crystal

Abstract

To provide a compound which can be used for prevention, treatment and control of aquaporin-mediated conditions such as diseases of water imbalance, for example, cerebral edema, a pharmaceutical composition, and a method for producing the same.SOLUTION: There is provided a hydrate of 2 - {[3, 5-bis (trifluoromethyl) phenyl] carbamoyl} - 4-chlorophenyl dihydrogen phosphate represented by the following structure, which exhibits an XRPD pattern comprising at least five 2 θ (°) 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 CuK α radiation of 1.54059 Å.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 336,549, filed May 13, 2016, and U.S. Provisional Application No. 62 / 336,652, filed May 13, 2016, both of which are incorporated by reference in their entireties.

[0002] Crystals comprising 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 comprising the same, and methods for making and using such crystals are provided. [Background technology]

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

[0004] Active pharmaceutical ingredients may exist in various physical forms (e.g., liquid or solid in various crystalline, amorphous, hydrated, or solvated forms), which may result in differences in processability, stability, solubility, bioavailability, or pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) and / or bioequivalence of the active pharmaceutical ingredient and pharmaceutical compositions containing it.

[0005] Thus, there is a need to identify active pharmaceutical ingredients that have advantageous physical forms (eg, solid, liquid, crystalline, hydrated, solvated, or amorphous forms). Summary of the Invention

[0006] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is shown as Formula I below. [ka]

[0007] In the case of stroke or other serious debilitating diseases or conditions, such as when the patient is unconscious or unable to swallow, IV infusion or IV rapid infusion may be preferred. Furthermore, when a patient has stroke or traumatic brain injury or spinal cord injury, rapidly achieving a therapeutically effective dose of a therapeutic agent may be important for successful treatment. In hospitals, especially in acute care settings for stroke, traumatic brain injury, and myocardial infarction, the best practice is to administer drugs via IV. However, therapeutic agents with limited solubility and / or limited stability in water and / or physiological media may make parenteral administration of the therapeutic agent difficult, for example, intravenous, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral administration. 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 in water at pH 7.4. The prodrug salt forms of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide exhibit 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 can revert to N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide even in the solid state.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") exhibit 1% hydrolysis per day in the solid state. Thus, there is a need for stable pharmaceutical compositions that allow for the rapid achievement of a therapeutically effective amount of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.

[0008] WO 2015 / 069956, which is incorporated herein by reference in its entirety, describes a formulation of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, which can enable rapid achievement of a therapeutically effective amount of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.For example, WO 2015 / 069956 describes a composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, wherein the composition is solid.

[0009] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form I) has been found to have a high propensity to exist as multiple polymorphic / solvated forms, such as an ethyl acetate solvate (Form A), a hydrate (Form N), and an anhydrous / nonsolvated form (Form B). The interconversion of Forms A, B, and N is shown in Figure 30. These forms differ from each other in their physical properties, spectral data, stability, and preparation method. Preparation of Form A allows for a final filtration that 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 a larger-scale synthesis of Form A, it was found that extraction with ethyl acetate failed to remove the trifluoroacetic acid and acetic acid impurities. Due to its lack of solvent content and low hygroscopicity (approximately 0.6% weight gain at 5-95% RH), Form B is pharmaceutically more desirable than Form A. Form N is pharmaceutically more preferable compared to Form A due to the lack of organic solvent content and because it exhibited low hygroscopicity (approximately 3% weight gain at 5-95% RH) due to DVS.

[0010] Provided herein is a crystalline form of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), which may be used in the pharmaceutical compositions, methods, or kits described in WO 2015 / 069956.

[0011] Thus, there is provided a hemisolvate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., ethyl hemiacetate, hemiacetonitrile, hemi-p-dioxane, or hemimethanol solvate), such as the solvates set forth in crystalline formulas 1 to 4 below.

[0012] moreover, [ka] Crystalline Form 1 is provided as follows: 1.1 Crystalline Form 1, wherein the molar ratio of ethyl acetate to Formula I is at most 0.5 moles of ethyl acetate per 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 mole of Formula I. 1.2 The crystalline form of 1 or 1.1, wherein the molar ratio of ethyl acetate to formula I is 0.5:1. 1.3 Any of the crystalline forms 1 and above, in which the crystalline form is an indefinite ethyl acetate solvate. 1.4 Ethyl hemiacetate solvate, i.e., any crystalline form of 1 above, in which the asymmetric unit contains formula I and one molecule of ethyl acetate. 1.5 Any crystalline form from 1 onwards that crystallizes in the monoclinic crystal system, belongs to the C2 / c space group, and has 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 The crystalline form has a calculated volume of 1.5. 1.7 Crystal structure is approximately 0.563 x 0.089 x 0.039 mm 3 a crystal having a volume of approximately 0.563 x 0.089 x 0.039 mm 3 Crystalline form of 1.5 or 1.6 obtained with colorless needles having a volume of 1.5 or 1.6. 1.8 Any of the crystalline forms of 1.5 to 1.7, the crystal structure of which is obtained using CuKα radiation, for example CuKα radiation with λ=1.54184 Å. 1.9 Any of the crystalline forms of 1.5 to 1.8, the crystalline structure of which is obtained at 150 K, e.g., 150.00(10) K. 1.10 Any of the crystalline forms of 1 and thereafter having the calculated XRPD pattern shown in Figure 8.

[0014] 1.11 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.12 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.13 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.14 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.15 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, e.g., at least 5, 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table A below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 1]

[0015] 1.16 Any of the crystalline forms of 1 and thereafter, exhibiting the 2θ (°) values ​​shown in Table A for crystalline form 1.15, and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 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. 4, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 2θ(°) value of 1.18 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 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. 2. Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, for example at least 14, such as 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 2θ (°) values ​​selected from the group consisting of 0.86, 28.22, 28.63 and 29.43, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 2θ(°) value of 1.20 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0016] 1.21 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table A below, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 2] 1.22 Any of the crystalline forms of 1 et seq., exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table B of crystalline form 1.21, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.23 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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. d-spacing (Å) values ​​of 1.24 or less: 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 crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.25 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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] d-spacing (Å) values ​​of 1.26 or less: 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 crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.27 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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. d-spacing (Å) values ​​below 1.28: 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 crystalline forms of 1 or later exhibiting an XRPD pattern comprising: 1.29 Any of the crystalline forms 1 et seq., which exhibit an XRPD pattern comprising at least 3, such as at least 5, d-spacing (Å) values ​​selected from the d-spacing (Å) values ​​set out in Table A of crystalline form 1.15. 1.30 Any crystalline form of 1 et seq., exhibiting an XRPD pattern containing the d-spacing (Å) values ​​shown in Table A of crystalline form 1.15.

[0018] 1.31 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, for example at least 30 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. d-spacing (Å) values ​​below 1.32: 1 or any of the crystalline forms thereof exhibiting an XRPD pattern having the following structure: 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. 3.03, 3.30, 3.25, 3.20, 3.16, 3.12 and 3.03, wherein the crystalline form is a crystalline form of at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40. d-spacing (Å) values ​​of 1.34 or less: 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 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 , 3.433, 3.397, 3.325, 3.302, 3.246, 3.199, 3.160, 3.115 and 3.033, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40 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] d-spacing (Å) values ​​below 1.36: 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 1.37 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40 d-spacing (Å) values ​​selected from the group consisting of the d-spacing (Å) values ​​set out in Table B of crystalline form 1.21. 1.38 Any crystalline form of 1 et seq., exhibiting an XRPD pattern having d-spacing (Å) values ​​as shown in Table B of crystalline form 1.21. 1.39 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, for example 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.40 Any of the crystalline forms of 1 and thereafter, which exhibit an XRPD pattern comprising 2θ (°) values ​​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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0020] 1.41 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.42 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising 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 radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 1.43 Any of the crystalline forms 1 and thereafter, which exhibit an XRPD pattern comprising at least 3, e.g., at least 5, 2θ (°) values ​​as set forth in Table AA below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 3] 1.44 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table AA for crystalline form 1.43, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 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 and 29.5, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å.

[0021] 2θ(°) value of 1.46 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 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 Any of the crystalline forms from 1 onwards, exhibiting an XRPD pattern comprising at least 3, for example at least 5, for example at least 9, for example at least 10, 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 2θ (°) values ​​selected from the group consisting of 0.11, 27.60, 28.35, 28.81 and 29.48, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 2θ(°) value of 1.48 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.49 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table BB below, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 4] 1.50 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​as shown in Table BB of crystalline form 1.49, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0022] 1.51 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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. d-spacing (Å) values ​​below 1.52: 17.3, 13.3, 6.1, 5.3, 4.6, 4.2, 4.0, 3.8 and 3.7 any of the crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.53 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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-spacing (Å) values: 17.30, 13.28, 6.06, 5.35, 4.60, 4.19, 4.02, 3.83 and 3.71 any of the crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.55 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising at least 3, such as at least 5, d-spacing (Å) values ​​selected from the group consisting of 17.299, 13.276, 6.064, 5.348, 4.597, 4.189, 4.024, 3.827 and 3.714.

[0023] d-spacing (Å) values ​​below 1.56: 17.299, 13.276, 6.064, 5.348, 4.597, 4.189, 4.024, 3.827 and 3.714 any of the crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.57 Any of the crystalline forms 1 et seq., which exhibit an XRPD pattern comprising at least 3, such as at least 5, d-spacing (Å) values ​​selected from the d-spacing (Å) values ​​set forth in Table AA for crystalline form 1.43. 1.58 Any crystalline form of 1 et seq., exhibiting an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table AA for crystalline form 1.43. 1.59 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30 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. d-spacing (Å) values ​​below 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula:

[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 of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40 selected from the group consisting of 0.43, 3.40, 3.36, 3.29, 3.23, 3.15, 3.10 and 3.03. d-spacing (Å) values ​​below 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 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 , 3.507, 3.463, 3.430, 3.396, 3.359, 3.287, 3.229, 3.146, 3.096 and 3.028, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, 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 d-spacing (Å) values ​​below 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 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 crystalline form of 1.49 comprising a d spacing (Å) value selected from the group consisting of the d spacing (Å) values ​​set out in Table BB of at least 3, such as at least 5, for example at least 9, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40.

[0025] 1.66 A crystalline form of 1.49, exhibiting an XRPD pattern having d-spacing (Å) values ​​selected from the group consisting of the d-spacing (Å) values ​​set forth in Table BB. 1.67 Any of the crystalline forms of 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.68 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising 2θ (°) values ​​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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.69 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10 2θ (°) values ​​selected from the group consisting of 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 radiation, for example the XRPD is measured using radiation of a wavelength of 1.54059 Å. 1.70 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern comprising 2θ (°) values ​​of 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0026] 1.71 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table CC below, and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 5] 1.72 Any of the crystalline forms of 1 and thereafter, which exhibit an XRPD pattern having 2θ (°) values ​​as shown in Table CC, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.73 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25 2θ (°) values ​​selected from the group consisting of 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, wherein the XRPD is measured using an incident beam of CuKα radiation, for example when the XRPD is measured using radiation of wavelength 1.54059 Å. 2θ(°) value of 1.74 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.75 From the group consisting of 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 2. Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25 2θ (°) values ​​selected from the group consisting of:

[0027] 2θ(°) value of 1.76 or less: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.77 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table DD below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 6] 1.78 Any of the crystalline forms of 1 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table DD for crystalline form 1.77, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.79 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, 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. d-spacing (Å) values ​​below 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 crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising:

[0028] 1.81 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10 selected from the group consisting of 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. d-spacing (Å) values ​​below 1.82: 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 crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.83 Any of the crystalline forms 1 hereinbefore exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10 selected from the group consisting of 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. d-spacing (Å) values ​​of 1.84 or less: 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 crystalline forms of 1 and thereafter exhibiting an XRPD pattern comprising: 1.85 Any crystalline form of 1.71 exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the d-spacing (Å) values ​​set out in Table CC.

[0029] 1.86 A crystalline form of 1.71 exhibiting an XRPD pattern with d-spacing (Å) values ​​shown in Table CC. 1.87 Any of the crystalline forms 1 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20 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. d-spacing (Å) values ​​below 1.88: 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 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, wherein the crystalline form is any of the crystalline forms 1 and 2. d-spacing (Å) values ​​below 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula:

[0030] 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, d-spacing (Å) values ​​below 1.92: 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 1 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 1.93 A crystalline form of 1.77, which exhibits an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, selected from the d-spacing (Å) values ​​set out in Table DD. 1.94 Any crystalline form of 1 or later which exhibits an XRPD pattern having d-spacing (Å) values ​​as shown in Table D for crystalline form 1.77. 1.95 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, such as all of the peaks in the XRPD shown in Figure 10, wherein the XRPD is measured using CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å.

[0031] 1.96 Any of the crystalline forms of 1 and thereafter, which exhibit an XRPD pattern containing the characteristic peaks of the XRPD pattern shown in Figure 10, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 1.97 shows an XRPD pattern including peaks representative of the XRPD pattern shown in Figure 10, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å, of any of the crystalline forms of 1 and subsequent examples. 1.98 Any of the crystalline forms of 1 and thereafter, which exhibit an XRPD pattern as shown in Figure 10, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 1.99 Any of the crystalline forms from 1 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, such as all of the peaks in the XRPD pattern shown in Figure 11, wherein the XRPD is measured using CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 1.100 Any of the crystalline forms of 1 and thereafter, which exhibit an XRPD pattern containing the characteristic XRPD peaks shown in Figure 11, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å.

[0032] 1.101 Any of the crystalline forms of 1 and thereafter, wherein the XRPD pattern includes peaks representative of the XRPD pattern shown in Figure 11, and the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 1.102 Any of the crystalline forms of 1 and thereafter, which have an XRPD pattern as shown in Figure 11, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 1.103 Any of the crystalline forms 1 and following, which exhibit an XRPD pattern comprising at least 5 peaks, e.g. all peaks, of the XRPD pattern shown in Figure 12a, and wherein the XRPD is obtained using a copper source, e.g. obtained using CuKα radiation. 1.104 Any of the crystalline forms of 1 and subsequent thereto, comprising the characteristic peaks in the XRPD pattern shown in Figure 12a, wherein the XRPD is obtained using a copper source, for example using CuKα radiation. 1.105 Any of the crystalline forms of 1 and following, comprising the representative peaks of the XRPD pattern shown in Figure 12a, and wherein the XRPD is obtained using a copper source, for example using CuKα radiation.

[0033] 1.106 Any of the crystalline forms of 1 and thereafter, which exhibit the XRPD pattern shown in Figure 12a, wherein the XRPD is obtained using a copper source, for example using CuKα radiation. 1.107 Any of the crystalline forms 1 and following, which exhibit an XRPD pattern comprising at least 5 peaks, e.g. all peaks, of the XRPD pattern shown in Figure 12a, and wherein the XRPD is obtained using a copper source, e.g. obtained using CuKα radiation. 1.108 Any of the crystalline forms of 1 and following, comprising the characteristic peaks in the XRPD pattern shown in Figure 12b, wherein the XRPD is obtained using a copper source, for example using CuKα radiation. 1.109 Any of the crystalline forms of 1 and subsequent thereto, comprising the representative peaks of the XRPD pattern shown in Figure 12b, wherein the XRPD is obtained using a copper source, for example using CuKα radiation. 1.110 Any of the crystalline forms of 1 and above, wherein the XRPD is obtained using a copper source, for example using CuKα radiation, and which exhibits the XRPD pattern shown in Figure 12b.

[0034] 1.111 Any of the crystalline forms 1 onwards, exhibiting an XRPD pattern comprising at least 3, such as at least 5, such as at least 10, such as at least 15, for example at least 20, such as at least 25, for example at least 30, such as at least 35, for example at least 40, such as all of the peaks shown in Figure 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, e.g. 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. 1.112 Any of the crystalline forms of 1 et seq. comprising the characteristic peaks in an XRPD pattern shown in Figure 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, e.g., as shown in 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.113 Any of the crystalline forms of 1 and thereafter, comprising the representative peaks of the XRPD pattern shown in Figure 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, e.g., as shown in 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.114 Any of the crystalline forms 1 and thereafter, exhibiting an XRPD pattern substantially as shown in Figure 10, 11, 12a, 12b, 31, 32, 33, 35, 36, 38, 39, 58 or 59, e.g., substantially as shown in 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, e.g., substantially as shown in any XRPD for crystalline form A as set forth herein, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.115 Any of the crystalline forms of 1 and subsequent thereto, comprising a weight loss between 90°C and 165°C, for example, a weight loss of 6-9 wt%, for example a weight loss of 7-9 wt%, for example a weight loss of 7-8 wt%, for example a weight loss of 7.8 wt%.

[0035] 1.116 Any crystalline form of 1 or later, exhibiting the thermogravimetric analysis (TGA) thermogram shown in Figure 25. 1.117 Any crystalline form of 1 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 113°C. 1.118 Any crystalline form of 1 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 123°C. 1.119 Any crystalline form of 1 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 131°C. 1.120 Any of the crystalline forms of 1 et seq., exhibiting a differential scanning calorimetry (DSC) thermogram including an endotherm at 176°C, e.g., an endotherm at 176°C with an onset at 170°C.

[0036] 1.121 Any of the crystalline forms of 1 and subsequent thereto, exhibiting the differential scanning calorimetry (DSC) thermogram shown in Figure 25. 1.122 Any crystalline form 1 or later that exhibits a dynamic (water) vapor sorption (DVS) isotherm comprising a weight gain of 7% or less with an increase in relative humidity (RH) between 5% and 95%, for example a weight gain of 6.5% or less, for example a weight gain of 6-7%, for example a weight gain of 2% or less at 5% to 75% relative humidity, and a weight gain of 5% or less at 75% to 95% relative humidity, for example a weight gain of 1-2% at 5% to 75% relative humidity and a weight gain of 4-5% at 75% to 95% relative humidity. 1.123 Any crystalline form from 1 onwards that exhibits the dynamic (water) vapor sorption (DVS) isotherm shown in Figure 34. 1.124 Any of the crystalline forms of 1 and thereafter, wherein purifying the crystals comprises acidifying an aqueous solution comprising one or more 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, e.g., to a pH of less than 2, e.g., less than 1, e.g., to a pH of 1, e.g., with 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, for example, ethyl acetate, to form an aqueous fraction and an organic fraction.

[0037] 1.126 The crystalline form of 1.125, further comprising separating the organic fraction. 1.127 A crystalline form of 1.126, further comprising drying the organic fraction, for example with sodium sulfate. 1.128 The crystalline form of 1.127, involving evaporation of the organic solvent. 1.129 The crystalline form of any of 1.124-1.128, further comprising isolating the crystals. 1.130 The crystalline form of any of 1.124-1.128, further comprising concentrating the organic solvent under reduced pressure to provide an oil.

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

[0039] 1.136 The crystalline form of any of 1.124-1.135, further comprising isolating the crystals. 1.137 Any of the crystalline forms of 1 and beyond, 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 A crystalline form of 1.137, further comprising adding an anti-solvent, for example an organic anti-solvent (e.g. n-heptane), optionally with stirring, for example adding excess anti-solvent, for example 2.5:1 anti-solvent to organic solvent, 5:1 or more anti-solvent to organic solvent, for example 12:1 or more anti-solvent to organic solvent, for example 2.5:1 to 12:1 anti-solvent to organic solvent. 1.139 A crystalline form of 1.138, further comprising isolating the solid, for example by filtration. 1.140 A crystalline form of 1.139, further comprising washing the solid with an anti-solvent, such as an organic anti-solvent (e.g., n-heptane).

[0040] 1.141 The crystalline form of 1.140, further comprising drying the solid under vacuum. 1.142 The crystalline form of any of 1.124-1.141, further comprising isolating the crystals. 1.143 Any crystalline form of 1 or later, wherein the crystals are produced by the steps of method 1 or later (see below). 1.144 Any crystalline form 1 et seq., wherein the crystals are prepared as described in any example of purified Form A. 1.145 Any crystalline form of 1 or later, whose XRPD pattern has an allowed deviation of ±0.2°.

[0041] [ka] Further provided is a crystalline hemi-sodium salt (crystalline form 2a) of

[0042] [ka] There is further provided an acetonitrile solvate (crystalline form 2b) of

[0043] Crystalline Form 2a and Crystalline Form 2b are further provided as follows. 2.1 The crystalline form is a hemi-sodium hemi-acetonitrile solvate, e.g., crystalline form 2a or crystalline form 2b, where the asymmetric unit contains four molecules of formula I (two neutral molecules of formula I and two mono-deprotonated molecules of formula I), two sodium cations, and two acetonitrile molecules. Na replaces one proton on the PO group of one half molecule. 2.2 A crystalline form of any of 2a, 2b, or 2.1, wherein the molar ratio of acetonitrile to Formula I is 0.5:1. 2.3 Crystalline forms of 2a, 2b or any of 2.1-2.2, wherein the molar ratio of sodium to formula I is 0.5:1. 2.4 Crystalline forms of 2a, 2b or any of 2.1-2.3, wherein the ratio of acetonitrile:sodium:Formula I is 0.5:0.5:1. 2.5 Crystalline forms of 2a, 2b, or any of 2.1-2.4, which crystallize in the monoclinic crystal system, belong to the P21 space group, and have 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 2.5 crystalline form, with a calculated volume of 2.7 The crystal structure is approximately 0.25 x 0.10 x 0.09 mm 3 a crystal having a volume of, for example, approximately 0.25x0.10x0.09 mm 3 2.5 or 2.6, wherein the crystalline form is obtained using rod-shaped crystals having a volume of 2.8 Crystalline forms of 2.5-2.7, the crystal structure of which is obtained using CuKα radiation, for example CuKα radiation with γ=1.54178 Å. 2.9 Crystalline form of 2.5-2.8, where the crystal structure is obtained at 100 K, e.g., 100(2) K. 2.10 Any of the crystalline forms of 2 and above having the calculated XRPD shown in Figure 20.

[0045] 2.11 Any crystalline form of 2 et seq., wherein the crystals are prepared as described in Example 5. 2.12 Any crystalline form of Method 2 or later, wherein the crystals are produced by the steps of Method 1 or later (see below). 2.13 Any of the crystalline forms 2 and above, having an XRPD pattern with an allowed deviation of ±0.2° in 2θ(°) values.

[0046] [ka] Further provided is a p-dioxane solvate of (Crystalline Form 3, also referred to herein as Formula I). ​​Crystalline Form 3 is further provided as follows:

[0047] 3.1 Crystalline Form 3, in which the crystalline form is a hemi-p-dioxane solvate, i.e., the molar ratio of p-dioxane to Formula I is 0.5:1. 3.2 A crystalline form of 3 or 3.1, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.3 Any of the crystalline forms of 3 and thereafter, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.4 Any of the crystalline forms 3 and thereafter, exhibiting an XRPD pattern comprising at least three, e.g., at least five, 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.5 Any of the crystalline forms of 3 and thereafter, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0048] 3.6 Any of the crystalline forms 3 and thereafter, exhibiting an XRPD pattern comprising at least 3, e.g., at least 5, 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table E below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 7] 3.7 Any of the crystalline forms of 3 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​set forth in Table E of the crystalline form of 3.6, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.8 From the 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 3 or higher, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 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 and 30.19, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å.

[0049] 3.11 2θ(°) values ​​of: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.12 Any of the crystalline forms from 3 onwards, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 8, such as at least 10, for example at least 15, such as at least 20, for example at least 25, for example at least 30 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table F below, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 8] 3.13 Any of the crystalline forms 3 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​set forth in Table F for crystalline form 3.12, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.14 Any of the crystalline forms 3 and above, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 13.9, 10.4, 5.4, 5.2, 4.6, 4.4, 4.1 and 3.8. d-spacing (Å) values ​​below 3.15: 13.9, 10.4, 5.4, 5.2, 4.6, 4.4, 4.1 and 3.8 Any of the crystalline forms 3 and above that exhibit an XRPD pattern comprising:

[0050] 3.16 Any of the crystalline forms 3 and thereafter, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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 If the crystal has the following d-spacing (Å) values: 13.87, 10.40, 5.42, 5.19, 4.60, 4.41, 4.11 and 3.76 Any of the crystalline forms 3 and above that exhibit an XRPD pattern comprising: 3.18 Any of the crystalline forms 3 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, d-spacing (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 d-spacing (Å) values ​​below: 13.870, 10.402, 5.422, 5.194, 4.600, 4.405, 4.108 and 3.758 Any of the crystalline forms 3 and above that exhibit an XRPD pattern comprising: 3.20 Any of crystalline forms 3 and beyond, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, as set forth in Table E of crystalline form 3.6.

[0051] 3.21 Any crystalline form of 3 or later which exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table E of crystalline form 3.6. 3.22 Any of the crystalline forms 3 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 8, such as at least 10, for example at least 15, such as at least 20, for example at least 25, selected from the group consisting of 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. 3.23 d-spacing (Å) values ​​below: Any of the crystalline forms 3 and above exhibiting XRPD patterns having the following structures: 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 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, d-spacing (Å) values ​​below 3.25: 3.87, 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 the crystalline forms 3 and above, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 8, such as at least 10, for example at least 15, such as at least 20, for example at least 25, for example at least 30 selected from the group consisting of 0, 3.145, 3.082, 3.059, 3.031, 2.988 and 2.958. 3.27 d-spacing (Å) values ​​below: 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 crystalline forms 3 and above exhibiting an XRPD pattern having the following structure: 3.28 Any of the crystalline forms 3 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 8, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30 d-spacing (Å) values ​​selected from the group consisting of the d-spacing (Å) values ​​set out in Table F for crystalline form 3.12. 3.29 Any crystalline form of 3 or later which exhibits an XRPD pattern having d-spacing (Å) values ​​as shown in Table F of crystalline form 3.12. 3.30 Any of the crystalline forms 3 and thereafter, which exhibit an XRPD pattern comprising an XRPD pattern comprising at least 3, such as at least 5, for example at least 8, such as at least 10, for example at least 15, such as at least 20, for example at least 25, such as at least 30, such as all of the peaks in the XRPDs shown in Figure 22, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å.

[0053] 3.31 Any of the crystalline forms of 3 and thereafter, comprising the characteristic peaks in the XRPD pattern shown in Figure 22, wherein the XRPD is measured using CuKα radiation, for example, the XRPD is measured using radiation of wavelength 1.54059 Å. 3.32 Any of the crystalline forms of 3 and thereafter, comprising the representative peaks of the XRPD pattern shown in Figure 22, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.33 Any of the crystalline forms of 3 and thereafter, comprising the XRPD pattern shown in Figure 22, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 3.34 Any of the crystalline forms 3 and above, wherein preparation of the crystals comprises dissolving Formula I in a solvent comprising p-dioxane, optionally with the aid of 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 The crystalline form of any of 3.34 to 3.36, further comprising isolating the crystals. 3.38 Any crystalline form of 3 et seq., wherein the crystals are prepared as described in Example 6. 3.39 Any of the crystalline forms 3 and above, having a deviation of ±0.2° in the 2θ (°) values ​​of the XRPD pattern. 3.40 Any crystalline form of 3 or later, wherein the crystals are produced by the steps of method 1 or later (see below).

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

[0056] 4.1 Crystalline Form 4, wherein the molar ratio of methanol to Formula I is 1 mole of Formula I to a maximum of 0.6 moles of methanol (i.e., up to 0.6 moles of methanol). 4.2 The crystalline form of 4 or 4.1, wherein the crystalline form is a hemisolvate, i.e., the molar ratio of methanol:Formula I is 0.5:1. 4.3 Any of the crystalline forms of 4 and subsequent thereto, exhibiting an XRPD pattern comprising 2θ (°) values ​​of 19.0, 20.3, 21.8, 22.0, and 26.0, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.4 Any of the crystalline forms of 4 and subsequent thereto, exhibiting an XRPD pattern comprising 2θ (°) values ​​of 18.98, 20.27, 21.75, 21.97, and 25.96, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.5 Any of the crystalline forms 4 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table G below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [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 Any of 4 and subsequent crystalline forms, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, for example at least 15, such as at least 20, for example at least 25, for example at least 30 selected 2θ (°) values, and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 4.7 2θ(°) values ​​below: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 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, 29.73 and 29.91, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 4.9 2θ(°) values ​​below: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.10 Any of the crystalline forms 4 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25, for example at least 30 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table H below, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 10]

[0058] 4.11 Any of the crystalline forms 4 and subsequent thereto, exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table H of crystalline form 4.10, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.12 d-spacing (Å) values ​​of: 4.7, 4.4, 4.1, 4.0 and 3.4 Any of the crystalline forms 4 and above exhibiting an XRPD pattern comprising: 4.13 If the crystal has the following d-spacing (Å) values: 4.67, 4.38, 4.08, 4.04 and 3.43 Any of the crystalline forms 4 and above exhibiting an XRPD pattern comprising: 4.14 d-spacing (Å) values ​​of: 4.671, 4.377, 4.083, 4.042 and 3.429 Any of the crystalline forms 4 and above exhibiting an XRPD pattern comprising: 4.15 Any crystalline form of 4 or later that exhibits an XRPD pattern containing the d-spacing (Å) values ​​set forth in Table G of crystalline form 4.5.

[0059] 4.16 Any of the crystalline forms 4 and above, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, 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. 4.17 d-spacing (Å) values ​​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 Any of the crystalline forms 4 and above exhibiting an XRPD pattern having the formula: 4.18 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, 4.19 d-spacing (Å) values ​​below: 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 crystalline forms 4 and above exhibiting an XRPD pattern having the formula: 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. 2.985, 3.277, 3.211, 3.114, 3.076, 3.043, 3.002 and 2.985, wherein the crystalline form is a crystalline form of any of 4 and above, and wherein the crystalline form exhibits an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25, for example at least 30 d-spacing (Å) values ​​selected from the group consisting of: 2.985, 3.277, 3.211, 3.114, 3.076, 3.043, 3.002 and 2.985.

[0060] 4.21 d-spacing (Å) values ​​of: 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 crystalline forms 4 and above exhibiting an XRPD pattern having the formula: 4.22 Any of the crystalline forms 4 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25, for example at least 30 d-spacing (Å) values ​​selected from the group consisting of the d-spacing (Å) values ​​set out in Table H of crystalline form 4.10. 4.23 Any crystalline form of 4 or later which exhibits an XRPD pattern having d-spacing (Å) values ​​as shown in Table H of crystalline form 4.10. 4.24 Any of the crystalline forms 4 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 20, such as at least 25, for example at least 30, such as all of the peaks in the XRPD shown in Figure 23, wherein the XRPD is measured using CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 4.25 Any crystalline form of 4 and thereafter, comprising the characteristic XRPD peaks shown in Figure 23, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0061] 4.26 Any of the crystalline forms 4 and subsequent thereto, comprising the representative XRPD peaks shown in Figure 23, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.27 Any of the crystalline forms 4 and subsequent thereto, including the XRPD shown in Figure 23, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 4.28 Any crystalline form of 4 and thereafter, exhibiting a thermogravimetric analysis (TGA) thermogram comprising a gradual weight loss between 90°C and 150°C, e.g., a 3-5 wt% weight loss, e.g., a 4-5 wt% weight loss, e.g., a 4.2 wt% weight loss. 4.29 Any crystalline form of 4 or later that exhibits the thermogravimetric analysis (TGA) thermogram shown in FIG. 4.30 Methanol, e.g., mixtures containing methanol and water, e.g., solvent mixtures with low water activity (a w ) (e.g. a w Any of the crystalline forms of 4 and above, dissolved in a solvent comprising a mixture containing methanol and water, having a σ of less than 0.9.

[0062] 4.31 The crystalline form of 4.30, further comprising slowly cooling the solution and optionally 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 optionally allowing it to warm 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 The crystalline form of any of 4.30 to 4.34, further comprising isolating the crystals.

[0063] 4.36 Any crystalline form of 4 et seq., wherein the crystals are prepared as described in Example 7. 4.37 Any crystalline form of 4 or later having an XRPD pattern with an allowed deviation of ±0.2° in 2θ(°) values. 4.38 Any crystalline form of 4 et seq., prepared by the steps of Method 1 et seq. (see below).

[0064] [ka] (Crystalline Form 5, also referred to herein as Form N). Crystalline Form 5 is further provided as follows:

[0065] 5.1 Crystalline Form 5, wherein the molar ratio of water:Formula I is 3:1 to 4:1. 5.2 Crystalline Form 5, wherein the molar ratio of water:Formula I is 4.5:1 or less, such as 4.2:1 or less, for example 4.2:1, such as the molar ratio of water:Formula I is 4:1 or less, such as 3:1 or less, for example 2:1 or less, such as 4:1, for example 3:1, for example 2:1. 5.3 Any of the crystalline forms 5 and beyond, where the crystalline form is a stoichiometric hydrate. 5.4 Any of the crystalline forms from 5 onwards, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.5 Any of the crystalline forms of 5 and thereafter, exhibiting an XRPD pattern comprising 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, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0066] 5.6 Any of the crystalline forms 5 and thereafter, exhibiting an XRPD pattern comprising at least three, e.g., at least five, 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.7 Any of the crystalline forms of 5 and thereafter, exhibiting an XRPD pattern comprising 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, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.8 Any of crystalline forms 5 and thereafter, exhibiting an XRPD pattern comprising at least five 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table I below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 11] 5.9 Any of crystalline forms 5 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​as set forth in Table I for crystalline form 5.8, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 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 25.8, 26.3, 26.5, 27.0, 27.2 and 27.4, wherein the crystalline form exhibits an XRPD pattern comprising at least 3, for example at least 5, for example at least 10, for example at least 12, 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 2θ (°) values ​​selected from the group consisting of 25.8, 26.3, 26.5, 27.0, 27.2 and 27.4.

[0067] 5.11 2θ(°) values ​​of: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 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, 26.52, 27.00, 27.16 and 27.42, wherein the XRPD pattern comprises at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40 2θ (°) values ​​selected from the group consisting of 26.52, 27.00, 27.16 and 27.42, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 5.13 2θ(°) values ​​below: 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 5.14 Any of the crystalline forms as set forth above, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table J below, wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 12] 5.15 Any of crystalline forms 5 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​set forth in Table J of crystalline form 5.14, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0068] 5.16 Any of the crystalline forms 5 and thereafter, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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 d-spacing (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 Any of the crystalline forms 5 and above that exhibit an XRPD pattern comprising: 5.18 Any of the crystalline forms 5 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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 d-spacing (Å) values ​​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 Any of 5 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 5.20 Any of the crystalline forms 5 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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 d-spacing (Å) values ​​of: 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 crystalline forms 5 and above that exhibit an XRPD pattern comprising: 5.22 Any of crystalline forms 5 and thereafter, which exhibit an XRPD pattern comprising a d-spacing (Å) value set forth in Table I for crystalline form 5.8 of at least 3, such as at least 5. 5.23 Any crystalline form of 5 or later that exhibits an XRPD pattern containing the d-spacing (Å) values ​​shown in Table I for crystalline form 5.8. 5.24 Any of the crystalline forms 5 and above, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, 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. d-spacing (Å) values ​​below 5.25: 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 5 and subsequent crystalline forms exhibiting an XRPD pattern having the formula:

[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 , 3.49, 3.45, 3.38, 3.36, 3.30, 3.28 and 3.25, wherein the crystalline form exhibits an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, for example at least 40. 5.27 d-spacing (Å) values ​​below: 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 5 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 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 , 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 5 or more crystalline forms exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, for example at least 12, such as 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 selected from the group consisting of: 5.29 d-spacing (Å) values ​​below: 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 5 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 5.30 Any of the crystalline forms 5 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40 d-spacing (Å) values ​​selected from the group consisting of the d-spacing (Å) values ​​set out in Table J of crystalline form 5.14.

[0071] 5.31 Any crystalline form of 5 or later which exhibits an XRPD pattern having d-spacing (Å) values ​​as shown in Table J of crystalline form 5.14. 5.32 Any of the crystalline forms 5 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, such as all of the peaks in the XRPD shown in Figure 24, wherein the XRPD is measured using CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 5.33 Any of the crystalline forms 5 and subsequent thereto, comprising the characteristic XRPD peaks shown in Figure 24, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.34 Any of the crystalline forms 5 and subsequent thereto, comprising the characteristic XRPD peaks shown in Figure 24, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.35 Any of the crystalline forms of 5 and subsequent thereto, having an XRPD as shown in Figure 24, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0072] 5.36 Any of the crystalline forms 5 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 12, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, such as all of the peaks shown in Figure 24, 44, 45, 46, 48, 50, 51, 52, 54 or 57, e.g. Figure 24 or 44 or 45 or 46 or 48 or 50 or 51 or 52 or 54 or 57, wherein the XRPD is measured using CuKα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 5.37 Any of the crystalline forms 5 et seq. comprising the characteristic XRPD peaks shown in Figure 24, 44, 45, 46, 48, 50, 51, 52, 54 or 57, e.g., Figure 24 or 44 or 45 or 46 or 48 or 50 or 51 or 52 or 54 or 57, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.38 Any of the crystalline forms 5 et seq. comprising the representative XRPD peaks shown in Figure 24, 44, 45, 46, 48, 50, 51, 52, 54 or 57, e.g., Figure 24 or 44 or 45 or 46 or 48 or 50 or 51 or 52 or 54 or 57, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.39 Any crystalline form of 5 et seq., substantially exhibiting an XRPD as shown in Figure 24, 44, 45, 46, 48, 50, 51, 52, 54 or 57, e.g., as shown in Figure 24 or 44 or 45 or 46 or 48 or 50 or 51 or 52 or 54 or 57, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 5.40 Any of the crystalline forms of 5 and thereafter, exhibiting a thermogravimetric analysis (TGA) thermogram comprising a weight loss of, for example, 3 to 4 wt %, for example, a 3.5 wt % weight loss, for example, a 3.7 wt % weight loss, between 20°C and 80°C, for example, between 23°C and 70°C.

[0073] 5.41 Any of the crystalline forms of 5 and subsequent thereto, exhibiting a thermogravimetric analysis (TGA) thermogram comprising a weight loss of, for example, 3 to 4 wt %, for example, a 3.6 wt % weight loss, for example, a 3.7 wt % weight loss, between 60°C and 110°C, for example, between 70°C and 105°C. 5.42 Crystalline Form 5, exhibiting a thermogravimetric analysis (TGA) thermogram comprising a weight loss between 100°C and 170°C, e.g., between 105°C and 160°C, e.g., a weight loss of 0.1 to 2 wt%, e.g., a weight loss of 0.6 wt%, e.g., a weight loss of 1.3 wt%. 5.43 Crystalline Form 5, exhibiting a thermogravimetric analysis (TGA) thermogram shown in Figure 26. 5.44 Any crystalline form of 5 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 85°C. 5.45 Any crystalline form of 5 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 91°C.

[0074] 5.46 Any crystalline form of 5 or later that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 95°C. 5.47 Any crystalline form of 5 or higher that exhibits a differential scanning calorimetry (DSC) thermogram containing an endotherm at 118°C. 5.48 Any of the crystalline forms of 5 et seq., exhibiting a differential scanning calorimetry (DSC) thermogram including an endotherm at 178°C, e.g., an endotherm at 178°C with an onset at 169°C. 5.49 Any of the crystalline forms 5 and subsequent thereto, which exhibit a differential scanning calorimetry (DSC) thermogram as shown in Figure 26 5.50 Any crystalline form from 5 onwards that exhibits a dynamic (water) vapor sorption (DVS) isotherm involving a 30% weight loss after equilibration at 5% relative humidity.

[0075] 5.51 Any crystalline form of 5 and subsequent thereto exhibiting a weight gain of 4% or less after an increase in relative humidity from 5% to 95%, e.g., a weight gain of 3% or less after an increase in relative humidity from 5% to 95%, e.g., a weight gain of 3% after an increase in relative humidity from 5% to 95%. 5.52 Any crystalline form from 5 onwards that exhibits the dynamic (water) vapor sorption (DVS) isotherm shown in Figure 27. 5.53 Any crystalline form of 5 or later containing 14% water by Karl Fischer (KF) analysis, e.g., 14.2% water (equivalent to 4.2 moles of water) by Karl Fischer (KF) analysis. 5.54 The preparation of crystals involves mixing with water (e.g., water alone) or a mixture containing water (e.g., the mixture has a high water activity (a w ) (e.g. a w 5 and any subsequent crystalline forms, comprising optionally stirring and mixing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate) having a σ of 0.9 or greater. 5.55 Crystalline form 5.54, further comprising isolating the solid, e.g., by filtration.

[0076] 5.56 Crystalline form 5.55, further comprising drying the solid under vacuum. 5.57 The crystalline form of any of 5.54 to 5.56, further comprising isolating the crystals. 5.58 Any of the crystalline forms 5 et seq., wherein the crystals are prepared as described in any example for preparing Form N. 5.59 Any crystalline form of 5 et seq., prepared by the steps of Method 1 et seq. (see below). 5.60 Any crystalline form of 5 or later prepared by the steps of Method 2 or later, Method 3 or later, or Method 4 or later (see below). 5.61 Any crystalline form of 5 or later, having an XRPD pattern with an allowed deviation of ±0.2° in 2θ(°) values.

[0077] [ka] (Crystalline Form 6, also referred to herein as Form B). Crystalline Form 6 is further provided as follows:

[0078] 6.1 Crystalline form 6, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.2 Crystalline Form 6 or 6.1, exhibiting an XRPD pattern comprising 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 radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.3 Any of the crystalline forms of 6 and thereafter, exhibiting an XRPD pattern comprising at least three, for example at least five, 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 radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 6.4 Any of crystalline forms 6 and thereafter, which exhibit an XRPD pattern comprising 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, and wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.5 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising at least 3, e.g., at least 5, 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table C below, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 13]

[0079] 6.6 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern having 2θ (°) values ​​set forth in Table C of crystalline form 6.5, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.7 Any of the crystalline forms 6 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 16, such as at least 20 2θ (°) values ​​selected from the group consisting of 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, wherein the XRPD is measured using an incident beam of CuKα radiation, for example when the XRPD is measured using radiation of wavelength 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. 6.9 Any of the crystalline forms 6 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 16, such as 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 radiation, for example when the XRPD is measured using radiation of wavelength 1.54059 Å. 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 and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å.

[0080] 6.11 Any of the crystalline forms 6 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 16, for example at least 20 2θ (°) values ​​selected from the 2θ (°) values ​​set out in Table D below, and wherein the XRPD is measured using an incident beam of CuKα radiation, for example the XRPD is measured using radiation of wavelength 1.54059 Å. [Table 14] 6.12 Any of crystalline forms 6 et seq. that exhibit an XRPD pattern having 2θ (°) values ​​as set forth in Table D of crystalline form 6.11, wherein the XRPD is measured using an incident beam of CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.13 Any of the crystalline forms 6 and above, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, 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 d-spacing (Å) values ​​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 Any of 6 and subsequent crystalline forms exhibiting an XRPD pattern comprising: 6.15 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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 d-spacing (Å) values ​​of: 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 6 and subsequent crystalline forms exhibiting an XRPD pattern comprising: 6.17 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, selected from the group consisting of 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 d-spacing (Å) values ​​of: 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 6 and subsequent crystalline forms exhibiting an XRPD pattern comprising: 6.19 Any of crystalline forms 6 and beyond, which exhibit an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, as set forth in Table C for crystalline form 6.5. 6.20 6 onwards, showing an XRPD pattern containing the d-spacing (Å) values ​​shown in Table C for crystalline form 6.5 Any crystalline form of.

[0082] 6.21 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 16, 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 d-spacing (Å) values ​​below: 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 6 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 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, wherein the crystalline form is any of the crystalline forms 6 and above, exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 15, for example at least 16, such as at least 20, selected from the group consisting of 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. 6.24 d-spacing (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 6 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 6.25 Any of the crystalline forms 6 and thereafter exhibiting an XRPD pattern comprising d-spacing (Å) values ​​of at least 3, such as at least 5, for example at least 10, such as at least 16, for example at least 20 selected from the group consisting of 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.

[0083] 6.26 d-spacing (Å) values ​​below: 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 6 and subsequent crystalline forms exhibiting an XRPD pattern having the formula: 6.27 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, such as at least 10, such as at least 16, such as at least 20 d-spacing (Å) values ​​selected from the d-spacing (Å) values ​​set out in Table D of crystalline form 6.11. 6.28 Any crystalline form of 6 or later which exhibits an XRPD pattern having d-spacing (Å) values ​​as shown in Table D of crystalline form 6.11. 6.29 Any of the crystalline forms 6 and thereafter, exhibiting an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, for example at least 25, such as at least 30, for example at least 35, such as at least 40, such as all of the peaks in the XRPD shown in Figure 21, wherein the XRPD is measured using CuKα radiation, for example when the XRPD is measured using radiation of wavelength 1.54059 Å. 6.30 Any of the crystalline forms 6 et seq., wherein the XRPD comprises the characteristic peaks in the XRPD shown in Figure 21 and wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0084] 6.31 Any of the crystalline forms 6 et seq. comprising the representative XRPD peaks shown in Figure 21, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.32 Any of the crystalline forms of 6 et seq. having an XRPD as shown in Figure 21, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.33 Any of the crystalline forms of 6 and thereafter, which exhibit an XRPD pattern comprising at least 3, such as at least 5, for example at least 10, such as at least 14, for example at least 15, such as at least 20, such as at least 25, for example at least 30, such as at least 35, for example at least 40, such as all of the peaks shown in Figure 21 , Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53 or Figure 55, e.g. Figure 21 or Figure 37 or Figure 41 or Figure 42 or Figure 43 or Figure 49 or Figure 53 or Figure 55, wherein the XRPD is measured using CuKα radiation, e.g. the XRPD is measured using radiation of wavelength 1.54059 Å. 6.34 Any of the crystalline forms of 6 and thereafter, comprising the characteristic XRPD peaks shown in Figure 21, Figure 37, Figure 41, Figure 42, Figure 43, Figure 49, Figure 53 or Figure 55, e.g., Figure 21 or Figure 37 or Figure 41 or Figure 42 or Figure 43 or Figure 49 or Figure 53 or Figure 55, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.35 Any of the crystalline forms of 6 and thereafter, comprising the typical XRPD peaks shown in Figure 21, 37, 41, 42, 43, 49, 53 or 55, e.g., Figure 21 or Figure 37 or Figure 41 or Figure 42 or Figure 43 or Figure 49 or Figure 53 or Figure 55, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å.

[0085] 6.36 Any of the crystalline forms of 6 et seq., having an XRPD substantially as shown in Figure 21, 37, 41, 42, 43, 49, 53 or 55, e.g., Figure 21 or Figure 37 or Figure 41 or Figure 42 or Figure 43 or Figure 49 or Figure 53 or Figure 55, wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 6.37 Any crystalline form of 6 or higher that exhibits a dynamic (water) vapor sorption (DVS) isotherm involving 0.6 wt% water vapor sorption at 5% to 95% relative humidity. 6.38 Any crystalline form from 6 onwards that exhibits the dynamic (water) vapor sorption (DVS) isotherm shown in Figure 28. 6.39 Any crystalline form of 6 et seq., exhibiting a differential scanning calorimetry (DSC) thermogram including an endotherm at 177°C, e.g., an endotherm at 177°C with an onset at 173°C. 6.40 Any crystalline form of 6 or later that exhibits the differential scanning calorimetry (DSC) thermogram shown in Figure 40.

[0086] 6.41 Any crystalline form of 6 or later that exhibits a thermogravimetric analysis (TGA) thermogram containing a weight loss of 0.1 to 1 wt %, e.g., 0.7 wt %, between 23°C and 150°C. 6.42 Any crystalline form of 6 or later that exhibits the thermogravimetric analysis (TGA) thermogram shown in Figure 40. 6.43 Any crystalline form of 6 et seq., wherein preparation of the crystals comprises mixing, optionally with stirring, 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. 6.44 Crystalline form 6.43, further comprising cooling the mixture. 6.45 A crystalline form of 6.43 or 6.44, further comprising isolating the solid, for example by filtration.

[0087] 6.46 Crystalline form 6.43, further comprising drying the solid under vacuum. 6.47 The crystalline form of any of 6.43 to 6.46, further comprising isolating the crystals. 6.48 Any crystalline form of 6 et seq., wherein the crystals are prepared by the steps of Method 1 et seq. (see below). 6.49 Any crystalline form of 6 et seq., wherein the crystals are prepared by the steps of method 5 et seq. (see below). 6.50 Any of the crystalline forms 6 et seq., wherein the crystals are prepared as described in any of the Examples for preparing Form B. 6.51 Any crystalline form of 6 or later having an XRPD pattern with an allowed deviation of ±0.2° in 2θ(°) values.

[0088] Further provided is a method (Method 1) for preparing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) in a crystalline form, e.g., for preparing 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, and crystalline Form 6 or later, e.g., crystalline Form 1. Method 1 is further provided as follows.

[0089] 1.1 Method 1 comprising acidifying an aqueous solution comprising one or more 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, e.g., to a pH of less than 2, e.g., to a pH of 1, e.g., with HCl, e.g., to a pH of 1 with HCl. 1.2 The method of 1.1, further comprising extracting with an organic solvent, e.g., ethyl acetate, to produce an aqueous fraction and an organic fraction. 1.3 The method of 1.2, further comprising separating the organic fraction. 1.4 The method of 1.3, further comprising drying the organic fraction with, for example, sodium sulfate. 1.5 The method of 1.4, further comprising evaporating the 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 the organic solvent under reduced pressure to provide. 1.8 The method of 1.7, further comprising dissolving the oily material in an organic solvent (e.g., ethyl acetate), optionally with stirring. 1.9 The method of 1.8, further comprising adding an anti-solvent, for example, an organic anti-solvent (e.g., n-heptane), optionally with stirring. 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 an anti-solvent, for example, an organic anti-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 processes since 1 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, optionally with stirring. 1.15 The method of 1.14, further comprising adding an anti-solvent, for example an organic anti-solvent (e.g., n-heptane), optionally with stirring.

[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 an anti-solvent, such as an organic anti-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 processes since 1 further comprising combining Formula I with an organic solvent and optionally an anti-solvent, e.g., combining 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 after 1, further comprising isolating the crystals. 1.22 Crystals containing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate produced by any of the methods described in 1 or later. 1.23 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 and Crystalline Form 6 or later, such as any of Crystalline Form 1 or later, wherein the crystal is prepared by any of the methods of Methods 1.1 to 1.21.

[0093] Further provided is a crystal produced by any of the methods described above.

[0094] Further provided is a method (Method 2) for preparing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) that includes crystallizing 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from an organic solvent (e.g., one or more of ethyl acetate, heptane, acetonitrile, methanol, toluene, e.g., ethyl acetate / heptane) to obtain a solvate, and stirring and / or washing the solvate with water to obtain organic solvent-free 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate. 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, comprising stirring the solvate with water, e.g., stirring the solvate with water at room temperature, e.g., stirring the solvate with water at room temperature for 2 hours. 2.3 The process of 2.2 further comprising isolating the solid, for example by filtration. 2.4 The method of 2.3, further comprising washing the solid with water. 2.5 The method of 2.4, further comprising drying the solid, e.g., drying the solid under vacuum for 1 hour. 2.6 Any of the methods 2 et seq. further comprising isolating the solid, optionally in crystalline form. 2.7 Any of the processes of 2 and above, wherein the final product is 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, e.g., a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, e.g., a crystal comprising any of crystalline forms 5 and above.

[0096] Crystals produced by any of the methods described above are also provided.

[0097] A method for producing a hydrate of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (e.g., any of crystalline Forms 5 or later) is provided (Method 3), which comprises combining 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., any of crystalline Forms 1 or later, e.g., Form A) with water, optionally with stirring. Method 3 is further provided as follows:

[0098] 3.1 Method 3, further comprising combining 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., any of Crystalline Form 1 or later) and water with an anti-solvent (e.g., toluene), optionally with stirring. 3.2 The process of 3 or 3.1, further comprising recovering the solids by filtration. 3.3 The method of 3.2, further comprising vacuum drying the solid. 3.4 Any of the methods 3 et seq., further comprising isolating the crystals.

[0099] Further provided are crystals produced by any of methods 3 and subsequent.

[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 Crystalline Forms 5 or later) is provided, comprising combining 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with water, optionally with stirring. Method 4 is further provided as follows:

[0101] 4.1 Method 4, comprising combining 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate with water and an organic solvent, such as an anti-solvent, optionally with stirring. 4.2 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate was dissolved in water at a high water activity (a w ) (e.g., 0.9 or greater) in a solvent mixture containing water. 4.3 Any of the processes set forth in 4 et seq., further comprising recovering the solids by filtration. 4.4 Any of the methods starting with 4, further comprising vacuum drying the solid. 4.5 Any of the methods after 4, further comprising isolating the solid.

[0102] Further provided is a crystal produced by any of the methods described in 4 and subsequent paragraphs.

[0103] Further provided is a method (Method 5) for preparing a non-solvated, non-hydrated crystalline form of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) (e.g., any of Crystalline Forms 6 and beyond), 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), optionally with stirring. Method 5 is further provided as follows:

[0104] 5.1 Method 5, wherein the organic solvent is a halogenated organic solvent, e.g., 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 set forth in 5 et seq. further comprising cooling the mixture. 5.4 Any of the processes above, including 5, further comprising isolating the solid, e.g., by filtration. 5.5 The method of 5.4, further comprising drying the solid under vacuum. 5.6 Any of the methods 5 et seq., further comprising isolating the crystals.

[0105] Further provided is a pharmaceutical composition (Composition 1) comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) in a crystalline form, such as any crystalline form 1 or later, any crystalline form 2 or later, any crystalline form 5 or later, and any crystalline form 6 or later, such as any crystalline form 1 or later, such as any crystalline form 5 or later, such as any crystalline form 6 or later, such as a pharmaceutical composition described in International Publication No. WO2015 / 069956, which is incorporated herein by reference in its entirety.

[0106] Further provided is a pharmaceutical composition (Composition 1) comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (crystalline Formula I), e.g., a crystal comprising any of crystalline Form 1 or later, crystalline Form 2 or later, crystalline Form 5 or later, and crystalline Form 6 or later, e.g., any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later. Composition 1 is further provided as follows:

[0107] 1.1 Composition 1 comprising 25 to 500 mg, for example 25 to 300 mg or 350 mg, for example 25 to 200 mg, for example 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, for example 35 mg, for example 350 mg, of crystalline Formula I. 1.2 A dose 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 a dose of 0.05-1 mg / kg or 5 mg / kg, for example a dose 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 a dose of 0.5-1 mg / 1. Composition 1 or 1.1, comprising crystalline Formula I in an amount sufficient to provide a dose of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, e.g., 1 to 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, or 50 mg / kg. 1.3 Compositions according to 1.1 to 1.2, wherein after dissolving the composition in a solvent, for example an aqueous solution, the composition comprises a base having a pH of 7, 7.5 or 8 to 10.5, such as 7, 7.5 or 8 to 9.5, for example 7 or 7.5 to 8, such as 7.5 to 8.5, for example 7.5, such as 8.5, for example 8 to 8.5, such as 8.2, for example a base having a pH of 6, 7, 8, 9 or 10 to 11, for example 6, 7, 8 or 9 to 10, for example 7 to 9, for example 8 to 9, wherein the base is: a)C 1-8 alkyl mono-, di- or tricarboxylates, for example succinates, for example metal succinates (e.g. alkali and / or alkaline citrates, for example alkaline citrates, for example sodium citrate and / or potassium citrate), for example tartrates (e.g. metal tartrates, alkaline tartrates, for example sodium tartrate), for example succinates (e.g. metal succinates, for example alkaline succinates, for example disodium succinate) and / or for example lactates (e.g. metal lactates, for example alkaline lactates, for example sodium lactate), b) phosphates, for example metal phosphates (e.g. alkali and / or alkaline phosphates, for example alkaline phosphates, for example sodium phosphates (e.g. NaH2PO4 and / or Na2HPO4) and / or potassium phosphates (e.g. KH2PO4 and / or K2HPO4)), c) amines and / or salts thereof (e.g., morpholine, piperazine, benethamine, benzathine, trimethylglycine, chloroprocaine, hydrabamine, 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 salts thereof (wherein each R 8 is independently C 1-8 Alkyl (e.g., C 1-6 -Alkyl, e.g., C 1-4 -alkyl, for example, -CH2CH3, for example, -CH3), and n is 0 or C 1-8 -Alkylene (e.g., C 1-6 -Alkylene, e.g. C 1-4 -Alkylene, for example -CH2-CH2-, for example -C(CH2)3-, for example one of R 8 is -CH3, and the other R 8 is —(CH)—), and each n is independently 1-8 (e.g., 1, 2, 3, 4, 5 or 6), e.g., tris(hydroxymethyl)aminomethane (also known as Tris base) and / or a salt thereof (e.g., tris(hydroxymethyl)aminomethane acetate (also known as Tris acetate), meglumine, dimethylethanolamine, diethylamine, diethylethanolamine, and / or diethanolamine), e.g., any of the foregoing, wherein the conjugate acid of the amine and / or a 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; d) acetates, for example metal acetates (for example alkali and / or alkaline acetates, for example alkali acetates, for example sodium acetate and / or potassium acetate); e) hydroxide and / or alkoxide salts, for example metal hydroxide and / or metal alkoxide salts (for example quaternary ammonium hydroxides, for example ammonium hydroxide and / or choline hydroxide, lithium hydroxide, aluminum hydroxide, for example alkali and / or alkaline hydroxide salts, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and / or magnesium ethoxide, for example sodium hydroxide), f) carbonates and / or bicarbonates, such as metal carbon carbonates and / or metal bicarbonates (e.g. alkali and / or alkaline carbonates, such as alkali and / or alkaline bicarbonates, e.g. sodium bicarbonate), or g) Borates, such as metal borates (e.g., alkali borates, e.g., sodium borate); or any combination thereof, For example, one or more of sodium citrate, Na2HPO4, tris(hydroxymethyl)aminomethane and tris(hydroxymethyl)aminomethane salts (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 compositions 1 and subsequent thereto, wherein

[0108] 1.4 The composition of 1.3 comprising 1 mg or 5 to 200 mg or 500 mg, 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 base. 1.5 The base is an amine and / or its salt (e.g., morpholine, amino acids (e.g., arginine), mono- and / or polyhydroxyalkylamines and / or their salts, e.g., HNR 20 , HNR 20 R 21 , N.R. 20 R 21 R 22 and / or salts thereof, where R 20 , R 21 and R 22 are independently optionally substituted with one or more —OH (e.g., optionally substituted with 1 to 8, e.g., 1, 2, 3, 4, 5, or 6 —OH). 1-8 -Alkyl (e.g., C 1-6 -Alkyl, e.g. C 1-4 Composition 1.3 or 1.4, any of the foregoing, wherein the conjugate acid of the amine and / or salt thereof has a pKa of 6, 7, 8, 9 or 10-11, such as 6, 7, 8, or 9-10, such as 7-9, for example 8-9. 1.6 Any of compositions 1.3 to 1.5, wherein the base is a Tris base. 1.7 Any of compositions 1.3-1.6, wherein 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, such as 6, 7, 8, or 9-10, such as 7-9, for example 8-9. 1.8 Any of compositions 1.3-1.7, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to base is at least 1:1, e.g., the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to base is at least 2:1.

[0109] 1.9 Any of compositions 1.3 to 1.7, wherein the molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to base is at least 1:2, such as at least 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8, 1:10, 1:15, 1:20 or 1:30, such as at least 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, or 1:30, such as at least 1:2.5, for example at least 1:5, such as at least 1:10. 1.10 Any of the compositions 1 and onward comprising a bulking agent, such as one or more of mannitol, glucose, sucrose, lactose, trehalose, sorbitol, glucose, raffinose, arginine, glycine, histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone, polyethylene glycol, and polypropylene glycol, such as one or more of mannitol, glucose, sucrose, lactose, trehalose, and dextran (e.g., dextran 40), e.g., dextran 40. 1.11 Any of compositions 1 and subsequent thereto comprising 5 mg or 10 mg or 50 mg to 2 g or 5 g of filler, e.g., 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 1 and subsequent, wherein the composition is a solid, e.g., wherein the pharmaceutically acceptable excipient, e.g., one or more bases, is a solid. 1.13 Any of the compositions 1 and above that are suitable for mixing with an aqueous solution in a pharmaceutically acceptable liquid (e.g., solution or suspension, e.g., solution). 1.14 Any of the compositions 1 and subsequent thereto for injection, e.g., subcutaneous, intramuscular, intravenous or intrathecal, e.g., intramuscular or intravenous, e.g., subcutaneous, intramuscular, intravenous or intrathecal bolus injection. 1.15 The composition of 1.14 for intravenous injection, e.g., IV bolus injection and / or IV infusion, e.g., IV bolus injection followed by IV infusion. 1.16 The composition of 1.14 for intramuscular injection, e.g., IM bolus injection and / or IM infusion, e.g., IM bolus injection followed by IM infusion. 1.17 Any of compositions 1.3 to 1.16, wherein crystalline Formula I and the base are powdered together.

[0110] 1.18 Composition 1 comprising 20-500 mg, for example 25-450 mg, for example 30-400 mg, for example 35-350 mg of crystalline Formula I, and a base, for example one or more of tris(hydroxymethyl)aminomethane, Na2HPO4, meglumine and sodium citrate, for example 15-1000 mg, for example 20-600 mg, for example 50-200 mg, for example 50-150 mg, for example 10-1500 mg, for example 15-1000 mg, for example 20-600 mg, for example 50-200 mg, for example 50-150 mg of base. 1.19 Composition 1.18 comprising 20-500 mg, for example 25-450 mg, for example 30-400 mg, for example 35-350 mg of crystalline Formula I and tris(hydroxymethyl)aminomethane, for example 10-600 mg, for example 20-500, for example 40-500 mg of tris(hydroxymethyl)aminomethane. 1.20 Stable at room temperature for at least 1 week, e.g., at least 1 month, 2 months, 4 months, 6 months, 8 months, or 12 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 1 and onwards comprising N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. 1.21 Any of compositions 1 and subsequent thereto, comprising less than 10%, less than 15%, or less than 20% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, e.g., less than 5%, less than 4%, less than 3%, or less than 2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide for at least 1 week, e.g., at least 1 month, 2 months, 4 months, 6 months, 8 months, or 12 months.

[0111] 1.22 Any of the compositions 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 1 and thereafter. 1.23 Any of the compositions 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 2 and thereafter. 1.24 Any composition 1 et seq., wherein crystalline Formula I is any of crystalline forms 5 et seq. 1.25 Any of compositions 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 6 and thereafter. 1.26 Any composition 1 et seq. for use in any of the methods described herein, for example, for use in any of Methods 1 et seq. and Methods 2 et seq. (see below). 1.27 Any of compositions 1 et seq., exhibiting an XRPD pattern substantially as shown in the upper part of Figure 47 (or as shown in the upper part of Figure 56), wherein the XRPD is measured using CuKα radiation, e.g., the XRPD is measured using radiation of wavelength 1.54059 Å. 1.28 Any of compositions 1 and thereafter, wherein the XRPD pattern of the composition comprises any of the 2θ (°) values ​​and / or d-spacing (Å) values ​​(e.g., characteristic, representative and / or major peaks) shown in any of crystalline forms 1 and thereafter, 2 and thereafter, 5 and thereafter, or 6 and thereafter.

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

[0113] 4.1 Monoanions of Formula I [ka] That's method 4. 4.2 Monoanions of Formula I [ka] That's method 4. 4.3 Any method of 4 et seq. comprising mixing any of compositions 1 et seq. and a liquid, e.g., an aqueous solution. 4.4 The concentration of the monoanion or dianion is 0.01 mM or 0.02 mM or 0.05 mM or 0.1 mM or 0.5 mM or 1 mM or 2 to 250 mM, for example 0.01 mM or 0.1 mM or 0.5 to 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 methods 4 and subsequent steps, wherein the concentration is 1 to 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 to 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 from 4 onwards, in which the liquid, e.g., aqueous solution, contains a base.

[0114] 4.6 The method of 4.5, wherein the base and the amount thereof are as set forth in any of 1.3 to 1.9, 1.12, 1.18 and 1.19, or any of the compositions above. 4.7 Any of methods 4 et seq., wherein the liquid comprises sterile water for injection, optionally containing a base as in method 4.5 or 4.6. 4.8 Any of methods 4 et seq., wherein the liquid is a sterile solution containing dextrose (e.g., Dextrose Injection 5%) that may optionally contain a base as in method 4.5 or 4.6. 4.9 Any of methods 4 et seq., wherein the liquid is a sterile solution containing sodium chloride (e.g., 0.9% sodium chloride injection) that may optionally contain a base as in method 4.5 or 4.6. 4.10 Any of methods 4 et seq., wherein the liquid is a sterile solution containing benzyl alcohol (e.g., bacteriostatic water for injection of benzyl alcohol or sodium chloride for injection of benzyl alcohol) that may optionally contain a base as in methods 4.5 or 4.6.

[0115] 4.11 Any of methods 4 et seq., wherein the liquid comprises lactated Ringer's solution, which may optionally contain a base as in method 4.5 or 4.6. 4.12 Any of the methods 4 et seq., comprising mixing 0.5 to 500 mL, for example 1 mL or 2 mL to 500 mL, for example 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, for example 1 mL or 2 mL to 5 mL, 10 mL, 25 mL, 50 mL, 75 mL, 100 mL or 200 mL, for example 3.5 mL or 5 to 10 mL, 25 mL, 50 mL or 100 mL, for example 3.5 mL or 35 mL of a liquid, for example an aqueous solution, for example any of the liquids set out in methods 4.5 to 4.11, with crystalline Formula I. 4.13 Any of the methods according to 4 onwards, wherein the pharmaceutical composition has a pH of 7, 7.5 or 8-10.5, such as 7, 7.5 or 8-9.5, for example 7 or 7.5-8, such as 7.5-8.5, for example 7.5, for example 8.5, such as 8-8.5, for example 8.2. 4.14 Any of the methods of 4 et seq., wherein the pharmaceutical composition is for injection, e.g., subcutaneous, intramuscular, intravenous, or intrathecal, e.g., intramuscular or intravenous, e.g., subcutaneous, intramuscular, intravenous, or intrathecal bolus injection. 4.15 Any of the methods under 4 et seq., which are for intravenous injection, e.g., IV bolus injection and / or IV infusion, e.g., IV bolus injection followed by IV infusion.

[0116] 4.16 Any of the methods 4 et seq., wherein the pharmaceutical composition is for intramuscular injection, IM bolus injection and / or IM infusion, e.g., IM bolus injection followed by IM infusion. 4.17 Any of the methods of 4.14-4.16, further comprising filtering the pharmaceutical composition to remove particles and microorganisms prior to injection. 4.18 Any of the methods 4 et seq., wherein crystalline Formula I is any of crystalline Forms 1 et seq. 4.19 Any of the methods 4 and subsequent thereto, wherein crystalline Formula I is any of crystalline Forms 2 and subsequent thereto. 4.20 Any of the methods 4 and subsequent thereto, wherein crystalline Formula I is any of crystalline forms 5 and subsequent.

[0117] 4.21 Any of the methods 4 and subsequent thereto, wherein crystalline Formula I is any of crystalline forms 6 and subsequent. 4.22 Any of the methods set forth above, wherein the pharmaceutical composition is prepared by, for example, mixing crystalline Formula I and a pharmaceutically acceptable liquid immediately prior to or before administration to a patient in need thereof. 4.23 Any of the methods set forth above, wherein the pharmaceutical composition is prepared within 24 hours, such as within 12 hours, for example within 10 hours, such as within 8 hours, for example within 2 hours, such as within 1 hour, for example within 30 minutes, such as within 20 minutes, for example within 15 minutes, such as within 10 minutes, for example within 5 minutes, such as within 3 minutes, for example within 2 minutes, such as within 1 minute, before administration to a patient in need thereof. 4.24 Any of the methods 4 et seq., wherein Formula I and the base are mixed (e.g., in solid form, e.g., both powdered) before mixing with the liquid. 4.25 Any of the processes starting with 4, wherein Formula I is mixed with a liquid, and the liquid contains a base.

[0118] The pH of the pharmaceutical compositions disclosed herein, e.g., any of Compositions 1 et seq., may be adjusted to achieve a desired pH when dissolved in a pharmaceutically acceptable liquid by the addition of a metal hydroxide salt (e.g., NaOH and / or KOH, e.g., NaOH) to the composition.

[0119] Further provided are kits comprising crystals comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (crystalline Formula I), e.g., any of crystalline Form 1 or later, any of crystalline Form 2 or later, any of crystalline Form 5 or later, and any of crystalline Form 6 or later, e.g., any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later. Kit 1 is further provided as follows:

[0120] 1.1 Kit 1 comprising 25 to 500 mg, for example 25 to 300 mg or 350 mg, for example from 25 to 200 mg, for example 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, for example 35 mg, for example 350 mg of crystalline Formula I. 1.2 1 or 1.1, wherein the composition comprises crystalline Formula I in a quantity sufficient to provide 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, e.g., 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, e.g., 0.5-1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg or 10-20 mg / kg, e.g., 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 The kit of 1 or 1.1 further comprising a base, for example, wherein the base and the amount thereof are as described in any of compositions 1.3-1.9, 1.12, 1.18, and 1.19 above. 1.4 Kit 1.3 containing 1 mg or 5 to 200 mg or 500 mg, 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 base. 1.5 The concentration of the base is 0.01 mM or 0.1 mM or 0.5 mM or 1 mM or 2 to 250 mM, for example 0.01 mM or 0.1 mM or 0.5 to 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 to 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 40 mM, 50 mM or 60 mM, for example 5 The kit according to 1.3 or 1.4, wherein the concentration is 5, 10, 15, 20, 25 or 50-100, 200, 250, 300, 400, 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, 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.

[0121] 1.6 The base is an amine and / or its salt (e.g., morpholine, amino acids (e.g., arginine), mono- and / or polyhydroxyalkylamines and / or their salts, e.g., HNR 20 , HNR 20 R 21 , N.R. 20 R 21 R 22 and / or salts thereof (wherein each R 20 , R 21 and R 22 are independently optionally substituted with one or more —OH (e.g., optionally substituted with 1 to 8, e.g., 1, 2, 3, 4, 5, or 6 —OH). 1-8 -Alkyl (e.g., C 1-6 -Alkyl, e.g. C 1-4any of the kits according to 1.3 to 1.5, wherein the conjugate acid of the amine and / or its salt 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. 1.7 Any of the kits 1.3 to 1.6, wherein the base is a Tris base. 1.8 Kits according to 1.3 to 1.7, wherein the conjugate acid of the base, e.g., an amine and / or a salt thereof, has a pKa of 6, 7, 8, 9 or 10-11, such as 6, 7, 8 or 9-10, for example 7-9, for example 8-9. 1.9 Any of the kits 1.3 to 1.8, comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in a molar ratio of at least 1:1 to the base, e.g., 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate in a molar ratio of at least 2:1 to the base. 1.10 Any of the kits 1.3 to 1.8, comprising a molar ratio of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to one or more bases of at least 1:2, such as at least 1:2, 1:3, 1:4, or 1:5 to 1:6, 1:7, 1:8 to 1:10, 1:15, 1:20 or 1:30, such as at least 1:2.5 to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20 or 1:30, such as at least 1:2.5, such as at least 1:5, for example at least 1:10.

[0122] 1.11 Any of the kits 1 and subsequent, further comprising a pharmaceutically acceptable excipient, e.g., a bulking agent, e.g., one or more of mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, arginine, glycine, histidine, dextran (e.g., dextran 40), polyvinylpyrrolidone, polyethylene glycol, and polypropylene glycol, e.g., one or more of mannitol, glucose, sucrose, lactose, trehalose, and dextran (e.g., dextran 40). 1.12 Kit 1.11, containing 5 mg or 10 mg or 50 mg to 2 g or 5 g of filler, e.g., 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. 1.13 Kit 1 comprising crystalline Formula I, for example 25-450 mg, for example 30-400 mg, for example 35-350 mg of crystalline Formula I, and a base, for example one or more of 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 according to 1.13 comprising 20-500 mg, for example 25-450 mg, for example 30-400 mg, for example 35-350 mg of crystalline Formula I and tris(hydroxymethyl)aminomethane, for example 10-600 mg, for example 20-500 mg, for example 40-500 mg of tris(hydroxymethyl)aminomethane. 1.15 Any of the kits 1 et seq., wherein crystalline Formula I is suitable for mixing in aqueous solution in a pharmaceutically acceptable liquid (e.g., solution or suspension, e.g., solution).

[0123] 1.16 Any of the kits 1 and onward comprising a pharmaceutically acceptable liquid, e.g., a sterile solution, e.g., an aqueous solution, which may optionally contain a base, e.g., a base and an amount thereof as described in any of the compositions 1.3 to 1.9, 1.12, 1.18 and 1.19 above, e.g., a base and an amount thereof as described in any of the kits 1.3 to 1.10, 1.13 or 1.14. 1.17 A kit of 1.16, wherein the liquid comprises sterile water for injection. 1.18 Kits of 1.16 or 1.17, wherein the liquid is a sterile solution containing dextrose (e.g., dextrose injection 5%). 1.19 Any of kits 1.16 to 1.18, in which the liquid is a sterile solution containing sodium chloride (e.g., 0.9% sodium chloride injection). 1.20 Any of kits 1.16 to 1.19, wherein 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 Any of kits 1.16-1.20 in which the liquid contains lactated Ringer's solution. 1.22 Any of the kits 1.16 to 1.21 comprising 0.5 to 500 mL of a liquid, e.g., an 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 an aqueous solution. 1.23 Any of the kits 1 and subsequent thereto comprising a pharmaceutical composition comprising crystalline Formula I, e.g., any of compositions 1 and subsequent thereto. 1.24 Any of the following kits, in which the components of the kit are present in the same container or in one or more different containers. 1.25 Kit of 1.24, wherein Formula I and the base are in the same container (Container 1) and the liquid is in a different container (Container 2).

[0125] 1.26 The kit of kit 1.24, wherein the liquid and base are in the same container (container 1) and Formula I is in a different container (container 2). 1.27 The kit of 1.24, wherein Formula I is present in a container (container 1), the base is present in a different container (container 2), and the liquid is present in a different container (container 3). 1.28 Any of the kits 1.25 to 1.27, wherein the pharmaceutically acceptable excipient is present in container 1. 1.29 Any of the kits 1.25 to 1.27, wherein the pharmaceutically acceptable excipient is present in container 2. 1.30 The kit of 1.27, wherein the pharmaceutically acceptable excipient is present in container 3.

[0126] 1.31 The kit of 1.24, wherein each of the crystalline Formula I, the base, the liquid, and the pharmaceutically acceptable excipient is present in a separate container. 1.32 Any of kits 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 1 and thereafter. 1.33 Any of kits 1 and subsequent thereto, wherein crystalline Formula I is any of crystalline forms 2 and subsequent thereto. 1.34 Any of kits 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 5 and thereafter. 1.35 Any of kits 1 and thereafter, wherein crystalline Formula I is any of crystalline forms 6 and thereafter. 1.36 any of kits 1 et seq. comprising instructions for using 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to treat or control an aquaporin-mediated disease or condition (e.g., for treating or controlling a disease or condition described herein, e.g., for use in any of Methods 1 et seq. and 2 et seq. above (see below)), e.g., instructions for administering 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate to a patient in need thereof, e.g., instructions for mixing crystalline Formula I with a base and / or a liquid; e.g., instructions for using the pharmaceutical composition of Kit 1.23 to treat or control an aquaporin-mediated disease or condition (e.g., for treating or controlling a disease or condition described herein, e.g., for use in any of Methods 1 et seq. and 2 et seq. above (see below)), e.g., instructions for administering the pharmaceutical composition of Kit 1.23 to a patient in need thereof, e.g., instructions for manufacturing the pharmaceutical composition of Kit 1.23. 1.37 Any kit 1 et seq. for any use described herein, e.g., for use in any of Methods 1 et seq. and Method 2 et seq. (see below).

[0127] Further provided is a method of treating or controlling an aquaporin-mediated disease or condition, e.g., a disease or condition of water imbalance and other diseases, comprising administering to a patient in need thereof an effective amount (or an effective amount of a pharmaceutical composition comprising) a crystal comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, e.g., any of crystalline Form 1 or later, any of crystalline Form 2 or later, any of crystalline Form 5 or later, and any of crystalline Form 6 or later, e.g., any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later (Method 1). Method 1 is further provided as follows:

[0128] 1.1 Method 1, wherein the disease or disorder is selected from edema, epilepsy, neuromyelitis optica, migraine, hyponatremia, retinal ischemia or other ocular disorders 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, wherein the disease or condition is edema, eg, cerebral or spinal cord edema. 1.3 The method of 1.2, wherein the disease or condition is cerebral edema, eg, cerebral edema due to ischemic stroke, eg, cytotoxic cerebral edema, eg, cytotoxic cerebral edema due to ischemic stroke. 1.4 The method of 1.3, wherein the disease or condition is cerebral edema, e.g., cytotoxic cerebral edema due to trauma (e.g., head trauma), stroke (e.g., ischemic stroke), traumatic brain injury, glioma, meningitis, acute mountain sickness, seizure, infection, metabolic disorder, hypoxia (including general systemic hypoxia and hypoxia due to heart attack or other interruption of blood perfusion to the brain), water intoxication, liver failure, hepatic encephalopathy or diabetic ketoacidosis, cerebral edema due to, e.g., head trauma, e.g., stroke (e.g., ischemic stroke), e.g., traumatic brain injury, e.g., hypoxia due to heart attack or other interruption of blood perfusion to the brain. 1.5 The method of 1.3, wherein the disease or condition is cerebral edema, e.g., cytotoxic cerebral edema due to microgravity exposure, radiation exposure, invasive central nervous system surgery (e.g., neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, or deep brain stimulation), abscess, eclampsia, Creutzfeldt-Jakob disease, or lupus encephalitis.

[0129] 1.6 The method of 1.2, wherein the disease or condition is spinal cord edema, e.g., spinal cord edema due to spinal cord injury, e.g., spinal cord compression. 1.7 The method of 1.2, wherein the disease or condition is retinal edema, ocular 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 Method of 1 or 1.1, wherein the disease or condition is selected from hyponatremia and excess fluid retention, e.g., hyponatremia or excess fluid retention due to heart failure, cirrhosis, nephrotic disorders, or syndrome of inappropriate antidiuretic hormone secretion (SIADH). 1.9 Method 1, wherein the disease or condition is selected from glioblastoma, ovarian hyperstimulation syndrome, pulmonary edema, fibromyalgia, and multiple sclerosis. 1.10 Any of methods 1 or 1.1-1.9, wherein the disease or condition is described in International Publication No. WO2013 / 169939 (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, each of which is incorporated herein.

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

[0131] 2.1 Method 2, which includes treating or preventing transplant rejection. 2.2 Method 2, which comprises inhibiting rejection of transplanted biological material. 2.3 Method 2, which includes preventing, treating, or controlling edema due to transplantation. 2.4 Any of the methods according to 2 and beyond, wherein the rejection or edema, e.g., transplant rejection, e.g., edema, is due to transplantation of an organ (e.g., kidney, liver, pancreas, lung, heart, thymus, intestine, uterus, e.g., heart) or part thereof. 2.5 Any of methods 2 or 2.1-2.3, wherein the edema, e.g., transplant rejection, e.g., the edema, is due to a face, limb (e.g., hand), eye, trachea, muscle, or esophagus transplant. 2.6 Any of the methods of 2 et seq., wherein the graft rejection is hyperacute or accelerated rejection, e.g., hyperacute rejection, e.g., accelerated rejection. 2.7 Any of methods 2 or 2.1-2.5, wherein the graft rejection is acute rejection. 2.8 Any of methods 2 or 2.1-2.5, wherein the graft rejection is chronic rejection. 2.9 Any of the methods 2 and subsequent thereto, wherein the inhibition of transplant rejection, rejection of transplanted biological material, or the prevention, treatment, or prevention, treatment, or control of transplant edema is as described in International Application No. PCT / US2015 / 060731, which is incorporated herein by reference in its entirety.

[0132] There is further provided a method for protecting the heart during cardiac surgery, e.g., open-heart surgery, comprising administering an effective amount of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, e.g., any of crystalline Form 1 or later, crystalline Form 2 or later, crystalline Form 5 or later, and crystalline Form 6 or later, e.g., a crystal comprising any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later (a pharmaceutical composition comprising an effective amount) to a patient in need thereof.

[0133] moreover, (i) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), such as any of crystalline Form 1 or later, crystalline Form 2 or later, crystalline Form 5 or later, and crystalline Form 6 or later, such as a crystal comprising any of crystalline Form 1 or later, such as any of crystalline Form 5 or later, for use in the methods described herein or in the treatment of any disease or condition; (ii) 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., any of crystalline Form 1 or later, crystalline Form 2 or later, crystalline Form 5 or later, and crystalline Form 6 or later, e.g., any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later, for treating (in the manufacture of a medicament) any disease or condition described herein; (iii) a pharmaceutical composition comprising a crystal comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate as described herein, e.g., any of Crystalline Form 1 or later, Crystalline Form 2 or later, Crystalline Form 5 or later, and Crystalline Form 6 or later, e.g., any of Crystalline Form 1 or later, e.g., any of Crystalline Form 5 or later, in combination with or with a pharmaceutically acceptable diluent or carrier, e.g., any of Compositions 1 or later; and (iv) A pharmaceutical composition comprising a crystal comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) as described herein, e.g., any of Crystalline Form 1 onwards, Crystalline Form 2 onwards, Crystalline Form 5 onwards, and Crystalline Form 6 onwards, e.g., any of Crystalline Form 1 onwards, e.g., Crystalline Form 5 onwards, in combination or with a pharmaceutically acceptable diluent or carrier, for use in the treatment of any of the diseases or conditions described herein. is provided. [Brief explanation of the drawings]

[0134] [Figure 1] 1 shows an atomic displacement ellipsoid drawing of the asymmetric unit of Form A. Atoms are represented by 50% probability anisotropic thermal ellipsoids. [Figure 2] Figure 1 shows an atomic displacement ellipsoid drawing for Form A. Atoms are represented by 50% probability anisotropic thermal ellipsoids. One of the two molecules of formula I is shown with atom labels. [Figure 3] 1 shows the packing diagram of Form A viewed parallel to the crystallographic axis a. [Figure 4] The packing diagram of Form A is shown, viewed parallel to the crystallographic axis b. [Figure 5]1 shows the packing diagram of Form A viewed parallel to the crystallographic axis c. [Figure 6] The hydrogen bonding environment around two molecules in the asymmetric unit of Form A is shown. [Figure 7] Form A shows hydrogen bonded chains parallel to the b axis. [Figure 8] 1 shows the calculated XRPD pattern of Form A. [Figure 9] 1 shows the experimental and calculated XRPD patterns of Form A. The top XRPD pattern is the experimental XRPD pattern at room temperature. The middle XRPD pattern is the calculated XRPD pattern adjusted to room temperature. The XRPD pattern is the calculated XRPD pattern at 150K. [Figure 10] 1 shows the XRPD pattern of Form A recovered using CuKα radiation. [Figure 11] 1 shows the XRPD pattern of Form A recovered using CuKα radiation. [Figure 12] Figures 12a (top) and 12b (bottom) show the XRPD patterns of Form A recovered using a copper source. [Figure 13] 1 shows an atomic displacement ellipsoid drawing of hemi-sodium hemiacetonitrile solvate, with atoms represented by 50% probability anisotropic thermal ellipsoids. [Figure 14] 1 shows an atomic displacement ellipsoid drawing of hemi-sodium hemiacetonitrile solvate, with atoms represented by 50% probability anisotropic thermal ellipsoids. [Figure 15] 1 shows the packing diagram of hemi-sodium hemiacetonitrile solvate viewed parallel to the crystallographic axis a. [Figure 16] 1 shows the packing diagram of hemi-sodium hemiacetonitrile solvate viewed parallel to the crystallographic axis b. [Figure 17] 1 shows the packing diagram of hemi-sodium hemiacetonitrile solvate viewed parallel to the crystallographic axis c. [Figure 18] The sodium interaction of Formula I with acetonitrile is shown parallel to the a-axis for the hemi-sodium hemiacetonitrile solvate. [Figure 19] 1 shows the hydrogen bond between the phosphate group and the hemi-sodium hemi-acetonitrile solvate. [Figure 20] 1 shows the calculated XRPD pattern of hemi-sodium hemiacetonitrile solvate. [Figure 21] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 22] 1 shows the XRPD pattern of Form I collected using CuKα radiation. [Figure 23] 1 shows an XRPD pattern of Form L collected using CuKα radiation. [Figure 24] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 25] 1 shows a DSC and TGA overlay for Form A. [Figure 26] 1 shows a DSC and TGA overlay for Form N. [Figure 27] 1 shows the DVS isotherm of Form N. [Figure 28] DVS isotherm of Form B is shown. [Figure 29] 1 shows the TGA thermogram of Form L. [Figure 30] The interconversion of forms A, B and N is shown. [Figure 31] 1 shows an XRPD pattern of Form A collected using CuKα radiation. [Figure 32] 1 shows an XRPD pattern of Form A collected using CuKα radiation. [Figure 33] 1 shows an overlay of Form A XRPD patterns. The top XRPD pattern is Form A from Example 2A (XRPD patterns shown in Figures 10 and 31). The bottom XRPD pattern is Form A from Example 3 (XRPD patterns shown in Figures 11 and 32). [Figure 34] 1 shows the DVS isotherm of Form A. [Figure 35] 1 shows an XRPD pattern of Form A collected using CuKα radiation. [Figure 36]An overlay of Form A XRPD patterns is shown. The top XRPD pattern is Form A from Example 2B (XRPD pattern shown in Figure 35). The bottom XRPD pattern is Form A from Example 2A (XRPD patterns shown in Figures 10 and 31). [Figure 37] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 38] 1 shows an XRPD pattern of Form A collected using CuKα radiation. [Figure 39] 1 shows the XRPD pattern of Form A (and an unknown minor component) collected using CuKα radiation. [Figure 40] 1 shows a DSC and TGA overlay of Form B. [Figure 41] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 42] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 43] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 44] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 45] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 46] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 47]

[0023] Figure 1 shows the XRPD patterns of Form A + Tris base, Form A, and Tris base. The top XRPD pattern is Form A powdered with Tris base. The middle XRPD pattern is Form A from Example 2A. The bottom XRPD pattern is Tris base. [Figure 48] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 49] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 50]1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 51] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 52] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 53] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 54] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 55] 1 shows an XRPD pattern of Form B collected using CuKα radiation. [Figure 56] 1 shows the XRPD pattern of Form A+ Tris Base. [Figure 57] 1 shows an XRPD pattern of Form N collected using CuKα radiation. [Figure 58] 1 shows an XRPD pattern of Form A collected using CuKα radiation. [Figure 59] 1 shows an XRPD pattern of Form A collected using CuKα radiation. DETAILED DESCRIPTION OF THE INVENTION

[0135] Detailed Description The crystallinity, morphology, and properties of any of the crystals described herein, such as 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, and crystalline form 6 or later, can be determined by a number of methods, including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction, polarized light 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) depending on the instrument used, the time and temperature of the sample when measured, and standard experimental error. Therefore, the 2θ values ​​(°2θ), d-spacing values, heights, and relative intensities of peaks have an acceptable level of deviation. For example, the values ​​may have an acceptable deviation of, for example, 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In certain embodiments, the 2θ (°) values ​​or d-spacing (Å) values ​​of the XRPD patterns of the crystalline forms described herein may have an acceptable deviation of 0.2° and / or ±0.2 Å. Furthermore, the XRPD patterns of the crystalline forms described herein may be identified by characteristic peaks recognized by those skilled in the art. For example, any of the crystalline forms described herein, such as crystalline forms 1 and above, 2 and above, 3 and above, 4 and above, or 5 and above, may be identified by, for example, two characteristic peaks, in some cases three characteristic peaks, and in other cases five characteristic peaks. Thus, the term "substantially as shown" in a particular figure refers to any crystal having an XRPD with major and / or characteristic and / or representative peaks recognized by one of ordinary skill in the art.

[0137] It is also understood that the differential scanning calorimetry and thermogravimetric analysis thermograms of a given sample may vary (standard deviation) depending on the instrument used, the time and temperature of the sample when measured, and standard experimental error. The temperature values ​​themselves may deviate by up to ±10°C, preferably ±5°C, preferably ±3°C of the reference temperature.

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

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

[0140] "Diagram peaks," if any, are a subset of the representative peaks that can be used to distinguish one polymorph from another (a polymorph that is a crystalline form having the same chemical composition). Characteristic peaks are determined by assessing which representative peaks, if any, are present in a polymorph of a compound to within ±0.2° 2θ of the peaks of all known polymorphs of that compound. Polymorphs of a compound do not necessarily have at least one characteristic peak.

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

[0142] As used herein, a "patient" includes humans and non-humans. In certain embodiments, the patient is a human. In other embodiments, the patient is a 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 of time, e.g., 60 minutes or less, 30 minutes or less, 20 minutes or less, 10 minutes or less, 5 minutes or less, e.g., 3 minutes or less, e.g., 1 minute or less. Bolus administration rapidly delivers a therapeutically effective amount of a therapeutic agent into the blood.

[0144] As used herein, the term "solvate" refers to a crystal that contains stoichiometric or non-stoichiometric amounts of solvent incorporated into the crystal structure.

[0145] As used herein, the term "non-solvate" refers to a crystal that is free or substantially free of solvent molecules within the crystalline structure.

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

[0147] As used herein, the term "non-hydrate" refers to a crystal that does not contain or is substantially free of water molecules within the crystal structure.

[0148] As used herein, "stoichiometric hydrate" refers to a crystalline material that has a specified water content over an extended relative humidity (RH) range.

[0149] As used herein, "variable hydrate" refers to a crystalline material that has a variable water content over an extended relative humidity (RH) range but does not change phase.

[0150] As used herein, the term "amorphous" refers to a solid with a disordered arrangement of molecules and does not possess a discernible crystal lattice.

[0151] As used herein, a "poor solvent" refers to a solvent in which 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) is 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, for example, less than 10 to 30 mg / ml, for example, less than 1 to 10 mg / ml, for example, less than 1 mg / ml.

[0152] As used herein, "crystalline Formula I" means 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I), e.g., a crystal including any of crystalline Form 1 or later, crystalline Form 2 or later, crystalline Form 5 or later, and crystalline Form 6 or later, e.g., any of crystalline Form 1 or later, e.g., any of crystalline Form 5 or later.

[0153] In some embodiments, the base used herein is a solid.

[0154] In some embodiments, a "base" as used herein is an inorganic or organic Bronsted base.

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

[0156] Example 1 General Methods Example 1A General XRPD Method XRPD patterns are collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using a long, finely focused light source. An ellipsoidal multilayer mirror is used to focus the Cu Kα X-rays through the sample and onto the detector. Prior to 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 in transmission geometry. A short anti-scatter extension and an anti-scatter knife edge are used to stop the beam and minimize background generated by air. Soller slits are used for the incident and diffracted beams to minimize spread from axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b.

[0157] Peaks in the range of up to about 30° 2θ are selected. Depending on the instrument used to collect data and / or inherent peak division, a rounding algorithm is used to process each peak to the nearest 0.1° 2θ or 0.01° 2θ. Peak position variation occurs within ±0.2° 2θ. Third-party measurements of samples independently prepared on different instruments can result in variations of ±0.2° 2θ or more.

[0158] Select prominent peaks from the observed peaks, preferably by identifying non-overlapping low angle peaks with strong intensities.

[0159] Example 1B - XRPD Indexing In the referenced figures for a given indexed XRPD pattern, agreement between the accepted peak positions, indicated by bars, and the observed peaks indicates a consistent unit cell determination. Unless otherwise stated, successful indexing of a pattern indicates that the sample consists primarily of a single crystalline phase. To confirm a tentative indexing solution, the molecular packing motif within the crystalline unit cell must be determined. No attempt at molecular packing has been made.

[0160] Example 1C Differential Scanning Calorimetry (DSC) a.Standard DSC DSC is performed using a TA Instruments 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 the weight is accurately recorded. A pre-weighed aluminum pan, designated as the sample pan, is placed on the reference side of the cell. Thermogram method codes are abbreviations for the onset and yield temperatures and heating rates; for example, (-30)-250-10 means "-30°C to 250°C, 10°C / min." The abbreviation T0C indicates the use of a T-zero crimp pan. b. Modulated DSC Modulated DSC data are acquired on a TA Instruments 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 the weight is accurately recorded. A weighed aluminum pan, configured as the sample pan, is placed on the reference side of the cell. Data are acquired from 2 to 200 °C at a heating rate of 2 °C / min using a 1.00 °C and 60-second modulation step. The reported glass transition temperature is obtained from the inflection point of the step change in the reversible component of the heat flow versus temperature curve.

[0161] Example 1D Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) data are collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP are used as calibration standards. Samples are not allowed to dry prior to analysis. Adsorption and desorption data are collected under a nitrogen purge over a range of 5% to 95% relative humidity (RH) in 10% RH increments. The equilibrium criteria used for analysis are less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. 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 Each sample is placed in an aluminum pan. The sample is sealed, the lid is pierced, and then inserted into the TG furnace. The furnace is heated under nitrogen. Data are collected at a ramp rate of 10°C / min.

[0163] Example 1F Energy Dispersive X-ray Spectroscopy (EDX) EDX was performed using an EDAX microscope equipped with an FEI Quanta 200 SEM. TM The X-rays were collected using a Sapphire X-ray detector and analyzed using EDAX Genesis software (v.3.5). The detector was calibrated using NIST-traceable aluminum and copper. Samples were prepared for analysis by placing a small amount on a carbon adhesive tab supported on an aluminum platform. The analysis time recorded in the detector effective measurement time was 200 seconds, using a 10 microsecond time and a 15 kV beam voltage.

[0164] Example 1G Karl Fischer Coulometric Titration Analysis (KF) Coulometric Karl Fischer analysis for water content determination is performed using a Mettler Toledo DL39 Karl Fischer titrator equipped with a Stromboli oven attachment. Two sample replicates are placed in a drying oven set at a temperature of approximately 130-140 °C. The drying oven is purged with dry nitrogen into the titrator. The sample is then titrated with a generator electrode to produce iodine via electrooxidation: 2I- → I2 + 2e-. A NIST traceable water standard (Hydranal Water Standard 10.0) is analyzed to check the operation of the coulometer.

[0165] Example 1H Crash Cooling (CC) A concentrated solution of Formula I is prepared in a solvent at elevated temperature. The solution is optionally filtered warm through a 0.2 μm nylon filter into a warm vial. The solution is capped and placed directly into a freezer for crash cooling. The solution is left in the freezer for a period of time to collect any solids present.

[0166] Example 1I Crushed Precipitate (CP) A solution of Formula I is prepared. The solution is optionally filtered through a 0.2 μm nylon filter. Aliquots of anti-solvent are dispensed while stirring until precipitation occurs. The solid is isolated.

[0167] Example 1J Rapid Cooling (FC) A concentrated solution of Formula I is prepared in a solvent at elevated temperature. The solution is optionally filtered, while still warm, through a 0.2 μm nylon filter into a warm vial. The solution is capped and placed directly on the lab bench to rapidly cool to room temperature. The solution is maintained at ambient conditions for a period of time, and any solids present are collected.

[0168] Example 1K Slow Evaporation (SE) Prepare a solution of Formula I. Optionally, filter the solution through a 0.2 μm nylon filter. Evaporate under conditions that result in reduced slow evaporation, such as in a loosely capped vial or a vial covered with punctured aluminum foil. Evaporate the solution to dryness unless the method is partial slow evaporation reduction (solids present with small amounts of solvent remaining). Isolate the solid.

[0169] Example 2A 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A) [ka] Step 1: [ka] Under a N2 atmosphere, 5-chlorosalicylic acid (43.7 g, 300 mmol, 1 equiv.) is dissolved in toluene (1500 mL), followed by the dropwise addition of phosphorus trichloride (10.5 mL, 150 mmol, 0.5 equiv.), followed by the addition of 3,5-bis(trifluoromethyl)aniline (50 g, 228 mmol, 0.87 equiv.). The reaction mixture is stirred under reflux for 12 h and cooled to room temperature. Another 0.1 equiv. of phosphorus trichloride (2 mL) is added, and the reaction is heated for an additional 4 h, cooled, and 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, yielding 70 g of product after evaporation of the solvent. 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] N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (40.0 g, 0.1 mol, 1 equiv.) was dissolved in CH3CN (400 mL), followed by the addition of DMAP (0.8 g, 0.001 mol, 0.06 equiv.), Hunig's base (34 mL, 0.21 mol, 2 equiv.), and CCl4 (82.02 g, 0.52 mol, 5 equiv.), in that order. The solution was cooled to 0 °C, and a solution of ((CH3)3SiCH2CHO)2P(O)H (46 g, 0.16 mol, 1.5 equiv.) in CH3CN (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h, after which water (6 L) was added and extracted twice with EtOAc (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 give the crude material which is 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 equiv.) was dissolved in a TFA:water (5:1, 500 mL) mixture. The reaction mixture was stirred at room temperature for 2 hours, after which the solvent was concentrated. The crude oil was dissolved in 1 L of water containing 0.4 M NaOH (16 g). The cloudy 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 fractions were dried over sodium sulfate and evaporated to give 24 g of an off-white solid which was crystalline by XRPD. Mass spectrum M+1 = 463.9946, calculated 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 optical emission spectrometry (ICP-OES) (Na + Analysis): 0.18% Na by IC + , 0.19% Na by ICP-OES (acid decomposition method) +

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

[0173] The XRPD pattern of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate prepared as described in this example is shown in Figure 10. The XRPD pattern is also shown in Figure 31. The XRPD pattern was obtained as described in General XRPD Methods in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD patterns shown in Figures 10 and 31 are provided above in Table B for crystalline form 1.21. Data collection 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: 1.01-39.98°2θ, step size: 0.017°2θ, collection time: 717 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0174] The XRPD pattern in Figure 10 (also shown in Figure 31) was successfully indexed, indicating that the material consists primarily or exclusively of a single crystalline phase. The unit cell volume obtained from the indexed solution can accommodate Formula I up to about 0.5 moles of EtOAc per mole of Formula I.

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

[0176] An overlay of the DSC and TGA thermograms is shown in Figure 25 (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 slight volatilization of EtOAc during weight loss, the weight loss is equivalent to 0.4 moles of EtOAc. Overlapping endotherms with maximal peaks at 113°C, 123°C, and 131°C occur and are thought to correspond to desolvation. A sharp endotherm is observed at 176°C (near 170°C), likely corresponding to melting. Decomposition appears to follow the melting, as evidenced by a sharp drop in the TGA thermogram.

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

[0178] The DVS isotherm is shown in Figure 34. Initially, the sample lost 0.76 wt% upon equilibration at 5% RH, likely corresponding to moisture loss from ambient storage and / or adsorption by bound EtOAc moieties. The material exhibits significant hygroscopicity, taking up 6.07 wt% of water from 5% to 95% RH (1.65% weight gain from 5% to 75% RH, 4.42% weight gain from 75% to 95% RH). Extensive water adsorption (4.42%) occurs from 75% to 95% RH. The adsorption isotherm exhibits significant hysteresis, with a fixed 8.73% weight loss occurring from 95% to 5% RH. The larger weight loss upon desorption indicates simultaneous adsorption of bound EtOAc and water. Two stages in the experiment reach maximum equilibration time: 85% to 95% RH for adsorption and 85% to 75% RH for desorption. If the equilibration time is longer, the sample may undergo further vapor adsorption or desorption at the corresponding RH conditions.

[0179] XRPD of the post-DVS sample shows a change to an unknown interfering substance.

[0180] A single crystal structure grown using this lot of Form A was dissolved as described in Example 5. The crystal structure is consistent with the hemi-ACN hemi-salt of Formula I. To determine whether the single crystal is representative of the entire lot of Form A, the material was analyzed by elemental analysis (EA), ion chromatography (IC), inductively coupled plasma optical emission spectroscopy (ICP-OES), and energy dispersive X-ray spectroscopy (EDX), and a comparison of the theoretical composition percentages and the measured values ​​is shown in Table 1. [Table 15]

[0181] The EA test is relatively comprehensive because measurements for C, H, N, Cl, F, and P cannot distinguish between the hemi-sodium salt and the free acid. Analysis by IC, ICP-OES (using acid digestion), and EDX all show negligible sodium content, confirming that this lot of Form A consists of Formula I (free acid). The hemi-Na salt analyzed by SCXRD may be due to a small amount of Na impurity in material that crystallized from solution as the hemi-Na salt.

[0182] Crash precipitation, slow evaporation reduction, crash cooling, and rapid cooling of Formula I in EtOAc / heptane mixtures all result in Form A.

[0183] Example 2B Repreparation of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A) A portion of the 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from Example 2A in EtOAc is mixed with 1N HCl. A white solid is isolated by evaporation. 600 MHz NMR indicates approximately 0.28 moles of EtOAc. The material was analyzed by EDX, and the results are shown in Table 2. [Table 16]

[0184] The XRPD pattern of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate prepared as described in this Example is shown in Figure 35. The XRPD pattern was obtained as described in General XRPD Method in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD pattern shown in Figure 35 are provided above in Table DD for crystalline form 1.77. Data collection 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, collection time: 716 seconds, scan rate: 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0185] The XRPD pattern shows the sample to be Form A with a possible minor unknown component.

[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 EtOAc and evaporated. The solid is then crash precipitated with EtOAc / heptane and vacuum filtered.

[0187] Further experimental details for the synthesis are provided in the following paragraphs. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from Example 2B (28.1 mg) was dissolved in EtOAc (0.1 mL) with sonication to produce a clear solution. Aliquots of heptane (4 x 0.1 mL) were added with stirring to produce precipitation. An opaque white suspension was observed. The resulting solid was 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 acetate solvate) is shown in Figure 11. The XRPD pattern is also shown in Figure 32. The XRPD pattern is obtained as described in General XRPD Methods in Example 1. The 2θ values, d-spacings and peak intensities of the XRPD patterns shown in Figures 11 and 32 are provided above in Table BB for crystalline form 1.49. Data collection 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, collection time: 721 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0189] The XRPD pattern of Form A exhibits peak shifts, believed to be caused by variable EtOAc content, which causes the crystal lattice to expand or contract.

[0190] For comparison purposes, the XRPD pattern of Figure 11 (also shown in Figure 32) is indexed. While slightly smaller in volume than that of Form A from Example 2A, the unit cell volume for this material also accommodates up to about 0.5 moles of EtOAc per mole of Formula I. An XRPD overlay showing the peak shifts observed between the XRPD patterns of Figures 10 and 31 and those of Figures 11 and 32 is shown in Figure 33. The indexing leads to the suggestion that very small differences in EtOAc content (and consequently unit cell volume) cause relatively significant peak shifts by XRPD.

[0191] Example 4 Preparation and single crystal structure determination of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl hemiacetate solvate (Form A). introduction The structure of the single crystal is determined by single crystal X-ray diffraction. Single crystal data collection, structure analysis, and refinement are performed in accordance with cGMP specifications.

[0192] Results and Discussion 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) Å. The formula weight of the asymmetric unit in the crystal structure of Form A is 1015.41 g mol, where Z = 8. -1 and 1.632 gcm -3 The calculated density of 15 is given. The spacing group is determined to be C2 / c (no. 15). A summary of the crystallographic data and crystallographic data collection parameters is provided in Table 3.

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

[0194] An atomic displacement ellipsoid drawing of the asymmetric unit of Form A is shown in FIG. 1 and atom labels are shown in FIG.

[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 an ethyl hemiacetate solvate.

[0196] One of the -CF3 moieties in each of the molecules of Formula I is modeled as disordered.

[0197] Packing diagrams viewed parallel to the crystallographic 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 from the amide nitrogen to the amide oxygen of adjacent molecules and between the phosphate moieties of adjacent molecules, forming one-dimensional chains down the b axis (Figure 7). Ethyl acetate molecules hydrogen bond to alternate phosphate molecules down the chain.

[0198] Figure 8 shows the calculated XRPD pattern of Form A resulting from the single crystal structure. The experimental XRPD pattern of Form A is overlaid with the calculated XRPD pattern in Figure 9. All peaks in the experimental pattern are represented in the calculated XRPD pattern.

[0199] Differences in intensities between calculated and experimental powder diffraction patterns are often due to preferred alignment. Preferred alignment is the tendency of crystals to align at a certain angle. This preferred alignment of the sample can have a significant effect on peak intensities in experimental powder diffraction patterns, but not on peak positions. Furthermore, some shifts in peak positions between calculated and experimental powder diffraction patterns can be expected because experimental powder diffraction patterns are corrected at ambient temperature, while single crystal data are corrected at 150 K. Lower temperatures are used in single crystal analysis to improve structural quality, but the crystals shrink, resulting in changes in unit cell parameters that are reflected in calculated powder diffraction patterns. These shifts are particularly evident at higher diffraction angles. Unit cell parameters derived from XRPD indexing are used to adjust the calculated patterns to room temperature.

[0200] Table 3. Crystallographic data and data collection parameters for Form A. [Table 17]

[0201] Experimental section manufacturing Single crystals are grown by temperature cycling in heptane / EtOAc 81:19 (v / v).

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

[0203] Further experimental details of the synthesis are described in this paragraph. A solution of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (31.2 mg) from Example 2B in 81:19 heptane / EtOAc (v / v, 2.35 mL) is heated to 74°C with stirring to obtain a clear solution. The solution is left on the heat block of a hot plate, the heat source is turned off, and the sample is allowed to cool slowly to ambient temperature. After standing at ambient temperature for 1 day, the sample is observed to consist of a clear liquid and a large amount of white solid. The sample is heated to 71°C with occasional manual swirling until a small amount of undissolved solid remains. The sample is again allowed to cool slowly to ambient temperature without stirring on the heat block of a hot plate. After standing at ambient temperature for 3 days, a white solid and a clear liquid phase are observed. The sample is reheated to 71°C with shaking using an orbital shaker until a small amount of undissolved solid remains. The orbital shaker is set to cool by 5°C every 30 minutes and allowed to cool to ambient temperature without shaking. After standing at ambient temperature for 1 day, a white solid and a clear liquid phase are observed. The sample is reheated to 72°C with 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 clear liquid and a white solid consisting of thin, birefringent needles. Single crystals are recovered 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 1000 Å are placed on the fiber in a random arrangement. Preliminary testing and data collection are performed using CuKα radiation (λ = 1.54184 Å) on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus-shielded X-ray tube and a Dectris Pilatus3 R 200K hybrid pixel array detector. Fine-tuning is performed using SHELXL-2014 (Sheldrick, GM, Acta Cryst., 2008, A64, 112-122). Cell consistency and alignment matrices for data collection are obtained from least-squares refinement using 13054 reflection angle settings in the range of 4° < θ < 77°. The spacing group was determined to be (no. 15) using CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). Data were collected at a temperature of 150 K and a maximum diffraction angle (2θ) of 154.67°.

[0205] Data organization Frames are integrated using CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). A total of 21,801 reflections are collected, of which 8,486 are unique. Lorentzian and polarization corrections are applied to the data. For CuKα radiation, the linear absorption coefficient is 3.221 mm -1 Numerical absorption correction was applied using CrysAlisPro (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). The transmission coefficient range was 0.424–0.888. A second attenuation correction was applied. The final coefficient, fine-tuned by least squares, was 0.000093(13) (absolute units). Equivalent reflection intensities were averaged. The averaged coincidence coefficient was 2.92% based on intensity.

[0206] Structural analysis and fine tuning The structure is solved by direct methods using Olex2 (Dolomanov, OV et al., J. Appl. Cryst., 2009, 42, 339-341) and SHELXT (Sheldrick, GM, Acta Cryst., 2015, A71, 3-8). 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 refined independently. All other hydrogen atoms are included in the refinement but are suppressed from being present on the bonding atom. Function:

number

[0207] The weight w is

number

[0208] The scattering factors are taken 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 the refinement, F o 2 >2σ(F o 2 ) are used to calculate the fit residual, R. A total of 7442 reflections are used in the calculation. The final cycle of fine-tuning involves 660 variable parameters, and the unweighted and weighted fit coefficients are:

number

[0209] The standard deviation of the unit weighted observations (goodness of fit) is 1.039. The highest peak in the final difference Fourier is 0.793 e / Å. 3 The smallest negative peak is -0.537e / Å. 3 It has a height of

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

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

[0212] Example 5 Preparation and Single Crystal Structure Determination 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 collection, structure analysis, and refinement are not performed according to cGMP specifications.

[0213] Results and Discussion 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 hemi-sodium hemiacetonitrile solvate is 990.34 gmol, where Z=4. -1 and 1.709 gcm -1 The calculated density of 1000 is given. The spacing group is determined to be P21 (no. 4). A summary of the crystallographic data and crystallographic data collection parameters is provided in Table 4.

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

[0215] An atomic displacement ellipsoid diagram of hemi-sodium hemiacetonitrile solvate is shown in Figure 13, with atom labels in Figure 14. The asymmetric unit shown in Figure 13 contains two molecules of Formula I, two monodeprotonated anions of Formula I, two sodium cations, and two acetonitrile molecules. Packing diagrams parallel to the crystallographic axes a, b, and c are shown in Figures 15-17, respectively. As shown in Figure 18, the sodium atom is in a pentagonal arrangement, forming interactions with two phosphate oxygen atoms and two amide oxygen atoms from four different Formula I molecules, in addition to the acetonitrile nitrogen atom, to form chains parallel to the a axis. As shown in Figure 19, hydrogen bonds occur between adjacent phosphate groups parallel to the b axis, resulting in a two-dimensional network.

[0216] Figure 20 shows the calculated XRPD pattern of hemi-sodium hemi-acetonitrile solvate resulting from the single crystal structure.

[0217] Table 4. Crystallographic data and data collection parameters for hemi-sodium 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 with sonication. The solution is filtered (0.2 μm nylon). Crystals are grown partially from the solution by slow evaporation (loosely capped vial). Long, thick needle-like crystals are observed.

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

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

[0221] The cell coherence and alignment matrix for data collection is obtained from least-squares refinement using a set of 42984 reflection angles in the range 1° < θ < 72°. The spacing group is determined to be P21 (no. 4) based on the following condition: regularity of 0k = 2n and subsequent least-squares refinement. Data are collected at a temperature of 100 K with a minimum diffraction angle (2θ) of 144.28°.

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

[0223] Structural analysis and fine tuning The structure is elucidated by direct methods 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). Oxygen atoms are refined independently. All other hydrogen atoms are included in the refinement but are suppressed from being present on the bonding atom. Function:

number

[0224] The weight w is

number

[0225] The scattering factors are taken 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 the refinement, F o 2 >2σ(F o 2 ) are used to calculate the fit residual, R. A total of 7442 reflections are used in the calculation. The final cycle of fine-tuning included 265 variable parameters, and the unweighted and weighted fit coefficients were:

number

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

[0227] Calculated X-ray powder diffraction (XRPD) patterns Mercury (Macrae, CF et al., J. Appl. Cryst., 2006, 39, 453-457) was used to generate calculated XRPD patterns for atomic arrangement, spacing group, and unit cell parameters from Cu irradiation and single crystal structures. Because the single crystal data was collected at low temperature (100 K), peak shifts, especially at large diffraction angles, can be evident between the pattern calculated from the low-temperature data and the room-temperature experimental powder diffraction pattern. The unit cell obtained from XRPD indexing is used to adjust the calculated XRPD pattern to room temperature.

[0228] Atomic displacement ellipses and packing diagrams Atomic displacement ellipses are generated using Mercury (Macrae, CF et al., J. Appl. Cryst., 2006, 39, 453-457). Atoms are represented by 50% probability anisotropic thermal vibration ellipses. Packing diagrams and further drawings are also generated 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) Rapid evaporation from p-dioxane produces 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate p-dioxane solvate.

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

[0231] 1H NMR 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 General XRPD Method in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD pattern shown in Figure 22 are provided above in Table F for crystalline form 3.12. Data collection 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, collection time: 721 sec, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0233] The XRPD pattern in Figure 22 indicates that the indexing was successful and the sample consists primarily or exclusively of a single crystalline phase. Indexed Solution The unit cell volume obtained from the indexed solution is consistent with a hemidioxane solvate (which can accommodate up to about 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 was dissolved in MeOH / water 26:74 (v / v, a w The solution is slowly cooled from 63°C to room temperature in a 0.89°C flask and allowed to stand at room temperature for 5 days. The solution is then stored in a freezer for 4 days. The solution is then allowed to equilibrate to room temperature and vacuum filtered.

[0235] Further experimental details of the synthesis are described in this paragraph. A solution of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (30.0 mg) from Example 2A in 26:74 MeOH / water (v / v, 1.32 ml) was heated to 63°C with stirring, resulting in a slightly cloudy 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 remained slightly cloudy. The solution was left in the heat block on the 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 the freezer for 4 days. Upon removal from the freezer, a translucent gel was observed. Upon equilibration to ambient temperature, the gel became a liquid with a white solid in suspension. The resulting solid was collected by vacuum filtration and air-dried on the filter under reduced pressure for 1 minute.

[0236] 1 H NMR 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 General XRPD Method in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD pattern shown in Figure 23 are provided above in Table H for crystalline form 4.10. Data collection 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, collection time: 718 sec, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 sec, mode: transmission.

[0238] The XRPD pattern in Figure 23 indicates that the indexing was successful and the sample consists primarily or exclusively of a single crystalline phase. The unit cell volume obtained from the indexed solution is consistent with the presence of up to about 0.5 moles of MeOH.

[0239] The TGA thermogram of the product (1.2348 mg) is shown in Figure 29. Almost no weight loss was observed up to 90°C (0.5 wt% loss from 60°C to 90°C). A gradual weight loss of 4.2 wt% was observed from 90°C to 150°C, which is thought to correspond to the loss of solvent. If only MeOH was considered to have evaporated, the weight loss corresponds to 0.6 mol 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 slurried in water (pH 5) at room temperature for 5 minutes. Slurrying is continued at room temperature for 24 hours. The solution is vacuum filtered. A subsample (portion 1), which appears as an off-white paste, is removed. The remainder (portion 2) is allowed to air dry on the filter for 5 minutes. The pH of the water after slurrying is 1.6.

[0241] Further experimental details of the synthesis are described in this paragraph. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (74.6 mg) from Example 2A is used to prepare a suspension of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate. The suspension is left stirring at 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 and recovered from the filter while still moist (portion 1). Another portion of the resulting solid is vacuum filtered and dried on the filter under reduced pressure for 5 minutes (portion 2).

[0242] The XRPD pattern of portion 1 is shown in Figure 24. The XRPD pattern is also shown in Figure 44. The XRPD pattern was obtained as described in the general XRPD method in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD pattern shown in Figure 23 are provided above in Table J for crystalline form 5.14. Data collection 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, collection time: 718 seconds, scan rate 3.3° / min, slits: DS:½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0243] The XRPD pattern in Figure 24 (also shown in Figure 44) indicates that the indexing was successful and the sample consists primarily or exclusively of a single crystalline phase. The unit cell volume obtained from the indexed solution can accommodate up to 3 moles of water in Formula I per mole of Formula I.

[0244] The XRPD pattern of portion 2 also indicates that it is Form N. The XRPD pattern of portion 2 is shown in Figure 45. The XRPD pattern was obtained as described in the general XRPD method in Example 1. Data collection 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, collection time: 719 seconds, scan rate 3.3° / min, slits: DS:½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0245] DSC and TGA thermograms were obtained for Portion 2 (DSC parameters: weight: 1.4620 mg, method: (-30)-250-10, T0C, instrument: 2920 MDSC V2.6A, TGA: 7.61023 mg). An overlay of the DSC and TGA thermograms is shown in Figure 26. The sample exhibited two separate weight loss steps of 3.5 wt% from 23°C to 70°C and 3.6 wt% from 70°C to 105°C, which correspond to a series of overlapping endotherms at 85°C, 91°C, and 95°C by DSC. If only water is considered to have evaporated, each weight loss corresponds to one 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% weight loss is observed in the TGA thermogram from 105°C to 160°C. Following dehydration, a small endotherm was observed at 118°C, likely corresponding to a crystallization event. A relatively sharp endotherm was seen at 178°C with an onset at 169°C, likely corresponding to concomitant melting and decomposition, as evidenced by a sharp drop in the TGA thermogram and erratic thermal behavior by DSC above 175°C. The possible melting onset is slightly lower than that for anhydrous / unsolvated Form B (169°C vs. 173°C for Form B), suggesting that Form N does not convert to Form B upon dehydration.

[0246] To further confirm the chemical composition of Form N, the material was slurried in hexafluoroisopropanol (HFIPA) for 1 day, resulting in conversion to Form B (containing a minor peak at 23°2θ) by XRPD. The XRPD pattern of the product is shown in Figure 49. The XRPD pattern was obtained as described in the General XRPD Method in Example 1. Data collection 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, collection time: 718 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 second, 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 EtOAc and evaporated. The solid is then slurried in water at room temperature and vacuum filtered.

[0248] Further experimental details for the synthesis are described in this paragraph. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (127.6 mg) from Example 2B and water (5 mL) are used to prepare a suspension of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate. The suspension is left stirring at 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 Form N. The XRPD pattern of the product is shown in Figure 46. The XRPD pattern was obtained as described in the General XRPD Method in Example 1. Data collection 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, collection time: 721 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0250] The DVS isotherm of the product is shown in Figure 27. The product exhibited a 30% weight loss upon equilibration to 5% relative humidity, which is believed to represent the loss of residual water. The presence of residual water is consistent with the >100% yield obtained from the preparation of the product. It is unclear whether potential unbound water is also lost during this equilibration step. Increasing the relative humidity from 5% to 95% resulted in a 3% weight gain for the sample, indicating hygroscopicity. All of this weight was lost via 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 was obtained as described in General XRPD Methodology in Example 1. Data collection 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, collection time: 720 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, 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 percent moisture content by KF is lower than the percent weight loss seen in the DVS test at 100% relative humidity, likely due to partial drying during analysis and / or preparation for KF analysis.

[0252] Example 10 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Form B) Add hexafluoroisopropanol (HFIPA) to 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, refrigerate the solution for 2 months, and vacuum filter.

[0253] Further experimental details for the synthesis are described in this paragraph. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (29.3 mg) from Example 2A was combined with hexafluoroisopropanol (HFIPA) under sonication to yield a thick, opaque suspension. The sample was stored refrigerated for 2 months, after which the solid was collected by vacuum filtration. The suspension was left stirring at ambient conditions to yield an opaque white suspension. The resulting solid was isolated by vacuum filtration and dried on the filter under reduced pressure for 0.5–1 min.

[0254] The solvent is 1 Not detected by 1 H NMR, indicating that this is a non-solvated material.

[0255] The XRPD pattern of the product is shown in Figure 21 (Form B + minor peak at approximately 23°θ). The XRPD pattern is also shown in Figure 37. The XRPD pattern was obtained as described in the general XRPD method in Example 1. The 2θ values, d-spacings, and peak intensities for the XRPD pattern shown in Figure 21 are provided above in Table D for crystalline Form 6.11. Data collection 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: 1.01-39.98°2θ, step size: 0.017°2θ, collection time: 718 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 second, mode: transmission.

[0256] The XRPD patterns in Figure 21 (also shown in Figure 37) were successfully indexed, indicating that the samples consist primarily or exclusively of a single crystalline phase. However, an additional broad peak at approximately 23°2θ is present in all XRPD patterns of Form B discussed herein, and the peak positions given by the indexed solutions do not match, indicating that the Form B samples contain an additional unknown phase. The unit cell volumes obtained from the indexed solutions are consistent with the anhydrous / non-solvated Formula I.

[0257] An overlay of the DSC and TGA thermograms is shown in Figure 40 (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 0.7% weight loss between 23°C and 150°C. No broad desolvation endotherm is observed by DSC, consistent with an anhydrous / unsolvated material. The DSC thermogram shows a sharp endotherm at 177°C (onset 173°C), which is believed to correspond to melting and simultaneous decomposition, as evidenced by erratic thermal behavior by DSC and a sharp 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 was stirred with 1N HCl in EtOAc and evaporated. Acetonitrile was then added to the solid with stirring for a few minutes. MeOH was added with stirring. Toluene was added with stirring (toluene / acetonitrile / MeOH 24:6:1 v / v / v). Partially evaporated slowly. The liquid phase was filtered and the solid was discarded. Evaporated under N2 for 5 minutes. Hexafluoroisopropanol (HFIPA) was added to the solid. Slurry at room temperature for 1 day, then vacuum filtered.

[0259] Further experimental details of the synthesis are described in this paragraph. While stirring, 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (86.9 mg) from Example 2B was dissolved in acetonitrile to obtain a clear solution. After stirring for several minutes, precipitation was observed. While stirring, MeOH (0.1 mL) was added to obtain a clear solution. Toluene (2.4 mL) was then added (toluene / acetonitrile / MeOH 24:6:1 v / v / v) to obtain a clear solution. The solution was allowed to stand and partially evaporate from a vial covered with punctured aluminum foil for 1 day to obtain a clear liquid phase with a small amount of solid on the solvent surface and bottom. The liquid phase was filtered through a 0.2 μm nylon filter to obtain a clear solution, and the solid was discarded. The filtered solution was connected to a rotary evaporator equipped with a water bath at 60-69 °C. After 30 minutes of evaporation, no significant volume loss was observed. The solution is then evaporated under a stream of N2 until no visible liquid remains (5 min). The resulting white solid is combined with hexafluoroisopropanol (HFIPA) (2 ml) until 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 min.

[0260] The XRPD pattern of the product indicates that it is Form B (Form B plus a minor 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 in Example 1. Data collection 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, collection time: 716 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0261] The hygroscopicity of Form B is assessed by DVS and by stress at elevated relative humidity, respectively (see Example 12 for elevated relative humidity).

[0262] The DVS isotherm for Form B is shown in Figure 28. The material exhibits a 0.04 wt% weight loss at 5% relative humidity. The material exhibits relatively low kinetic hygroscopicity, picking up 0.6 wt% water vapor by absorbing from 5% to 95% relative humidity. All of this weight loss is due to desorption, with slight hysteresis noted. XRPD analysis of the material after DVS indicates that the form remains unchanged. The XRPD pattern of the material after DVS is shown in Figure 55. The XRPD pattern was obtained as described in General XRPD Methodology in Example 1. Data collection 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: 1.01-39.98°2θ, step size: 0.017°2θ, collection time: 719 seconds, scan rate 3.3° / min, slits: DS: ½°, 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 slurried at room temperature for 4 days and then vacuum filtered.

[0264] XRPD of the product shows it to be Form B (Form B plus a minor peak at approximately 23°θ). The XRPD pattern of the product is shown in Figure 42. The XRPD pattern was obtained as described in the General XRPD Method in Example 1. Data collection 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: 1.01-39.98°2θ, step size: 0.017°2θ, collection time: 719 seconds, scan rate: 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0265] The product is loaded at 97% relative humidity for 7 days, resulting in partial conversion to Form N. The noted partial conversion after 7 days indicates that Form B is completely converted to hydrate Form N after an extended period of time.

[0266] The product is converted to Form N by slurrying with water at room temperature for 7 days and vacuum filtered. The XRPD pattern of the product is shown in Figure 50. The XRPD pattern was obtained as described in Example 1, General XRPD Method. Data collection 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, collection time: 715 seconds, scan rate: 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0267] The slurrying was repeated for 19 hours to determine how quickly the conversion occurred and Form N reappeared, indicating a change in form within 19 hours (starting materials were products 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 General XRPD Method in Example 1. Data collection 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, collection time: 719 seconds, scan rate: 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, 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 equiv.) was dissolved in toluene (1500 mL) and phosphorus trichloride (22 mL, 250.82 mmol, 0.5 equiv.) was added in small portions over 15 minutes at room temperature. 3,5-bis-trifluoromethyl-phenylamine (100 g, 436.4 mmol, 0.87 equiv.) was then added in one portion to the reaction mixture at room temperature. The reaction mixture was heated to 105 ± 5 °C and stirred at this temperature for an additional 16 hours. After completion of the reaction by TLC (10% ethyl acetate:hexane), the reaction was then cooled to room temperature. The reaction mixture was quenched with a solution of NaHCO3 (50 g) in water (800 mL), and the resulting solution was stirred for 15–20 minutes. Both the organic and aqueous layers were separated and collected. The upper organic layer is washed with a solution of concentrated hydrochloric acid (25 mL) in water (400 mL) and brine (400 mL) and dried over Na2SO4. The organic layer is filtered and concentrated under reduced pressure to give a white solid. Heptane (500 mL) is added to the white solid and the resulting suspension is stirred at room temperature for 30 minutes and filtered to give 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 N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (145 g, 377.9 mmol, 1 equiv.) was dissolved in CH3CN (1450 mL). DMAP (2.77 g, 22.67 mmol, 0.06 equiv.), N,N-diisopropylethylamine (DIPEA) (97.74 g, 755.98 mmol, 2 equiv.), and CCl4 (290.7 g, 1889.9 mmol, 5 equiv.) were added to the solution in this order at room temperature under stirring. The reaction mixture was cooled to 0 °C and, while maintaining the temperature below 2 °C, a solution of the phosphite reagent ((CH3)3SiCH2CHO)2P(O)H) (160.7 g, 599.9 mmol, 1.5 equiv.) in CH3CN (145 mL) was added dropwise over 30 min. The reaction mixture is allowed to warm to room temperature and stirred at room temperature for 22 hours. After completion of the reaction by 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 extracts are washed with brine (1.450 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to give crude material (271 g), which is used directly in the next step. HPLC=82.9%

[0270] Step 3 Phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester 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 completion of the reaction by 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 give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl]ester as an off-white solid (160 g).

[0271] Step 4 Purification The crude solid (160 g, 345.05 mmol, 1 equiv.) was added to a solution of NaOH (80 g, 2000 mmol, 5.8 equiv.) in water (4 L) and stirred at room temperature for 45 min. The aqueous solution was extracted twice with ethyl acetate (2 × 1.6 L). The aqueous solution was then acidified to pH 1 with concentrated HCl (230–250 mL) and extracted twice with ethyl acetate (2 × 1.6 L). The combined ethyl acetate extracts obtained after acidification were dried over sodium sulfate and concentrated under reduced pressure to give 140 g of a colorless oil. The oil was dissolved in ethyl acetate (160 mL) and stirred at room temperature for 30 min. With continued stirring, n-heptane (1.44 L) was added. The reaction mixture was stirred at room temperature for 3 h and filtered. The solid is washed with n-heptane (80 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester as an off-white solid (124 g). NMR shows an acetic acid peak. HPLC=98.8%

[0272] Step 5 Re-purification The off-white solid (124 g) is dissolved in ethyl acetate (124 mL), stirred at room temperature for 30 minutes, and n-heptane (1.11 L) is added with stirring. The reaction mixture is stirred at room temperature for 3 hours and filtered. The solid is washed with n-heptane (62 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] 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 equiv.) was dissolved in toluene (1500 mL) and phosphorus trichloride (22 mL, 250.82 mmol, 0.5 equiv.) was added in small portions over 15 minutes at room temperature. 3,5-bis-trifluoromethyl-phenylamine (100 g, 436.4 mmol, 0.87 equiv.) was then added in one portion to the reaction mixture at room temperature. The reaction mixture was heated to 105 ± 5 °C and stirred at this temperature for an additional 16 hours. The reaction progress was monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After completion of the reaction by TLC (10% ethyl acetate:hexane), the reaction was then cooled to room temperature. The reaction mixture was quenched with a solution of NaHCO3 (50 g) in water (800 mL), and the resulting solution was stirred for 15–20 minutes. Both the organic and aqueous layers were separated and collected. The upper organic layer is washed with a solution of concentrated hydrochloric acid (25 mL) in water (400 mL) and brine (400 mL) and dried over Na2SO4. The organic layer is filtered and concentrated under reduced pressure to give a white solid. Heptane (500 mL) is added to the white solid and the resulting suspension is stirred at room temperature for 30 minutes and filtered to give 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, triethylamine (228 g, 2.255 mol, 2.0 eq) was added to a cooled solution of trimethylsilylethanol (400 g, 3.382 mol, 3.0 eq) in DCM (7.0 L) at 0 °C. PCl3 (154.8 g, 1.127 mol, 1.0 eq) was then added in small portions over 45 min at 0–10 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was allowed to warm to room temperature. DM water (2.0 L) was added to the reaction mixture and stirred at room temperature for 1 h. The lower organic layer was separated, and the upper aqueous layer was extracted with DCM (1.6 L). The combined organic extracts were washed with DM water (2.0 L) and dried over Na2SO4. The organic layer is concentrated under vacuum at 45°C and degassed at 4°C for 30 minutes to give the crude phosphite reagent as a light brown oil (450.0 g) which is stored at 0-5°C.

[0275] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (150 g, 391 mmol, 1 equiv.) was dissolved in CH3CN (1500 mL). DMAP (2.86 g, 23.46 mmol, 0.06 equiv.), DIPEA (101.07 g, 782 mmol, 2 equiv.), and CCl4 (300 g, 1955 mmol, 5 equiv.) were added to the above solution in this order at room temperature under stirring. The reaction mixture was cooled to 0 °C and, while maintaining the temperature below 2 °C, a solution of the phosphite reagent {((CH3)3SiCH2CHO)2P(O)H)} (166 g, 586.5 mmol, 1.5 equiv.) in CH3CN (150 mL) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 22 h. The progress of the reaction is monitored by TLC (mobile phase 10% ethyl acetate in hexane). After completion of the reaction by 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 extracts are washed with brine (1.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to give the crude material (285 g), which is used directly in the next step.

[0276] Step 3 Phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester 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 completion of the reaction 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 give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl]ester as an off-white wet solid (212 g).

[0277] The wet solids (212 g) are divided into two equal parts.

[0278] Dry the first wet portion (106 g) at room temperature for 14 hours to obtain the dried solid as an off-white solid (88 g). HPLC = 96.0%

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

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

[0281] Step 4(i) Purification The crude solid (25 g from the first portion of Step 3 + 25 g from the second portion of Step 3, total 50 g, 107.82 mmol, 1 equiv.) was added to a solution of NaOH (25 g, 625 mmol, 5.8 equiv.) in water (1.25 L) and stirred at room temperature for 45 min. The aqueous solution was extracted twice with ethyl acetate (2 x 0.5 L) to remove impurities. The aqueous solution was then acidified with concentrated HCl (70-80 mL) and extracted twice with ethyl acetate (2 x 0.5 L). The combined ethyl acetate extracts obtained after acidification were dried over sodium sulfate and concentrated under reduced pressure to give 41 g of a colorless oil. The oil was dissolved in ethyl acetate (50 mL) and stirred at room temperature for 30 min. While stirring, n-heptane (0.450 L) was added. The reaction mixture was stirred at room temperature for 3 h and filtered. The solid is washed with n-heptane (25 mL) and dried under vacuum for 30 minutes to give the product, phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester as an off-white solid (25 g). HPLC=96.7%

[0282] Step 4(ii) Purification of the remaining amount (110 g) from Step 3 The crude solid (60 g from the first portion of Step 3 + 50 g from the second portion of Step 3, total 110 g, 237.22 mmol, 1 equiv.) was added to a solution of NaOH (55 g, 1375 mmol, 5.8 equiv.) in water (1.75 L) and stirred at room temperature for 45 min. The aqueous solution was extracted twice with ethyl acetate (2 x 1.1 L) to remove impurities. The aqueous solution was then acidified with concentrated HCl (160-180 mL) and extracted twice with ethyl acetate (2 x 1.1 L). The combined ethyl acetate extracts obtained after acidification were dried over sodium sulfate and concentrated under reduced pressure to give 105 g of a colorless oil. The oil was dissolved in ethyl acetate (110 mL) and stirred at room temperature for 30 min. While stirring, n-heptane (0.990 L) was added. The reaction mixture was stirred at room temperature for 3 h and filtered. The solid is washed with n-heptane (55 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester product-1 (65 g). The precipitate in the filtrate is filtered again to give product-2 as a white solid (11 g). NMR shows a peak for acetic acid. HPLC=95.8%

[0283] Step 5 Re-purification The off-white solid (Product-1 and Product-2) (76 g) is dissolved in ethyl acetate (76 mL), heated to 50° C. to completely dissolve the solid, stirred at room temperature for 30 minutes, and n-heptane (684 mL) is added with stirring. The reaction mixture is stirred at room temperature for 3 hours and filtered. The solid is washed with n-heptane (38 mL) and dried under vacuum for 30 minutes to obtain the pure product, repurified phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester, Product-1 (35 g). The precipitate that reappears in the filtrate is filtered to obtain repurified Product-2 as a white solid (30 g). Repurified Product-1 HPLC = 97.6%, Repurified Product-2 HPLC = 99.5%

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

[0285] The XRPD patterns of the products are shown in Figure 52 (Form N and unknown). The XRPD patterns were obtained as described in General XRPD Method in Example 1. Data collection 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, collection time: 719 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

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

[0287] Example 15 2.5 to 5 equivalents of tris(hydroxymethyl)aminomethane is added to crystalline 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (e.g., 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 vortex or sonicate the solution to obtain a 10 mg / ml to 20 mg / ml solution that is stable for at least 24 hours.

[0289] The HPLC conditions for assaying the stability of a composition 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 per minute of 10% to 100% acetonitrile (containing a solution of 2 g of ammonium acetate per 4 L of water) Waters 2695 hplc running Millennium 32 software No baseline subtraction

[0290] Example 16 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate 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 equiv.) was dissolved in toluene (375.0 mL) and phosphorus trichloride (5.5 mL, 63.45 mmol, 0.5 equiv.) was added in small portions over 15 minutes at room temperature. 3,5-bis-trifluoromethyl-phenylamine (25.0 g, 110.4 mmol, and 0.87 equiv.) was then added in one lot to the reaction mixture at room temperature. The reaction mixture was heated to 105 ± 5 °C and stirred at this temperature for an additional 16 hours. The progress of the reaction was monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After completion of the reaction by TLC (10% ethyl acetate:hexane), the reaction was cooled to room temperature. The reaction mixture was poured onto a silica gel (0.5 kg) column, and after evaporation of the solvent, the column was eluted with ethyl acetate (1.5 L) to obtain a white solid. The solid thus obtained 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 give 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] To a cooled solution of trimethylsilylethanol (50.0 g, 422.8 mmol, 3.0 equiv.) in DCM (0.875 L) under a nitrogen atmosphere at 0 °C, triethylamine (28.5 g, 281.8 mmol, 2.0 equiv.) is added. PCl3 (19.3 g, 281.07 mmol, 1.0 equiv.) is then added in small portions over 45 min at 0–10 °C. The reaction mixture is stirred at 0 °C for 1 h. The reaction mixture is allowed to warm to room temperature. DM water (0.25 L) is added to the reaction mixture, stirred at room temperature for 1 h, and the layers are separated. The aqueous layer is extracted with DCM (0.25 L). The combined organic extracts are washed with DM water (0.25 L) and dried over Na2SO4. The organic layer is concentrated under vacuum at 45°C and degassed at 45°C for 30 minutes to give the crude phosphite reagent as a light brown oil (45.0 g) which is stored at 0-5°C.

[0292] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenylbis(2-(trimethylsilyl)ethyl)phosphate N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (30.0 g, 78.19 mmol, 1.0 equiv.) was dissolved in CH3CN (300.0 mL). DMAP (0.57 g, 4.69 mmol, 0.06 equiv.), DIPEA (27.2 mL, 156.38 mmol, 2.0 equiv.), and CCl4 (60.1 g, 390.96 mmol, 5.0 equiv.) were added to the above solution in this order at room temperature while stirring. The reaction mixture was cooled to 0 °C and, under controlled conditions below 2 °C, a solution of the phosphite reagent (33.10 g, 117.28 mmol, 1.5 equiv.) in CH3CN (30 mL) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 22 h. The progress of the reaction is monitored by TLC (mobile phase 10% ethyl acetate in hexane). After completion of the reaction by 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 extracts are washed with brine (0.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to give the crude material (56.0 g), which is used directly in the next step.

[0293] Step 3: Phosphoric acid mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl]ester [ka] Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate (55.0 g, 82.81 mmol, 1.0 equiv) 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 reaction progress is monitored by TLC (mobile phase 10% ethyl acetate in hexane). The reaction mixture is concentrated under vacuum below 70 °C to remove volatile solvents. The residue is added to a solution of NaOH (18.0 g, 450.0 mmol, and 5.4 equiv) in water (0.55 L) and stirred at room temperature for 15 minutes. The aqueous solution is washed twice with ethyl acetate (2 × 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 × 0.825 L). The combined ethyl acetate extracts obtained after acidification are dried over sodium sulfate and concentrated under reduced pressure to give 35 g of a colorless oil. The oil is dissolved in ethyl acetate (35 mL) and, with stirring, n-heptane (175.0 mL) is added. The reaction mixture is stirred at room temperature for 3 hours and filtered. The solid is washed with n-heptane (55 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester as an off-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 was obtained as described in General XRPD Method in Example 1. Data collection 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, collection time: 720 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0295] Example 17 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A+minor 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 equiv.) was dissolved in toluene (375.0 mL) and phosphorus trichloride (5.5 mL, 63.45 mmol, 0.5 equiv.) was added in small portions over 15 minutes at room temperature. 3,5-bis-trifluoromethyl-phenylamine (25.0 g, 110.4 mmol, and 0.87 equiv.) was then added in one lot to the reaction mixture at room temperature. The reaction mixture was heated to 105 ± 5 °C and stirred at this temperature for an additional 16 hours. The progress of the reaction was monitored by TLC (mobile phase: 10% ethyl acetate in hexane). After completion of the reaction by TLC (10% ethyl acetate:hexane), the reaction was cooled to room temperature. The reaction mixture was poured onto a silica gel (0.5 kg) column, and after evaporation of the solvent, the column was eluted with ethyl acetate (1.5 L) to obtain a white solid. The solid thus obtained is suspended in n-heptane (150.0 mL) and stirred at room temperature for 1 hour. The suspension is filtered to give 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 To a cooled solution of trimethylsilylethanol (50.0 g, 422.8 mmol, 3.0 equiv.) in DCM (0.875 L) under a nitrogen atmosphere at 0 °C, triethylamine (28.5 g, 281.8 mmol, 2.0 equiv.) is added. PCl3 (19.3 g, 281.07 mmol, 1.0 equiv.) is then added in small portions over 45 min at 0–10 °C. The reaction mixture is stirred at 0 °C for 1 h. The reaction mixture is allowed to warm to room temperature. DM water (0.25 L) is added to the reaction mixture, stirred at room temperature for 1 h, and the layers are separated. The aqueous layer is extracted with DCM (0.25 L). The combined organic extracts are washed with DM water (0.25 L) and dried over Na2SO4. The organic layer is concentrated under vacuum at 45°C and degassed at 45°C for 30 minutes to give the crude phosphite reagent as a light brown oil (44.0 g) which is stored at 0-5°C.

[0297] Preparation of 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (30.0 g, 78.19 mmol, 1.0 equiv.) was dissolved in CH3CN (300.0 mL). DMAP (0.57 g, 4.69 mmol, 0.06 equiv.), DIPEA (27.2 mL, 156.38 mmol, 2.0 equiv.), and CCl4 (60.1 g, 390.96 mmol, 5.0 equiv.) were added to the above solution in this order at room temperature while stirring. The reaction mixture was cooled to 0 °C and, under controlled conditions below 2 °C, a solution of phosphite reagent (33.10 g, 117.28 mmol, 1.5 equiv.) in CH3CN (30 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 22 h. The progress of the reaction is monitored by TLC (mobile phase 10% ethyl acetate in hexane). After completion of the reaction by 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 extracts are washed with brine (0.5 L), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to give the crude material (56.0 g), which is used directly in the next step.

[0298] Step 3: Phosphoric acid mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl]ester Crude 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl bis(2-(trimethylsilyl)ethyl)phosphate (55.0 g, 82.81 mmol, 1.0 equiv) is added to a mixture of TFA:water (5:1, 428.0 mL). The reaction mixture is stirred at room temperature for 3.0 h. The reaction progress is monitored by TLC (mobile phase 10% ethyl acetate in hexane). The reaction mixture is concentrated under vacuum below 70 °C to remove volatile solvents. The residue is added to a solution of NaOH (18.0 g, 450.0 mmol, and 5.4 equiv) in water (0.55 L) and stirred at room temperature for 15 min. The aqueous solution is washed twice with ethyl acetate (2 × 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 × 0.825 L). The combined ethyl acetate extracts obtained after acidification are dried over sodium sulfate and concentrated under reduced pressure to give 38.0 g of a colorless oil. The crude oil is dissolved in ethyl acetate (15.0 mL) and, with stirring, n-heptane (175.0 mL) is added. The reaction mixture is stirred at room temperature for 3.0 hours and filtered. The solid is washed with n-heptane (35.0 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester as an off-white solid (12.4 g). HPLC = 96.4%

[0299] The XRPD pattern of the product is shown in Figure 39 (Form A and unknown components). The XRPD pattern was obtained as described in General XRPD Method in Example 1. Data collection 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, collection time: 721 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0300] Example 18 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 (165.0 g, 0.355 mol, 1.0 equiv.) was added to a solution of NaOH (82.5 g, 2.062 mol, 5.8 equiv.) in water (4.12 L) and stirred at room temperature for 45 min. The aqueous solution was washed twice with ethyl acetate (2 x 1.65 L) to remove impurities. The combined organic layers were extracted with water (0.82 L). The combined aqueous layers were acidified with concentrated HCl (230.0-250.0 mL) and extracted twice with ethyl acetate (2 x 1.65 L). The combined ethyl acetate extracts obtained after acidification were dried over sodium sulfate and concentrated under reduced pressure to give 140.0 g of a colorless oil. The oil was dissolved in ethyl acetate (165.0 mL) and stirred at room temperature for 30 min. While stirring, n-heptane (82.0 mL) is added. The mixture is stirred at room temperature for 3.0 hours and filtered. The solid is washed with n-heptane (82.0 mL) and dried under vacuum for 30 minutes to give phosphoric acid mono[2-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-4-chloro-phenyl] ester as an off-white solid (118.0 g). HPLC=95.0%

[0301] Dissolve the off-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 the pure wet product. Dry the wet solid at room temperature for 3 days and 17 hours to obtain the dry product as an off-white solid (95.0 g). HPLC = 99.4%

[0302] The off-white solid (95.0 g) was stirred with toluene (0.95 L) for 30 minutes and filtered. The solid was washed with toluene (95.0 mL) to give phosphoric acid mono[2-(3,5-bis-trifluoromethylphenylcarbamoyl)-4-chlorophenyl] ester as a white solid (90.0 g). HPLC = 99.4%

[0303] The XRPD pattern of the product is shown in Figure 48 (Form N). The XRPD pattern was obtained as described in General XRPD Method in Example 1. Data collection 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, collection time: 721 seconds, scan rate 3.2° / min, slits: DS:½°, SS: null, rotation time: 1.0 seconds, 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 from Example 2A in 2,2,2-trifluoroethanol (TFE) is capped and slowly cooled from 73°C to room temperature and allowed to stand at room temperature for 3 days. The solution is stored at room temperature for 29 days and then vacuum filtered. XRPD of the product indicates that the product is Form B (Form B + minor peak at approximately 23°θ, PO). The XRPD of the product is shown in Figure 43. The XRPD pattern is obtained as described in General XRPD Methodology in Example 1. Data collection 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: 1.01-39.98°2θ, step size: 0.017°2θ, collection time: 718 seconds, scan rate 3.3° / min, slits: DS: ½°, 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 from Example 2A. The sample is stirred (500 rpm) at ambient temperature for 24 hours. After 24 hours, the sample is centrifuged (13,000 rpm for 5 minutes) and the supernatant is filtered through a 0.45 μm PVDF filter. The XRPD pattern of the solid from the centrifuged sample is shown in Figure 57, indicating that the solid is Form N. The XRPD pattern is obtained as described in the general XRPD method in Example 1. Data collection 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: 1.00-39.98°2θ, step size: 0.017°2θ, collection time: 720 seconds, scan rate 3.2° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, 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 from Example 2B is slurried in hexafluoroisopropanol (HFIPA) for 4 days and vacuum filtered. XRPD of the product indicates that the product is Form B (Form B + minor peak at approximately 23°θ, PO). The XRPD pattern of the product is shown in Figure 53. The XRPD pattern is obtained as described in the general XRPD method in Example 1. Data collection 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, collection time: 719 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0307] Example 22 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate ethyl acetate solvate (Form A) powdered with Tris base 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate is powdered with Tris base. The top XRPD pattern in Figure 47 shows Form A powdered with Tris base. The XRPD is also shown in Figure 56. The XRPD pattern is consistent with a physical mixture of Form A and Tris base, indicating that the formulation does not alter the form. The XRPD pattern is obtained as described in Example 1, General XRPD Method. Data collection 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, collection time: 717 seconds, scan rate: 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0308] Example 23 Drying Test of Form A Several attempts are made to dry Form A. Stringent conditions are initially selected due to the high temperature range (90°C) at which TGA weight loss is observed. Drying at 80°C under vacuum for 1 day yields a brown solid that adheres to the vial. A weight loss of 30% is calculated by gravimetric measurement, and the resulting solid does not appear crystalline by optical microscopy.

[0309] A drying experiment under milder conditions is attempted. The experiment begins by drying under vacuum at ambient temperature. No significant gravimetric weight change is measured, so the temperature is gently increased and the weight monitored. After 6 hours at 63-65°C, a small weight loss is observed, so the sample is held at this temperature for 1 day in a vacuum oven, resulting in an 11% gravimetric weight loss. The resulting light brown solid sticks to the vial and is not crystalline under an optical microscope. These experiments indicate that vacuum drying of Form A at elevated temperatures tends to cause decomposition and disruption of the crystalline structure.

[0310] Example 24 Form A 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from Example 2B is crash-cooled in a freezer from a solution of heptane / EtOAc (80:20, v / v) at 75° C. and then allowed to stand in the freezer for 3 hours. The liquid phase is decanted and the solid is briefly dried under N. The XRPD pattern of the product is shown in Figure 58 (Form A, PO). The XRPD pattern is obtained as described in General XRPD Methodology in Example 1. Data collection 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, collection time: 718 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission.

[0311] 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate from Example 2B is rapidly cooled to room temperature from a solution in heptane / EtOAc (80:20, v / v) at 75° C., and then allowed to stand at room temperature for 3 hours. The liquid phase is decanted, and the solid is briefly dried under N. The XRPD pattern of the product is shown in Figure 59 (Form A, PO). The XRPD pattern is obtained as described in General XRPD Methodology in Example 1. Data collection 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, collection time: 718 seconds, scan rate 3.3° / min, slits: DS: ½°, SS: null, rotation time: 1.0 seconds, mode: transmission. Furthermore, the present invention includes the following aspects: 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the structure below, exhibiting an XRPD pattern including at least five 2θ (°) values ​​selected from the group consisting of: 1.8.8, 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 radiation at 1.54059 Å. [ka] Hydrate of. At least one XRPD pattern containing at least five 2θ (°) values ​​selected from the group consisting of: 2.4.7, 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. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the structure below, wherein the XRPD is measured using an incident beam of CuKα radiation or exhibits an XRPD pattern including d-spacing (Å) values ​​of at least 5 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 [ka] Hydrate of. The hydrate of paragraph 2, exhibiting an XRPD pattern comprising at least 12 d-spacing (Å) values ​​selected from the group consisting of paragraphs 3.1, 8.7, 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. Section 4. The hydrate described in section 2, exhibiting an XRPD pattern comprising d-spacing (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. Section 5. The hydrate of section 2, exhibiting at least one of an XRPD pattern comprising 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 radiation having a wavelength of 1.54059 Å; or an XRPD pattern comprising d-spacing (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. Item 6. At least one XRPD pattern containing at least five 2θ (°) values ​​as set forth in Table I below, wherein the XRPD is measured using an incident beam of CuKα radiation with a wavelength of 1.54059 Å; or [Table 19] exhibiting an XRPD pattern containing at least 5 2θ (°) values ​​as set forth in Table J below, wherein the XRPD is measured using an incident beam of CuKα radiation having a wavelength of 1.54059 Å; [Table 20] Or the hydrate according to item 2, which exhibits an XRPD pattern containing at least 5 d-spacing (Å) values ​​shown in Table I or Table J above. Item 7. At least one XRPD pattern comprising the 2θ (°) values ​​set forth in Table I below, wherein the XRPD is measured using an incident beam of CuKα radiation with a wavelength of 1.54059 Å; [Table 21] 1 shows an XRPD pattern comprising the 2θ (°) values ​​shown in Table J below, wherein the XRPD is measured using an incident beam of CuKα radiation with a wavelength of 1.54059 Å; [Table 22] Or the hydrate according to item 2, which has an XRPD pattern including the d-spacing (Å) values ​​shown in Table I or Table J above. Item 8. The hydrate according to any one of Items 1 to 7, which contains 14% water according to Karl Fischer analysis. Item 9. A pharmaceutical composition comprising the hydrate according to any one of items 1 to 8. Item 10. The pharmaceutical composition according to Item 9 for treating edema, epilepsy, neuromyelitis optica, migraine, hyponatremia, retinal ischemia or other eye diseases associated with abnormalities in intraocular pressure and / or tissue hydration, excess water retention, myocardial ischemia, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, glioblastoma, ovarian hyperstimulation syndrome, pulmonary edema, fibromyalgia or multiple sclerosis. Item 11. The pharmaceutical composition according to Item 10, wherein the edema is cerebral edema. Item 12. The pharmaceutical composition according to Item 11, wherein the cerebral edema is caused by ischemic stroke. Item 13. The pharmaceutical composition according to Item 11 or 12, wherein the cerebral edema is cytotoxic cerebral edema. Item 14. The pharmaceutical composition according to Item 10, wherein the edema is spinal cord edema or cardiac edema. Item 15. The pharmaceutical composition according to Item 14, wherein the cardiac edema is due to cardiac ischemia or other obstruction of blood flow to the heart. Item 16. The pharmaceutical composition according to Item 15, wherein the edema is caused by transplantation. Item 17. A method for producing a pharmaceutical composition containing the mono- or dianion of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, the method comprising mixing the hydrate according to any one of Items 1 to 8 with a pharmaceutically acceptable liquid. Item 18. The method according to Item 17, wherein the pharmaceutically acceptable liquid is an aqueous solution containing a base. Item 19. The method of item 17, wherein the hydrate and the base are mixed before mixing with the pharmaceutically acceptable liquid. Item 20. The method according to Item 18 or 19, wherein the base is an amine and / or a salt thereof. Item 21. The method according to Item 20, wherein the base is tris(hydroxymethyl)aminomethane and / or a salt thereof, meglumine and / or diethanolamine. Item 22. The method according to any one of Items 17 to 21, wherein the pharmaceutical composition is for injection.

Claims

1. 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the structure below, exhibiting an XRPD pattern containing at least five 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 radiation at 1.54059 Å. 【Chemistry 1】 Hydrate of.

2. exhibiting at least one XRPD pattern comprising at least five 2θ (°) values ​​selected from the group consisting of: 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; 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, represented by the structure below, wherein the XRPD is measured using an incident beam of CuKα radiation or exhibits an XRPD pattern including at least 5 d-spacing (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 【Chemistry 2】 Hydrate of.

3. 3. The hydrate of claim 2, exhibiting an XRPD pattern comprising at least 12 d-spacing (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. 3. The hydrate of claim 2, exhibiting an XRPD pattern comprising d-spacing (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. 3. The hydrate of claim 2, wherein the hydrate exhibits at least one of an XRPD pattern comprising 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 radiation having a wavelength of 1.54059 Å; or an XRPD pattern comprising d-spacing (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. exhibiting at least one XRPD pattern containing at least five 2θ (°) values ​​as set forth in Table I below, wherein the XRPD is measured using an incident beam of CuKα radiation having a wavelength of 1.54059 Å; Table 1 exhibiting an XRPD pattern containing at least 5 2θ (°) values ​​as set forth in Table J below, wherein the XRPD is measured using an incident beam of CuKα radiation having a wavelength of 1.54059 Å; Table 2 or the hydrate of claim 2, which exhibits an XRPD pattern comprising a d-spacing (Å) value of at least 5 as shown in Table I or Table J above.

7. exhibiting at least one XRPD pattern comprising the 2θ (°) values ​​set forth in Table I below, wherein the XRPD is measured using an incident beam of CuKα radiation having a wavelength of 1.54059 Å; Table 3 1 shows an XRPD pattern with 2θ (°) values ​​as shown in Table J below, wherein the XRPD is measured using an incident beam of CuKα radiation with a wavelength of 1.54059 Å; Table 4 or the hydrate of claim 2, which exhibits an XRPD pattern comprising the d-spacing (Å) values ​​shown in Table I or Table J above.

8. 8. The hydrate according to any one of claims 1 to 7, which contains 14% water according to Karl Fischer analysis.

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

10. 10. The pharmaceutical composition of claim 9 for treating edema, epilepsy, neuromyelitis optica, migraine, hyponatremia, retinal ischemia or other eye diseases associated with abnormalities in intraocular pressure and / or tissue hydration, excess water 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 of claim 10, wherein the edema is cerebral edema.

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

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

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

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

16. 16. The pharmaceutical composition of claim 15, wherein the edema is due to transplantation.

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

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

19. 18. The method of claim 17, wherein the hydrate and the base are mixed prior to mixing with the pharmaceutically acceptable liquid.

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

21. 21. The method of 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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