0267] The slurrying process was repeated for 19 hours, and the rate at which the transformation occurred and morphology N reappeared was measured, indicating that the morphology changed within 19 hours (the starting material is the product derived from this example and Example 21). The XRPD pattern of the product is shown in Figure 51. The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD were: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 719 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0268] Example 13: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate Step 1: N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide Under a nitrogen atmosphere, 5-chlorosalicylic acid (86.5 g, 501.6 mmol, 1 equivalent) is dissolved in toluene (1500 mL), and phosphorus trichloride (22 ml, 250.82 mmol, 0.5 equivalent) is added in small amounts over 15 minutes at room temperature. Then, 3,5-bis-trifluoromethylphenylamine (100 g, 436.4 mmol, 0.87 equivalents) is added to the reaction mixture in one lot at room temperature. The reaction mixture is heated to 105 ± 5 °C and stirred at this temperature for a further 16 hours. After the reaction is complete by TLC (10% ethyl acetate:hexane), the reaction mixture is then cooled to room temperature. The reaction mixture is quenched with an aqueous solution of NaHCO3 (50 g) (800 mL), and the resulting solution is stirred for 15-20 minutes. Both the organic and aqueous layers are separated and collected. The upper organic layer is washed with an aqueous solution of concentrated hydrochloric acid (25 mL) (400 mL) and brine (400 mL), and dried over Na₂SO₄. The organic layer is filtered and concentrated under reduced pressure to obtain a white solid. Heptane (500 mL) is added to the white solid, and the resulting suspension is stirred at room temperature for 30 minutes. It is then filtered to obtain N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide as a white solid (150 g). HPLC = 99%

[0269] Step 2: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate Dissolve N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (145 g, 377.9 mmol, 1 equivalent) in CH3CN (1450 mL). Under stirring conditions, at room temperature, add DMAP (2.77 g, 22.67 mmol, 0.06 equivalents), N,N-diisopropylethylamine (DIPEA) (97.74 g, 755.98 mmol, 2 equivalents), and CCl4 (290.7 g, 1889.9 mmol, 5 equivalents) in the above solution in this order. Cool the reaction mixture to 0°C and control the temperature to below 2°C, then add a solution of phosphite reagent ((CH3)3SiCH2CH2O)2P(O)H) (160.7 g, 599.9 mmol, 1.5 equivalents) in CH3CN (145 mL) dropwise over 30 minutes. The reaction mixture is heated to room temperature and stirred at room temperature for 22 hours. After the reaction is complete using TLC (10% ethyl acetate:hexane), water (2.175 L) is added to the reaction mixture, and the resulting mixture is extracted twice with ethyl acetate (2.175 L and 1.160 L). The combined organic extract is washed with brine (1.450 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to obtain the crude substance (271 g), which is used directly in the next step. HPLC = 82.9%

[0270] Step 3: Mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate (270 g) is added to a mixture of TFA:water (5:1, 2.1 L). The reaction mixture is stirred at room temperature for 3 hours. After the reaction is complete with TLC (10% ethyl acetate:hexane), the reaction mixture is poured into a mixture of toluene:water (20:30, 13.5 L) and stirred at room temperature for 1 hour. The reaction mixture is filtered and washed with toluene (0.54 L) to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white solid (160 g).

[0271] Step 4 Purification Add the crude solid (160 g, 345.05 mmol, 1 equivalent) to an aqueous solution of NaOH (80 g, 2000 mmol, 5.8 equivalents) (4 L) and stir at room temperature for 45 minutes. Extract the aqueous solution twice with ethyl acetate (2 x 1.6 L). Acidify the aqueous solution to pH 1 using concentrated HCl (230-250 mL) and extract twice with ethyl acetate (2 x 1.6 L). Dry the combined ethyl acetate extract obtained after acidification over sodium sulfate and concentrate under reduced pressure to obtain 140 g of a colorless oily substance. Dissolve the oily substance in ethyl acetate (160 mL) and stir at room temperature for 30 minutes. While continuing to stir, add n-heptane (1.44 L). Stir the reaction mixture at room temperature for 3 hours and filter. The solid was washed with n-heptane (80 mL) and dried under vacuum for 30 minutes to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white solid (124 g). NMR showed a peak for acetic acid. HPLC = 98.8%

[0272] Step 5 Re-purification Dissolve the grayish-white solid (124 g) in ethyl acetate (124 mL), stir at room temperature for 30 minutes, and add n-heptane (1.11 L) while stirring. Stir the reaction mixture at room temperature for 3 hours and filter. Wash the solid with n-heptane (62 ml), dry under vacuum for 30 minutes to obtain phosphate mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl]ester as a white solid (103 g).

[0273] Example 14: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hydrate (Form N) Step 1: N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide Under a nitrogen atmosphere, 5-chlorosalicylic acid (86.5 g, 501.6 mmol, 1 equivalent) is dissolved in toluene (1500 mL), and phosphorus trichloride (22 ml, 250.82 mmol, 0.5 equivalent) is added in small amounts over 15 minutes at room temperature. Then, 3,5-bis-trifluoromethylphenylamine (100 g, 436.4 mmol, 0.87 equivalents) is added to the reaction mixture in one lot at room temperature. The reaction mixture is heated to 105 ± 5 °C and stirred at this temperature for a further 16 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete by TLC (10% ethyl acetate:hexane), the reactants are then cooled to room temperature. The reaction mixture is quenched with an aqueous solution of NaHCO3 (50 g) (800 mL), and the resulting solution is stirred for 15-20 minutes. Both the organic and aqueous layers are separated and collected. The upper organic layer is washed with an aqueous solution of concentrated hydrochloric acid (25 mL) (400 mL) and brine (400 mL), and dried over Na₂SO₄. The organic layer is filtered and concentrated under reduced pressure to obtain a white solid. Heptane (500 mL) is added to the white solid, and the resulting suspension is stirred at room temperature for 30 minutes. It is then filtered to obtain N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide as a white solid (150 g). HPLC = 99%

[0274] Step 2: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate Preparation of bis(2-(trimethylsilyl)ethyl) hydrogen phosphite reagent Under a nitrogen atmosphere, at 0°C, triethylamine (228g, 2.255mol, 2.0equivalents) is added to a 7.0L solution of cooled trimethylsilylethanol (400g, 3.382mol, 3.0equivalents) in DCM. PCl3 (154.8g, 1.127mol, 1.0equivalent) is then added in small amounts over 45 minutes at 0-10°C. The reaction mixture is stirred at 0°C for 1 hour. The reaction mixture is allowed to return to room temperature. DM water (2.0L) is added to the reaction mixture and stirred at room temperature for 1 hour. The lower organic layer is separated, and the upper aqueous layer is extracted with DCM (1.6L). The combined organic extracts are washed with DM water (2.0L) and dried over Na2SO4. The organic layer is concentrated at 45°C under vacuum, and then degassed at 4°C for 30 minutes to obtain a crude phosphite reagent as a light brown oily substance (450.0 g), which is then stored at 0-5°C.

[0275] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate Dissolve N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (150 g, 391 mmol, 1 equivalent) in CH3CN (1500 mL). Under stirring conditions at room temperature, add DMAP (2.86 g, 23.46 mmol, 0.06 equivalents), DIPEA (101.07 g, 782 mmol, 2 equivalents), and CCl4 (300 g, 1955 mmol, 5 equivalents) in this order to the above solution. Cool the reaction mixture to 0°C and control the temperature to below 2°C, then dropwise add a solution of phosphite reagent {((CH3)3SiCH2CH2O)2P(O)H)} (166 g, 586.5 mmol, 1.5 equivalents) in CH3CN (150 mL) over 30 minutes. Raise the reaction mixture to room temperature and stir at room temperature for 22 hours. The reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete using TLC (10% ethyl acetate:hexane), water (2.25 L) is added to the reaction mixture, and the resulting mixture is extracted twice with ethyl acetate (2.25 L and 1.2 L). The combined organic extract is washed with brine (1.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to obtain a crude substance (285 g), which is used directly in the next step.

[0276] Step 3: Mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate (285 g) is added to a mixture of TFA:water (5:1, 2.2 L). The reaction mixture is stirred at room temperature for 3 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete by TLC (10% ethyl acetate:hexane), the reaction mixture is poured into a mixture of toluene:water (20:30, 14.25 L) and stirred at room temperature for 1 hour. The reaction mixture is filtered and washed with toluene (0.57 L) to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white wet solid (212 g).

[0277] Divide the wet solid (212g) into two equal parts.

[0278] The first wet portion (106g) was dried at room temperature for 14 hours to obtain a dry solid (88g) as a grayish-white solid. HPLC = 96.0%

[0279] The second wet portion (106 g) is dissolved in ethyl acetate (212 ml), heated to 50°C to completely dissolve the solid, then cooled to room temperature, and n-heptane is added under stirring conditions. The suspension is stirred at room temperature for 3 hours, filtered, and the precipitate is washed with n-heptane (55 mL) to obtain 98 g of wet solid, which is dried at room temperature for 9 hours to obtain 78 g as a grayish-white solid. HPLC = 99.1%

[0280] Several additional peaks are still present in the NMR spectrum.

[0281] Step 4(i) Purification Crude solid (25g from the first part of step 3 + 25g from the second part of step 3, total 50g, 107.82 mmol, 1 equivalent) is added to an aqueous solution of NaOH (25g, 625 mmol, 5.8 equivalents) (1.25L) and stirred at room temperature for 45 minutes. The aqueous solution is extracted twice with ethyl acetate (2 x 0.5L) to remove impurities. The aqueous solution is then acidified with concentrated HCl (70-80mL) and extracted twice with ethyl acetate (2 x 0.5L). The combined ethyl acetate extract obtained after acidification is dried over sodium sulfate and concentrated under reduced pressure to obtain 41g of a colorless oily substance. The oily substance is dissolved in ethyl acetate (50mL) and stirred at room temperature for 30 minutes. While stirring, n-heptane (0.450L) is added. The reaction mixture is stirred at room temperature for 3 hours and then filtered. The solid was washed with n-heptane (25 mL) and dried under vacuum for 30 minutes to obtain the product, mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate, as a grayish-white solid (25 g). HPLC = 96.7%

[0282] Step 4(ii) Purification of the remaining amount (110g) from Step 3 Crude solid (60g from the first part of step 3 + 50g from the second part of step 3, total 110g, 237.22 mmol, 1 equivalent) is added to an aqueous solution of NaOH (55g, 1375 mmol, 5.8 equivalents) (1.75L) and stirred at room temperature for 45 minutes. The aqueous solution is extracted twice with ethyl acetate (2 x 1.1L) to remove impurities. The aqueous solution is then acidified with concentrated HCl (160-180mL) and extracted twice with ethyl acetate (2 x 1.1L). The combined ethyl acetate extract obtained after acidification is dried over sodium sulfate and concentrated under reduced pressure to obtain 105g of a colorless oily substance. The oily substance is dissolved in ethyl acetate (110mL) and stirred at room temperature for 30 minutes. While stirring, n-heptane (0.990L) is added. The reaction mixture is stirred at room temperature for 3 hours and then filtered. The solid was washed with n-heptane (55 mL) and dried under vacuum for 30 minutes to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl]phosphate product-1 (65 g). The precipitate formed in the filtrate was filtered again to obtain product-2 as a white solid (11 g). NMR showed a peak for acetic acid. HPLC = 95.8%

[0283] Step 5 Re-purification Dissolve the grayish-white solid (product-1 and product-2) (76 g) in ethyl acetate (76 mL), heat to 50°C to completely dissolve the solid, stir at room temperature for 30 minutes, and add n-heptane (684 mL) while stirring. Stir the reaction mixture at room temperature for 3 hours and filter. Wash the solid with n-heptane (38 mL), dry under vacuum for 30 minutes to obtain the pure product, re-purified mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl]ester phosphate, product-1 (35 g), and re-purified product-2 as a white solid (30 g) by filtering the precipitate that forms again in the filtrate. Re-purified product-1 HPLC = 97.6%, re-purified product-2 HPLC = 99.5%

[0284] Process 6: Water Treatment The re-purified product-1 (7 g out of 35 g) is a grayish-white solid suspended in DM water (140 mL). The suspension is stirred at room temperature for 2 hours, filtered, and the solid is washed with DM water (35 mL). It is dried under vacuum for 1 hour to obtain ethyl acetate-free phosphate mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl]ester as a white solid (6 g). HPLC = 99.5%

[0285] The XRPD patterns of the products are shown in Figure 52 (morphology N and unknown substance). The XRPD patterns were obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD were: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 719 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0286] A TGA thermogram of the product (3.3710 mg) is obtained. The sample shows two distinct weight loss stages: a 3.7% weight loss between 29°C and 70°C, and another 3.7% weight loss between 70°C and 105°C. A 1.3% weight loss is observed in the TGA thermogram between 105°C and 160°C.

[0287] Example 15 2.5 to 5 equivalents of tris(hydroxymethyl)aminomethane are added to the crystalline 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (for example, any of crystalline form 1 or later, crystalline form 2 or later, crystalline form 3 or later, crystalline form 4 or later, crystalline form 5 or later, or crystalline form 6 or later).

[0288] Add water to the mixture and stir or sonicate the solution. Obtain a stable 10 mg / ml to 20 mg / ml solution for at least 24 hours.

[0289] The HPLC conditions for assaying the stability of compositions formed from crystalline 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate and a base, such as tris(hydroxymethyl)aminomethane, are as follows: HPLC conditions: c18 SB Agilent 4.6x125mm column, 3 or 5u. 1.5 mL of 10% to 100% acetonitrile per minute (containing a solution of 2 g of ammonium acetate per 4 L of water) Waters 2695 HPLC running Millennium 32 software No baseline deduction

[0290] Example 16: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate (Form A) Step 1: N-(3,5-bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide [ka] Under a nitrogen atmosphere, 5-chlorosalicylic acid (21.9 g, 126.9 mmol, 1.0 equivalent) is dissolved in toluene (375.0 mL), and phosphorus trichloride (5.5 mL, 63.45 mmol, 0.5 equivalent) is added in small portions over 15 minutes at room temperature. Then, 3,5-bis-trifluoromethylphenylamine (25.0 g, 110.4 mmol, and 0.87 equivalents) is added to the reaction mixture in one lot at room temperature. The reaction mixture is heated to 105 ± 5 °C and stirred at this temperature for a further 16 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete by TLC (10% ethyl acetate:hexane), the reactants are cooled to room temperature. The reaction mixture is poured onto a silica gel (0.5 kg) column, the solvent is evaporated, and then the column is eluted with ethyl acetate (1.5 L) to obtain a white solid. The solid obtained in this manner is suspended in n-heptane (150.0 mL) and stirred at room temperature for 1 hour. The suspension is filtered through a Buchner funnel to obtain N-(3,5-bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide as a white solid (31.0 g). HPLC = 98.9%

[0291] Step 2: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylbis(2-(trimethylsilyl)ethyl)phosphate [ka] Preparation of bis(2-(trimethylsilyl)ethyl) hydrogen phosphite reagent [ka] Under a nitrogen atmosphere, at 0°C, add triethylamine (28.5g, 281.8mmol, 2.0 equivalents) to a 0.875L solution of cooled trimethylsilylethanol (50.0g, 422.8mmol, 3.0 equivalents) in DCM. Then, add PCl3 (19.3g, 281.07mmol, 1.0 equivalent) in small amounts over 45 minutes at 0-10°C. Stir the reaction mixture at 0°C for 1 hour. Allow the reaction mixture to return to room temperature. Add DM water (0.25L) to the reaction mixture and stir at room temperature for 1 hour to separate the layers. Extract the aqueous layer with DCM (0.25L). Wash the combined organic extracts with DM water (0.25L) and dry over Na2SO4. The organic layer is concentrated at 45°C under vacuum, and degassed at 45°C for 30 minutes to obtain a crude phosphite reagent as a light brown oily substance (45.0 g), which is then stored at 0-5°C.

[0292] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylbis(2-(trimethylsilyl)ethyl)phosphate Dissolve N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (30.0 g, 78.19 mmol, 1.0 equivalent) in CH3CN (300.0 mL). While stirring, add DMAP (0.57 g, 4.69 mmol, 0.06 equivalent), DIPEA (27.2 mL, 156.38 mmol, 2.0 equivalent), and CCl4 (60.1 g, 390.96 mmol, 5.0 equivalent) to the above solution in this order at room temperature. Cool the reaction mixture to 0°C and control the temperature to below 2°C, then dropwise add a solution of phosphite reagent (33.10 g, 117.28 mmol, 1.5 equivalent) in CH3CN (30 mL) over 30 minutes. Raise the reaction mixture to room temperature and stir at room temperature for 22 hours. The reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete using TLC (10% ethyl acetate:hexane), the reaction mixture is diluted with ethyl acetate (1.0 L) and water (1.0 L), and the layers are separated. The aqueous phase is extracted twice with ethyl acetate (2 x 0.5 L). The combined organic extract is washed with brine (0.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to obtain the crude substance (56.0 g), which is used directly in the next step.

[0293] Step 3: Mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl] phosphate [ka] Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate (55.0 g, 82.81 mmol, 1.0 equivalent) is added to a mixture of TFA:water (5:1, 428.0 mL). The reaction mixture is stirred at room temperature for 3 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). The reaction mixture is concentrated under vacuum at less than 70°C to remove volatile solvents. The residue is added to an aqueous solution of NaOH (18.0 g, 450.0 mmol, and 5.4 equivalents) (0.55 L) and stirred at room temperature for 15 minutes. The aqueous solution is washed twice with ethyl acetate (2 x 0.55 L) to remove impurities. The aqueous solution is then acidified with concentrated HCl (35.0 mL) and extracted twice with ethyl acetate (2 x 0.825 L). The combined ethyl acetate extract obtained after acidification is dried over sodium sulfate and concentrated under reduced pressure to obtain 35 g of a colorless oily substance. The oily substance is dissolved in ethyl acetate (35 mL) and n-heptane (175.0 mL) is added while stirring. The reaction mixture is stirred at room temperature for 3 hours and then filtered. The solid is washed with n-heptane (55 mL) and dried under vacuum for 30 minutes to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white solid (12.0 g). HPLC = 97.7%

[0294] The XRPD pattern of the product is shown in Figure 38 (Form A). The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 720 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0295] Example 17: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate (Form A + trace peak) Step 1: N-(3,5-bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide Under a nitrogen atmosphere, 5-chlorosalicylic acid (21.9 g, 126.9 mmol, 1.0 equivalent) is dissolved in toluene (375.0 mL), and phosphorus trichloride (5.5 mL, 63.45 mmol, 0.5 equivalent) is added in small portions over 15 minutes at room temperature. Then, 3,5-bis-trifluoromethylphenylamine (25.0 g, 110.4 mmol, and 0.87 equivalents) is added to the reaction mixture in one lot at room temperature. The reaction mixture is heated to 105 ± 5 °C and stirred at this temperature for a further 16 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete by TLC (10% ethyl acetate:hexane), the reactants are cooled to room temperature. The reaction mixture is poured onto a silica gel (0.5 kg) column, the solvent is evaporated, and then the column is eluted with ethyl acetate (1.5 L) to obtain a white solid. The solid obtained in this manner is suspended in n-heptane (150.0 mL) and stirred at room temperature for 1 hour. The suspension is filtered to obtain N-(3,5-bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide as a white solid (31.0 g). HPLC = 98.9%

[0296] Step 2: 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate Preparation of bis(2-(trimethylsilyl)ethyl) hydrogen phosphite reagent Under a nitrogen atmosphere, at 0°C, add triethylamine (28.5g, 281.8mmol, 2.0 equivalents) to a 0.875L solution of cooled trimethylsilylethanol (50.0g, 422.8mmol, 3.0 equivalents) in DCM. Then, add PCl3 (19.3g, 281.07mmol, 1.0 equivalent) in small amounts over 45 minutes at 0-10°C. Stir the reaction mixture at 0°C for 1 hour. Allow the reaction mixture to return to room temperature. Add DM water (0.25L) to the reaction mixture and stir at room temperature for 1 hour to separate the layers. Extract the aqueous layer with DCM (0.25L). Wash the combined organic extracts with DM water (0.25L) and dry over Na2SO4. The organic layer is concentrated at 45°C under vacuum, and degassed at 45°C for 30 minutes to obtain a crude phosphite reagent as a light brown oily substance (44.0 g), which is then stored at 0-5°C.

[0297] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate Dissolve N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (30.0 g, 78.19 mmol, 1.0 equivalent) in CH3CN (300.0 mL). While stirring, add DMAP (0.57 g, 4.69 mmol, 0.06 equivalent), DIPEA (27.2 ml, 156.38 mmol, 2.0 equivalent), and CCl4 (60.1 g, 390.96 mmol, 5.0 equivalent) to the above solution in this order at room temperature. Cool the reaction mixture to 0°C and control the temperature to below 2°C, then dropwise add a solution of phosphite reagent (33.10 g, 117.28 mmol, 1.5 equivalent) in CH3CN (30 mL) over 15 minutes. Raise the reaction mixture to room temperature and stir at room temperature for 22 hours. The reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After the reaction is complete using TLC (10% ethyl acetate:hexane), the reaction mixture is diluted with ethyl acetate (1.0 L) and water (1.0 L), and the layers are separated. The aqueous phase is extracted twice with ethyl acetate (2 x 0.5 L). The combined organic extract is washed with brine (0.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to obtain the crude substance (56.0 g), which is used directly in the next step.

[0298] Step 3: Mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl] phosphate Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl) phosphate (55.0 g, 82.81 mmol, 1.0 equivalent) is added to a mixture of TFA:water (5:1, 428.0 mL). The reaction mixture is stirred at room temperature for 3.0 hours. The progress of the reaction is monitored by TLC (mobile phase: 10% ethyl acetate in hexane). The reaction mixture is concentrated under vacuum at less than 70°C to remove volatile solvents. The residue is added to an aqueous solution of NaOH (18.0 g, 450.0 mmol, and 5.4 equivalents) (0.55 L) and stirred at room temperature for 15 minutes. The aqueous solution is washed twice with ethyl acetate (2 x 0.55 L) to remove impurities. The aqueous solution is then acidified with concentrated HCl (35.0 mL) and extracted twice with ethyl acetate (2 x 0.825 L). The combined ethyl acetate extract obtained after acidification was dried over sodium sulfate and concentrated under reduced pressure to obtain 38.0 g of a colorless oily substance. The crude oily product was dissolved in ethyl acetate (15.0 mL) and n-heptane (175.0 mL) was added while stirring. The reaction mixture was stirred at room temperature for 3.0 hours and filtered. The solid was washed with n-heptane (35.0 mL) and dried under vacuum for 30 minutes to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white solid (12.4 g). HPLC = 96.4%

[0299] The XRPD patterns of the product are shown in Figure 39 (morphology A and unknown component). The XRPD patterns were obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD were: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 721 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0300] Example 18: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hydrate (Form N) 165.0 g, 0.355 mol, 1.0 equivalent of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is added to an aqueous solution of NaOH (82.5 g, 2.062 mol, 5.8 equivalents) (4.12 L), and the mixture is stirred at room temperature for 45 minutes. The aqueous solution is washed twice with ethyl acetate (2 x 1.65 L) to remove impurities. The combined organic layers are extracted with water (0.82 L). The combined aqueous layer is acidified with concentrated HCl (230.0-250.0 mL) and extracted twice with ethyl acetate (2 x 1.65 L). The combined ethyl acetate extract obtained after acidification is dried over sodium sulfate and concentrated under reduced pressure to obtain 140.0 g of a colorless oily substance. The oily substance is dissolved in ethyl acetate (165.0 mL) and stirred at room temperature for 30 minutes. While stirring, add n-heptane (82.0 mL). Stir the mixture at room temperature for 3.0 hours and filter. Wash the solid with n-heptane (82.0 mL), dry under vacuum for 30 minutes to obtain mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chlorophenyl] phosphate as a grayish-white solid (118.0 g). HPLC = 95.0%

[0301] Dissolve the grayish-white solid (108.0 g) in water (2.36 L). Stir the mixture at room temperature for 3.0 hours and filter. Wash the solid with water (0.590 L) and dry under vacuum for 1.0 hour to obtain a pure wet product. Dry the wet solid at room temperature for 3 days and 17 hours to obtain the dried product as a grayish-white solid (95.0 g). HPLC = 99.4%

[0302] The grayish-white solid (95.0 g) was stirred with toluene (0.95 L) for 30 minutes and filtered. Washed with solid toluene (95.0 mL), mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl] phosphate was obtained as a white solid (90.0 g). HPLC = 99.4%

[0303] The XRPD pattern of the product is shown in Figure 48 (morphology N). The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 721 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0304] Example 19: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form B) A concentrated solution of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A in 2,2,2-trifluoroethanol (TFE) was capped and slowly cooled from 73°C to room temperature, then allowed to stand at room temperature for 3 days. The solution was stored at room temperature for 29 days, after which it was filtered by vacuum. The XRPD of the product indicates that the product is in morphology B (morphology B + a trace peak at approximately 23°θ, PO). The XRPD of the product is shown in Figure 43. The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.01-39.98°²θ, step size: 0.017°²θ, acquisition time: 718 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0305] Example 20: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate hydrate (Form N) A saturated solution is prepared by adding 3 mL of water to 75 mg of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2A. The sample is stirred (500 rpm) at ambient temperature for 24 hours. After 24 hours, the sample is centrifuged (13000 rpm for 5 minutes), and the supernatant is filtered through a 0.45 μm PVDF filter. Figure 57 shows the XRPD pattern of the solid derived from the centrifuged sample, indicating that the solid is morphology N. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.98°²θ, step size: 0.017°²θ, acquisition time: 720 seconds, scan speed: 3.2° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 second, mode: transmission.

[0306] Example 21: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form B) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2B was slurryed in hexafluoroisopropanol (HFIPA) for 4 days and then vacuum filtered. The XRPD of the product indicates that the product is in morphology B (morphology B + a trace peak at approximately 23°θ, PO). The XRPD pattern of the product is shown in Figure 53. The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 719 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0307] Example 22 Tris base and powdered 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl solvate (Form A) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is powdered with a Tris base. The upper XRPD pattern in Figure 47 shows morph A powdered with the Tris base. The XRPD is also shown in Figure 56. The XRPD pattern is consistent with the physical mixture of morph A and the Tris base, indicating that the morphology does not change with the formulation. The XRPD pattern is obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 717 sec, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0308] Example 23 Drying test of form A Several attempts were made to dry morphology A. Strict conditions were initially selected, within the high-temperature range (90°C) where TGA weight loss was observed. Drying at 80°C under vacuum for one day yielded a brown solid fixed to the vial. A 30% weight loss was calculated by gravimetric analysis, and the resulting solid did not appear crystalline under an optical microscope.

[0309] We will attempt drying tests under milder conditions. We will begin the experiment by drying under vacuum at ambient temperature. Since no significant gravimetric weight change is measured, we will gradually increase the temperature and monitor the weight. After 6 hours at 63-65°C, a small weight loss was observed, so we will hold the sample at this temperature in a vacuum oven for 1 day, obtaining a gravimetric weight loss of 11%. The resulting light brown solid adheres to the vial and cannot be confirmed as crystalline by optical microscopy. These experiments indicate that vacuum drying of morphology A at elevated temperatures tends to cause decomposition and collapse of the crystalline structure.

[0310] Example 24: Form A 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2B was crush-cooled in a freezer from a heptane / siRNA (80:20, v / v) solution at 75°C, and then allowed to stand in the freezer for 3 hours. The liquid phase was decanted, and the solid was dried briefly under N2. The XRPD pattern of the product is shown in Figure 58 (morphology A, PO). The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 718 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0311] The 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate derived from Example 2B was rapidly cooled to room temperature from a heptane / siRNA (80:20, v / v) solution at 75°C, and then allowed to stand at room temperature for 3 hours. The liquid phase was decanted, and the solid was dried briefly under N2. The XRPD pattern of the product is shown in Figure 59 (morphology A, PO). The XRPD pattern was obtained as described in the general XRPD method of Example 1. The data acquisition parameters for the XRPD are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray tube: Cu (1.54059 Å), voltage: 45 kV, amperage: 40 mA, scan range: 1.00-39.99°²θ, step size: 0.017°²θ, acquisition time: 718 seconds, scan speed: 3.3° / min, slit: DS: 1 / 2°, SS: null, rotation time: 1.0 seconds, mode: transmission.

Claims

1. The XRPD pattern shows at least 5 2θ(°) values ​​selected from the group consisting of 8.8±0.2, 9.5±0.2, 11.1±0.2, 15.2±0.2, 15.5±0.2, 16.4±0.2, 20.2±0.2, 20.6±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2, and 27.2±0.2, where the XRPD is measured using an incident beam irradiated with CuKα at 1.54059 Å, and the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate represented by the following structure. 【Chemistry 1】 A hydrate crystal.

2. 4.7±0.2, 5.4±0.2, 5.6±0.2, 8.8±0.2, 9.5±0.2, 9.9±0.2, 10.8±0.2, 11.1±0.2, 13.1±0.2, 14.0±0.2, 14.9±0.2, 15.2±0.2, 15.5±0.2, 16.4±0.2, 16.5±0.2, 17.6±0.2, 17.7±0.2, 18.8±0.2, 19.1±0.2, 19.3±0.2, 19.5±0.2, 19.8±0.2, 20.0±0.2, 20.2±0.2, 20.6±0.2, 20.9±0.2, 21.2±0.2, 21.7±0.2, 21.9±0.2, 22.4±0.2, 22.7±0.2, 22.8±0.2, 23.2±0.2, 23.3±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2, 25.5±0.2, 25.8±0.2, 26.3 The XRPD pattern includes at least 5 2θ(°) values ​​selected from the group consisting of ±0.2, 26.5±0.2, 27.0±0.2, 27.2±0.2, and 27.4±0.2, where the XRPD is measured using an incident beam of CuKα irradiation, or 18.7, 16.5, 15.9, 10.0, 9.3, 9.0, 8.2, 8.0, 6.8, 6.3, 5.9, 5.8 , 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the following structure, exhibits an XRPD pattern containing at least 5 d-interval (Å) values ​​selected from the group consisting of 5.7, 5.4, 5.0, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, and 3.

3. 【Chemistry 2】 A hydrate crystal.

3. A crystal of the hydrate according to claim 2, exhibiting an XRPD pattern containing at least 12 d-interval (Å) values ​​selected from the group consisting of 18.7, 16.5, 15.9, 10.0, 9.3, 9.0, 8.2, 8.0, 6.8, 6.3, 5.9, 5.8, 5.7, 5.4, 5.0, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, and 3.

3.

4. A crystal of the hydrate according to claim 2, exhibiting an XRPD pattern including d-interval (Å) values ​​of 18.7, 16.5, 15.9, 10.0, 9.3, 9.0, 8.2, 8.0, 6.8, 6.3, 5.9, 5.8, 5.7, 5.4, 5.0, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, and 3.

3.

5. The crystal of the hydrate according to claim 2, which exhibits at least one XRPD pattern including 2θ(°) values ​​of 8.8±0.2, 9.5±0.2, 11.1±0.2, 15.2±0.2, 15.5±0.2, 16.4±0.2, 20.2±0.2, 20.6±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2 and 27.2±0.2, wherein the XRPD is measured using an incident beam of CuKα irradiation at a wavelength of 1.54059 Å, or which exhibits an XRPD pattern including d-interval (Å) values ​​of 10.0, 9.3, 8.0, 5.8, 5.7, 5.4, 4.4, 4.3, 3.8, 3.7, 3.6 and 3.

3.

6. The following table I shows at least one XRPD pattern containing at least five 2θ(°) values, where the XRPD is measured using an incident beam irradiated with CuKα at a wavelength of 1.54059 Å. Table 1 The XRPD pattern shown in Table J below contains at least 5 2θ(°) values, where the XRPD is measured using an incident beam irradiated with CuKα at a wavelength of 1.54059 Å. Table 2 Alternatively, the crystal of the hydrate according to claim 2, which exhibits an XRPD pattern containing at least 5 d-interval (Å) values ​​as shown in Table I or Table J above.

7. The following table I shows at least one XRPD pattern containing the 2θ(°) values, where the XRPD is measured using an incident beam irradiated with CuKα at a wavelength of 1.54059 Å. Table 3 The XRPD pattern including the 2θ(°) values ​​shown in Table J below is shown, where the XRPD is measured using an incident beam irradiated with CuKα at a wavelength of 1.54059 Å. Table 4 Alternatively, the crystal of the hydrate according to claim 2, which exhibits an XRPD pattern including the d-interval (Å) values ​​shown in Table I or Table J above.

8. A hydrate crystal according to any one of claims 1 to 7, containing 14% water as determined by Karl Fischer analysis.

9. A pharmaceutical composition comprising crystals of the hydrate according to any one of claims 1 to 8.

10. The pharmaceutical composition according to claim 9 for treating edema, epilepsy, neuromyelitis optica, migraine, hyponatremia, other eye diseases associated with retinal ischemia or abnormalities in intraocular pressure, and / or tissue hydration, excess fluid retention, myocardial ischemia, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, glioblastoma, ovarian hyperstimulation syndrome, pulmonary edema, fibromyalgia, or multiple sclerosis.

11. The pharmaceutical composition according to claim 10, wherein the edema is cerebral edema.

12. The pharmaceutical composition according to claim 11, wherein the cerebral edema is due to ischemic stroke.

13. The pharmaceutical composition according to claim 11 or 12, wherein the cerebral edema is cytotoxic cerebral edema.

14. The pharmaceutical composition according to claim 10, wherein the edema is spinal cord edema or cardiac edema.

15. The pharmaceutical composition according to claim 14, wherein the cardiac edema is due to cardiac ischemia or other obstruction of blood flow to the heart.

16. The pharmaceutical composition according to claim 15, wherein the edema is due to a transplant.

17. A method for producing a pharmaceutical composition comprising a mono or dianion of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, comprising mixing a hydrate crystal according to any one of claims 1 to 8 with a pharmaceutically acceptable liquid.

18. The method according to claim 17, wherein the pharmaceutically acceptable liquid is an aqueous solution containing a base.

19. The method according to claim 17, wherein the hydrate crystals and the base are mixed before being mixed with a pharmaceutically acceptable liquid.

20. The method according to claim 18 or 19, wherein the base is an amine and / or a salt thereof.

21. The method according to claim 20, wherein the base is tris(hydroxymethyl)aminomethane and / or a salt thereof, meglumine and / or diethanolamine.

22. The method according to any one of claims 17 to 21, wherein the pharmaceutical composition is for injection.

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