Polymorphs of dihydroorotate dehydrogenase (DHOD) inhibitors

Abstract

The present disclosure provides polymorphs of 3-(2, 3, 5, 6-tetrafluoro-3 '-trifluoromethoxy-biphenyl-4-ylamino formyl)-thiophene-2-carboxylic acid, as well as methods of making such polymorphs. The disclosure further provides pharmaceutical compositions and kits comprising the polymorphs of the invention and methods of treating, preventing, or ameliorating a disease or condition comprising administering the polymorphs of the invention.

Description

Technical Field

[0001] The present disclosure provides polymorphs of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, and methods for preparing such polymorphs. The present disclosure further provides pharmaceutical compositions and kits comprising the polymorphs of the present invention, and methods for treating, preventing or ameliorating diseases or conditions comprising administering the polymorphs of the present invention. Background Art

[0002] The small molecule compound 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (referred to herein as PP-001) represented by the following general formula I is an effective DHODH inhibitor.

[0003]

[0004] See, for example, US7365094, US8354433 and US9795590, incorporated herein by reference. PP-001 has been used to treat diseases and disorders associated with DHOD activity. Summary of the invention

[0005] In some embodiments, the present disclosure relates to a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, as shown in the following general formula I:

[0006]

[0007] In some embodiments, the polymorph is Form A, comprising an X-ray powder diffraction (XRPD) comprising three or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.5±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2, or Form B, comprising an X-ray powder diffraction (XRPD) comprising three or more 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2.

[0008] In some embodiments, the polymorph is Form A. In some embodiments, the polymorph is Form A and comprises four or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.5±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the polymorph is Form A and comprises five or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.5±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the polymorph is Form A and comprises Figure 2A XRPD pattern shown.

[0009] In some embodiments, the polymorph is Form A and comprises one or more characteristics selected from the following:

[0010] a.DSC spectrum (5°C / min) including an endothermic onset temperature of 178.3±1.0°C and a second endothermic onset temperature of 227.3±1.0°C;

[0011] b.DSC spectrum (10°C / min) including an endothermic onset temperature of 177.6±1.0°C and an endothermic onset temperature of 227.9±1.0°C;

[0012] c.DSC spectrum (20°C / min) including an endothermic onset temperature of 178.5±1.0°C, endothermic onset temperatures of 222.5±1.0°C and 224.3±1.0°C, and a subsequent endothermic onset temperature of 227.8±1.0°C;

[0013] d.DSC spectrum (50°C / min) including double endothermic onset temperatures of 88.0±1.0°C and 92.6±1.0°C, a second endothermic onset temperature of 180.5±1.0°C, a sharp endothermic onset temperature / exothermic onset temperature of 224.7±1.0°C, and an endothermic onset temperature of 229.5±1.0°C;

[0014] e. Melt-quench-cool (MDSC) including an endothermic onset temperature of 177.7±1.0°C and an endothermic onset temperature of 227.8±1.0°C; or

[0015] f. VT-XRPD pattern with observable changes at 200 °C.

[0016] In some embodiments, the polymorph is Form B. In some embodiments, the polymorph is Form B and comprises four or more 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the polymorph is Form B and comprises five or more 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the polymorph is Form B and comprises Figure 2B XRPD pattern shown.

[0017] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising Form A or Form B of a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, and a pharmaceutically acceptable excipient, carrier or diluent.

[0018] In some embodiments, the present disclosure relates to a kit comprising Form A or Form B of a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, and a container.

[0019] In some embodiments, the present disclosure relates to a method for preparing a polymorphic form A of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, the method comprising:

[0020] a) obtaining a sample comprising 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid;

[0021] b) dissolving the sample of (a) in a solvent comprising a C1-C5 alcohol, a C1-C5 ketone or a C1-C5 acetate solvent at 20° C. to 60° C. to form a solution; and

[0022] c) removing the solvent from the solution to obtain Form A polymorph.

[0023] In some embodiments, the C1-C5 alcohol is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol or isoamyl alcohol. In some embodiments, the C1-C5 ketone is selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) or acetone. In some embodiments, the C1-C5 acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate or amyl acetate.

[0024] In some embodiments, the solution is greater than 80% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate. In some embodiments, the solution comprises 0% to 20% water.

[0025] In some embodiments, after dissolving in (b), the solution is cooled to a culture temperature of 1°C to 10°C and maintained for a period of time. In some embodiments, cooling to the culture temperature is performed at a rate of about 0.02°C / min to about 1°C / min until the culture temperature is reached. In some embodiments, the cooling to the culture temperature is performed at a rate of about 0.05°C / min to about 0.5°C / min until the culture temperature is reached.

[0026] In some embodiments, the period of time for the culture temperature is about 1 hour to about 48 hours. In some embodiments, the period of time for the culture temperature is about 6 hours to about 18 hours.

[0027] In some embodiments, the removal of the solvent is performed by evaporation. In some embodiments, the removal of the solvent is performed by filtration. In some embodiments, the evaporation occurs at about 20°C to about 35°C.

[0028] In some embodiments, the present invention relates to a method of treating, preventing or ameliorating a disease or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of Form A of the polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid.

[0029] In some embodiments, the present invention is directed to a method for preparing a pharmaceutical composition, comprising combining Form A of the polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid with one or more pharmaceutically acceptable excipients, diluents or carriers. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The chemical structure of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001) is shown.

[0031] Figures 2A-2D The X-ray powder diffraction (XRPD) curves of Form A, Form B, the superposition of Form A and Form B, and amorphous PP-001 of PP-001 are shown respectively.

[0032] Figure 3A-3BShown are the results of solubility evaluation of PP-001 in different solvent systems and processing conditions.

[0033] Figure 4A-4B Shown are the results of a crystalline polymorph screen of PP-001 using the indicated solvent systems and processing conditions.

[0034] Figure 5 Shown are the results of a solubility screen of amorphous PP-001 using the indicated solvent systems and processing conditions.

[0035] Figure 6A-6B Observations and results of ripening amorphous PP-001 at 5°C using the specified solvents are shown.

[0036] Figure 7 Shown are the XPRD patterns of Form A and Form B of PP-001 and the superposition of "Pattern 3" obtained by ripening amorphous PP-001 at 5°C using heptane.

[0037] Figures 8A-8B Observations and results of ripening amorphous PP-001 by temperature cycling using specified solvents are presented.

[0038] Figures 9A-9B Observations and results of ripening of amorphous PP-001 at 50 °C using the specified solvents are presented.

[0039] Fig.10 Observations and results of antisolvent polymorph screening using the indicated solvents and conditions are presented.

[0040] Figures 11A-11B Shown are crystals of Form A polymorph of PP-001 using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM).

[0041] Fig.12 The gravimetric vapor sorption (GVS) isotherm of Form A of PP-001 is shown.

[0042] Figures 12A-12C HPLC curves of (A) Form A of the starting material PP-001, (B) Form A of PP-001 after storage at 40°C / 75% relative humidity for 8 days, and (C) Form A of PP-001 after storage at 25°C / 97% relative humidity for 8 days are shown.

[0043] 13A-13B show the superposition of XPRD spectra of the starting material PP-001, Form A of PP-001 after storage at 40°C / 75% relative humidity for 8 days, and (C) Form A of PP-001 after storage at 25°C / 97% relative humidity for 8 days.

[0044] Figures 14A-14D Shown are the results of differential scanning calorimetry (DSC) analysis of Form A of PP-001 at (A) 5°C / min, (B) 10°C / min, (C) 20°C / min, and (D) 50°C / min.

[0045] Figures 15A-15B The results of DSC melt / quench cooling analysis of Form A of PP-001 are shown.

[0046] Fig.16 TGA and DSC analyses of Form B of PP-001 are shown.

[0047] Figures 17A-17B Shown are crystals of Form B polymorph of PP-001 using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM).

[0048] Figures 18A-18C HPLC curves of (A) Form B of the starting material PP-001, (B) Form B of PP-001 after storage at 40°C / 75% relative humidity for 8 days, and (C) Form B of PP-001 after storage at 25°C / 97% relative humidity for 8 days are shown.

[0049] Fig.19 The GVS isotherm of Form B of PP-001 is shown.

[0050] Figures 20A-20C Shown are the results of differential scanning calorimetry (DSC) analysis of Form B of PP-001 at (A) 5°C / min, (B) 20°C / min, and (C) 50°C / min.

[0051] Fig.21 Shown are XRPD overlays of Form A of PP-001, Form B of PP-001, and a mixture of Form A and Form B of PP-001 (DS-2054-47).

[0052] Fig. 22 Shown is an XRPD overlay of aliquots collected during competitive slurrying of Form A and Form B of PP-001 after 5 days.

[0053] Fig.23 Shown is the XRPD of Form B of PP-001 after thermodynamic solubility determination.

[0054] Fig.24 A summary of the competitive slurry results of Form A and Form B of PP-001 is shown.

[0055] Fig.25A diagram showing different crystalline forms of PP-001.

[0056] Fig.26 Shown is the XRPD analysis of a 1 g crystal scale of Form A of PP-001.

[0057] Fig. 27 Comparison of the XRPD patterns of the provided Form A of PP-001 and Form A of PP-001 crystallized using four crystallization methods is shown.

[0058] Fig.28 Comparison of PLM images of Form A of the starting material PP-001 and Form A crystals of PP-001 after crystallization at a 1 g scale is shown.

[0059] Fig.29 Shown is the XRPD curve of Form A of PP-001 crystallized using a large groove sample holder.

[0060] Fig.30 A superposition of the crystal structures of Form A and Form B is shown. DETAILED DESCRIPTION

[0061] The present disclosure relates to polymorphs of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, a dihydroorotate dehydrogenase (DHODH) inhibitor, methods for preparing the polymorphs, pharmaceutical compositions containing the polymorphs, and their use in treating and preventing diseases, particularly in diseases in which they have advantages in inhibiting dihydroorotate dehydrogenase (DHODH).

[0062] Different polymorphs of a given compound (e.g., PP-001) can have different properties, such as solubility, dissolution rate, suspension stability, stability during grinding, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filterability, dryness, density, melting point, degradation stability, stability against phase transition to other crystalline forms, color, and even chemical reactivity. More importantly, in some embodiments, different crystalline forms of a small molecule compound (e.g., PP-001) can change its solubility, dissolution properties, pharmacokinetics, and bioavailability, which in some cases can affect the efficacy and safety of the drug.

[0063] In particular, in some embodiments, the crystal form of PP-001 can affect its dissolution and absorption in the body, thereby affecting its clinical therapeutic effect and safety to a certain extent. In some embodiments, the crystal form of PP-001 is crucial for drug quality control. The present disclosure relates to polymorphs of PP-001, compositions and kits thereof, methods for making polymorphs of PP-001, and methods for treating, preventing or ameliorating diseases, disorders or conditions by administering a therapeutically effective amount of polymorphs of PP-001.

[0064] The present disclosure provides novel polymorphs of PP-001. The present application describes the chemical and physical properties of these polymorphs and discloses methods of making these polymorphs.

[0065] The abbreviations used in this specification are listed in Table 1.

[0066] Table 1. List of abbreviations

[0067]

[0068]

[0069] Unless otherwise defined, the scientific and technological terms used in this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context requires otherwise, singular terms shall include the plural, and plural terms shall include the singular. As used herein, "a" or "an" may refer to one or more. As used herein, when used with the word "comprising", the word "a" or "an" may refer to one or more. As used herein, "another" or "further" may refer to at least a second or more.

[0070] Throughout the application, the term "about" is used to indicate that a value includes the inherent error variation for the method / device used to determine the value, or the variation that exists between subjects. Typically, the term "about" means approximately including or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% variability, depending on the specific circumstances.

[0071] The term "or" used in the claims means "and / or" unless explicitly stated to refer to only alternatives or the alternatives are mutually exclusive, although the present disclosure supports a definition referring to only alternatives and "and / or."

[0072] As used herein, the terms "comprising" (and any variations or forms of comprising, such as "comprise" and "comprises"), "having" (and any variations or forms of having, such as "have" and "has"), "including" (and any variations or forms of including, such as "includes" and "include"), or "containing" (and any variations or forms of containing, such as "contains" and "contain") are inclusive or open-ended, and do not exclude additional, uncited, elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to the salts, methods and / or kits of the present disclosure. In addition, the salts and / or kits of the present disclosure can be used to implement the methods of the present disclosure.

[0073] The term "for example" and its corresponding abbreviation "eg" (whether italicized or not) indicate that the specific term referenced is a representative example and implementation of the present disclosure, which is not limited to the specific example referenced or referenced unless expressly stated otherwise.

[0074] As used herein, "between" is a range that includes the ends of the range. For example, the numbers between x and y specifically include the numbers x and y, and any numbers that fall between x and y.

[0075] For characteristic diffraction peaks expressed as 2θ (2θ) angles, the term "about" means that the variation of the listed value does not exceed 0.2°, for example, about X°, it means X±0.2°, preferably X±0.1°. Therefore, in some embodiments, any one of the 2θ angles cited herein can be ±0.1.

[0076] As used herein, the term "room temperature" generally refers to 4°C to 30°C, 18°C ​​to 22°C, 19°C to 21°C, or 20±5°C.

[0077] Disclosed herein are various crystalline forms of polymorphs of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001), such as Form A, Form B and amorphous form.

[0078] In some embodiments, the PP-001 is a polymorph of Form A. In some embodiments, the term "Form A" refers to a polymorph of PP-001, comprising an X-ray powder diffraction (XRPD) comprising three or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2.

[0079] In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 14.8±0.2, and two additional 2θ values ​​selected from 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 15.6±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 16.5±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 19.6±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 20.8±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 25.6±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 26.1±0.2, and two additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, and 25.6±0.2.

[0080] In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 14.8±0.2, and three additional 2θ values ​​selected from 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 15.6±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 16.5±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 19.6±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 20.8±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 25.6±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, and 26.1±0.2. In some embodiments, the Form A polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 26.1±0.2, and three additional 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, and 25.6±0.2.

[0081] In some embodiments, the polymorphic form A comprises four or more 2θ values ​​selected from 14.8 ± 0.2, 15.6 ± 0.2, 16.5 ± 0.2, 19.6 ± 0.2, 20.8 ± 0.2, 25.6 ± 0.2, and 26.1 ± 0.2. In some embodiments, the polymorphic form A comprises five or more 2θ values ​​selected from 14.8 ± 0.2, 15.6 ± 0.2, 16.5 ± 0.2, 19.6 ± 0.2, 20.8 ± 0.2, 25.6 ± 0.2, and 26.1 ± 0.2.

[0082] In some embodiments, the Form A of the polymorph comprises six or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the Form A of the polymorph comprises 2θ values ​​of 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2. In some embodiments, the term Form A refers to at least 7, 8, 9, 10 or more 2θ peaks, as shown in Table 10. In some embodiments, the XRPD pattern of Form A of PP-001 is as shown in Figure 2A Those skilled in the art will recognize how to determine the major 2θ values ​​from an XRPD pattern.

[0083] In some embodiments, the crystalline form A of the polymorph can be determined by differential scanning calorimetry (DSC) to determine the endothermic onset of the polymorph. In some embodiments, the DSC spectrum can be determined at different rates, such as 2°C / min to 10°C / min, 4°C / min to 6°C / min, or 5°C / min. In some embodiments, the DSC spectrum can be determined at different rates, such as 10°C / min to 30°C / min, 15°C / min to 25°C / min, or 20°C / min. In some embodiments, the DSC spectrum can be determined at different rates, such as 30°C / min to 70°C / min, 40°C / min to 60°C / min, or 50°C / min.

[0084] In some embodiments, any DSC endotherm start temperature described herein may be ±1.0°C. In some embodiments, any of the DSC endotherm start temperatures may be ±0.5°C, ±0.2°C, or ±0.1°C. Thus, for example, if Form A is described as having a DSC spectrum, and the DSC spectrum comprises an endotherm start temperature of about 178.3°C at 5°C / min, this would include 178.3±1.0°C, 178.3±0.5°C, 178.3±0.2°C, 178.3±0.1°C, or 178.3°C.

[0085] In some embodiments, Form A comprises a DSC spectrum (5°C / min) comprising an endothermic onset temperature at about 175°C to about 180°C (e.g., about 178°C to about 179°C, such as 178.3°C, or such as 178.3°C ± 0.1). In some embodiments, Form A comprises a DSC spectrum (5°C / min) comprising a second endothermic onset temperature at about 225°C to about 230°C (e.g., about 227°C to about 228°C, such as 227.3°C, or such as 227.3°C ± 0.1).

[0086] In some embodiments, Form A comprises a DSC spectrum (10°C / min) comprising an endothermic onset temperature at about 175°C to about 180°C (e.g., about 177°C to about 178°C, such as 177.6°C, or such as 177.6°C ± 0.1). In some embodiments, Form A comprises a DSC spectrum (10°C / min) comprising an endothermic onset temperature at about 225°C to about 230°C (e.g., about 227°C to about 228°C, such as 227.9°C, or such as 227.9°C ± 0.1).

[0087] In some embodiments, Form A comprises a DSC spectrum (20°C / min) comprising an endothermic onset temperature at about 175°C to about 180°C (e.g., about 178°C to about 179°C, such as 178.5°C, or such as 178.5°C ± 0.1). In some embodiments, Form A comprises additional endothermic onset temperatures at about 220°C to about 225°C (e.g., 222.5°C) and about 221°C to about 226°C (e.g., 224.3°C, or such as 224.3°C ± 0.1). In some embodiments, Form A comprises an additional endothermic onset temperature at about 225°C to about 230°C (e.g., 227.8°C, or such as 227.8°C ± 0.1).

[0088] In some embodiments, Form A comprises a DSC spectrum (50°C / min) comprising dual endothermic onset temperatures at about 85°C to about 90°C (e.g., 88.0°C) and about 90°C to about 95°C (e.g., 92.6°C or, e.g., 92.6°C ± 0.1). In some embodiments, the endothermic onset temperature is about 178°C to about 182°C (e.g., 180.5°C or, e.g., 180.5°C ± 0.1), the endothermic onset / exothermic onset temperature is about 221°C to about 226°C (e.g., 224.7°C or, e.g., 224.7°C ± 0.1), and the endothermic onset temperature is about 227°C to about 231°C (e.g., 229.5°C or, e.g., 229.5°C ± 0.1).

[0089] In some embodiments, Form A exhibits a DSC spectrum at one or more of the above rates (eg, 5°C / min, 10°C / min, 20°C / min, and / or 50°C / min).

[0090] In some embodiments, any polymorph described herein having a melt-quench-cool (MDSC) endotherm onset temperature may be ±1.0° C. In some embodiments, any of the MDSC endotherm onset temperatures may be ±0.5° C., ±0.2° C., or ±0.1° C. Thus, for example, if Form A is described as having an MDSC spectrum, and the MDSC spectrum includes an endotherm onset temperature of about 178.3° C., this would include 178.3±1.0° C., 178.3±0.5° C., 178.3±0.2° C., 178.3±0.1° C., or 178.3° C.

[0091] In some embodiments, Form A of the polymorph comprises a melt-quench-cool (MDSC) comprising an endothermic onset at about 175°C to about 180°C (e.g., 177.7°C or such as 177.7°C ± 0.1), an endothermic onset at about 225°C to about 230°C (e.g., 227.8°C or such as 227.8°C ± 0.1).

[0092] In some embodiments, Form A of the polymorph comprises a variable temperature XRPD (VT-XRPD) pattern having an observable change at about 190°C to about 210°C (eg, 200°C).

[0093] In some embodiments, the present disclosure provides Form A of a crystalline polymorph of PP-001, characterized by one or more crystal structure parameters as shown in Table 2.

[0094] Table 2. Crystal structure parameters of polymorphic form A of PP-001

[0095]

[0096]

[0097]

[0098] Unit cell parameters are defined by three parameters: the length of the side of the unit cell, the relative angle between the sides, and the volume of the unit cell. The length of the side of the unit cell is defined by a, b, and c. The relative angle between the sides is defined by α, β, and γ. Embodiments of the present invention further include a polymorphic form A of PP-001 having atomic positions of all atoms relative to the origin of the unit cell as listed in Tables 3 and 4. Tables 3 and 4 list the atomic coordinates of the Form A of PP-001 described herein as well as the parameters of bond lengths and bond angles. These parameters define the atomic arrangement in the crystal structure of the Form A of PP-001 described herein.

[0099] Table 3. Atomic coordinates of Form A of the polymorph of PP-001 (x10 4 ) and the equivalent isotropic displacement parameter (A 2 x10 3 )

[0100]

[0101]

[0102] Table 4. Bond lengths of Form A of the polymorph of PP-001 and bond angle [°]

[0103]

[0104]

[0105]

[0106]

[0107] The DSC, GVS, PLM, SEM and HPLC characterization of Form A of PP-001 are discussed and exemplified in more detail in Example 3 below, and thermal studies of Form A are discussed in more detail in Example 4.

[0108] In some embodiments, the polymorph of PP-001 is Form B. In some embodiments, Form B comprises an X-ray powder diffraction (XRPD) comprising three or more 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2.

[0109] In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 14.9±0.2, and two additional 2θ values ​​selected from 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 17.6±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 19.3±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 20.9±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 24.0±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 24.9±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 25.4±0.2, and two additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, and 24.9±0.2.

[0110] In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 14.9±0.2, and three additional 2θ values ​​selected from 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 17.6±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 19.3±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 20.9±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 24.0±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.9±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 24.9±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, and 25.4±0.2. In some embodiments, the Form B polymorph of PP-001 comprises an X-ray powder diffraction (XRPD) comprising a 2θ value at 25.4±0.2, and three additional 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, and 24.9±0.2.

[0111] In some embodiments, the Form B polymorph comprises four or more 2θ values ​​selected from 14.8 ± 0.2, 17.6 ± 0.2, 19.3 ± 0.2, 20.9 ± 0.2, 24.0 ± 0.2, 24.9 ± 0.2, and 25.4 ± 0.2. In some embodiments, the Form B polymorph comprises five or more 2θ values ​​selected from 14.8 ± 0.2, 17.6 ± 0.2, 19.3 ± 0.2, 20.9 ± 0.2, 24.0 ± 0.2, 24.9 ± 0.2, and 25.4 ± 0.2. In some embodiments, the polymorph Form B comprises six or more 2θ values ​​selected from 14.8 ± 0.2, 17.6 ± 0.2, 19.3 ± 0.2, 20.9 ± 0.2, 24.0 ± 0.2, 24.9 ± 0.2, and 25.4 ± 0.2. In some embodiments, the polymorph Form B comprises 2θ values ​​of 14.8 ± 0.2, 17.6 ± 0.2, 19.3 ± 0.2, 20.9 ± 0.2, 24.0 ± 0.2, 24.9 ± 0.2, and 25.4 ± 0.2.

[0112] In some embodiments, the term Form B refers to at least 7, 8, 9, 10 or more 2θ peaks, as shown in Table 17. In some embodiments, the XRPD pattern of Form B of PP-001 is as follows Figure 2B shown.

[0113] In some embodiments, the present disclosure provides Form A of a crystalline polymorph of PP-001, characterized by one or more crystal structure parameters as shown in Table 5.

[0114] Table 5. Crystal structure parameters of polymorph B of PP-001

[0115]

[0116]

[0117]

[0118] Embodiments of the present invention further include a polymorph of PP-001, Form B, having the atomic positions of all atoms relative to the unit cell origin as listed in Tables 6 and 7. Tables 6 and 7 list the atomic coordinates and bond lengths and bond angles of Form B of PP-001 described herein. These parameters define the atomic arrangement in the crystal structure of Form B of PP-001 described herein.

[0119] Table 6 Atomic coordinates of Form B of the polymorph of PP-001 (x10 4 ) and the equivalent isotropic displacement parameter (A 2 x103 )

[0120]

[0121]

[0122] Table 7. Bond lengths of Form B of polymorph of PP-001 and bond angle [°]

[0123]

[0124]

[0125]

[0126] In some embodiments, the DSC, GVS, PLM, SEM, and HPLC characteristics of Form B of PP-001 are discussed in more detail in Example 5 below.

[0127] Method for preparing polymorphs

[0128] In some embodiments, the present disclosure provides a method for preparing Form A of a polymorph. In some embodiments, the present disclosure provides a method for preparing Form A of a polymorph of PP-001, the method comprising: (a) obtaining a sample comprising 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; (b) dissolving the sample in (a) in a solvent comprising a C1-C5 alcohol, a C1-C5 ketone or a C1-C5 acetate solvent at 20° C. to 60° C. to form a solution; and (c) removing the solvent from the solution to obtain Form A of the polymorph.

[0129] The present disclosure provides that PP-001 is dissolved in a low alkyl solvent such as a C1-C5 alcohol, a C1-C5 ketone or a C1-C5 acetate before removing the solvent and crystallizing to form a crystalline form A of the polymorph. As used herein, the terms "C1-C5 alcohol", "C1-C5 ketone" and "C1-C5 acetate" refer to any alcohol, ketone or acetate containing 1 to 5 carbon atoms, respectively. In some embodiments, the C1-C5 alkyl group is a linear carbon or a branched carbon. In some embodiments, the C1-C5 alcohol is methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, isopentanol or a combination thereof. In some embodiments, the C1-C5 ketone is selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) or acetone. In some embodiments, the C1-C5 acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate or amyl acetate.

[0130] In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution is greater than 80% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate, greater than 85% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate, greater than 90% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate, greater than 95% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate, greater than 98% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate, or greater than 99% of C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate.

[0131] In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution is greater than 80% C1-C5 alcohol, greater than 85% C1-C5 alcohol, greater than 90% C1-C5 alcohol, greater than 95% C1-C5 alcohol, greater than 98% C1-C5 alcohol, or greater than 99% C1-C5 alcohol.

[0132] In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution is greater than 80% C1-C5 ketones, greater than 85% C1-C5 ketones, greater than 90% C1-C5 ketones, greater than 95% C1-C5 ketones, greater than 98% C1-C5 ketones, or greater than 99% C1-C5 ketones.

[0133] In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution is greater than 80% C1-C5 acetate, greater than 85% C1-C5 acetate, greater than 90% C1-C5 acetate, greater than 95% C1-C5 acetate, greater than 98% C1-C5 acetate, or greater than 99% C1-C5 acetate.

[0134] In some embodiments, PP-001 forms crystals using a solvent containing little or no water, such as Form A of the polymorph. In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution contains less than 20% water, less than 15% water, less than 10% water, less than 5% water, or less than 2% water (vol / vol). In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution contains 0% to 20% water, 0% to 10% water, 0% to 5% water, or 0% to 2% water. In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution contains 0% to 1% water. In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solvent is an anhydrous solvent.

[0135] In some embodiments, PP-001 forms crystals (e.g., Form A of the polymorph) comprising a solvent and a small amount of water (e.g., about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water). In some embodiments, PP-001 forms crystals (e.g., Form A of the polymorph) comprising a solvent and a small amount of water (e.g., about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water).

[0136] In some embodiments, PP-001 forms crystals comprising C1-C5 alcohols and a small amount of water (e.g., about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water) (e.g., polymorph Form A). In some embodiments, PP-001 forms crystals comprising C1-C5 ketones and a small amount of water (e.g., about 1% to 15%, about 1% to about 10%, about 1% to about 5% water) (e.g., polymorph Form A). In some embodiments, PP-001 forms crystals comprising C1-C5 acetates and a small amount of water (e.g., about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water) (e.g., polymorph Form A).

[0137] The temperature used to dissolve PP-001 in the solvent can be determined by one skilled in the art and can depend on the concentration of PP-001 in the solvent as well as the temperature at which dissolution occurs and the time over which dissolution lasts.

[0138] In some embodiments, the PP-001 is dissolved in a solvent at 20°C to 60°C to form a solution. In some embodiments, this may be referred to as the "dissolution temperature". In some embodiments, the PP-001 is dissolved in a solvent at 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C to 60°C to form a solution. In some embodiments, the PP-001 is dissolved in a solvent at 25°C to 30°C, 30°C to 35°C, 35°C to 40°C, 40°C to 45°C, 45°C to 50°C, or 50°C to 60°C to form a solution.

[0139] In some embodiments, the solvent content of the PP-001 dissolved in the solution is less than 10% (wt / vol), less than 5% (wt / vol), less than 2% (wt / vol), less than 1% (wt / vol), less than 0.5% (wt / vol), or less than 0.1% (wt / vol). In some embodiments, the concentration of PP-001 is less than the saturation point at a given solvent and temperature, for example, if the saturation point of PP-001 at a given solvent and temperature is "X mg / mL", then the concentration of PP-001 is less than "X mg / mL", for example, less than 20%, less than 50%, or less than 80%.

[0140] In some embodiments, the PP-001 is dissolved in a solvent to form a solution, wherein the solution is cooled to a culture temperature. In some embodiments, the culture temperature is maintained for a "period of time". In some embodiments, the period of time is greater than 1 hour, greater than 2 hours, greater than 3 hours, greater than 4 hours, greater than 5 hours, greater than 6 hours, greater than 8 hours, greater than 10 hours, greater than 12 hours, greater than 15 hours, greater than 20 hours, greater than 24 hours, more than 2 days, or more than 3 days. In some embodiments, the period of time at the culture temperature is about 1 hour to about 48 hours, about 2 hours to about 36 hours, about 3 hours to about 24 hours, about 4 hours to about 20 hours, or about 6 hours to about 18 hours.

[0141] In some embodiments, the culture temperature is maintained for a period of time at about 1° C. to about 10° C. In some embodiments, the culture temperature is maintained for a period of time at about 2° C. to about 8° C., about 3° C. to about 7° C., or about 4° C. to about 6° C.

[0142] In some embodiments, the temperature change from the dissolution temperature to the culture temperature can be completed within a specified time period, i.e., the rate of change of temperature within a given time. In some embodiments, cooling from the dissolution temperature to the culture temperature is performed at a rate of about 0.02°C / minute to about 1°C / minute until the culture temperature is reached. In some embodiments, the cooling to the culture temperature is performed at a rate of about 0.05°C / minute to about 0.5°C / minute until the culture temperature is reached. In some embodiments, the cooling to the culture temperature is performed at a rate of about 0.1°C / minute to about 0.3°C / minute until the culture temperature is reached.

[0143] In some embodiments, after the incubation temperature is maintained for a period of time, the solvent is removed and the PP-001 crystallizes. In some embodiments, the crystallization process can be initiated using a seed crystal or other initiating composition. In some embodiments, the solvent is removed within a specified time (i.e., the removal time) and the polymorph is formed. Those skilled in the art will recognize that as the solvent concentration decreases, the concentration of PP-001 will increase until the crystallization process begins. Those skilled in the art will also recognize that many factors may affect the removal time, such as the amount of solvent to be removed, the type of solvent to be removed, temperature, pressure, etc., all of which will affect the removal time of the solvent.

[0144] In some embodiments, the removal time is greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 45 minutes, greater than 1 hour, greater than 2 hours, greater than 3 hours, greater than 4 hours, greater than 6 hours, greater than 9 hours, greater than 12 hours, greater than 15 hours, greater than 18 hours, greater than 21 hours, or greater than 24 hours. In some embodiments, the removal time is greater than 1 day, 2 days, 3 days, 4 days, 5 days, or 6 days.

[0145] In some embodiments, the solvent is removed by evaporation. Those skilled in the art will recognize that the evaporation rate will be determined by many factors, including but not limited to the characteristics of the solvent, temperature, pressure, etc. In some embodiments, the evaporation is carried out at the culture temperature. In some embodiments, the evaporation temperature can vary, for example, it can vary over time. In some embodiments, the evaporation temperature is constant. In some embodiments, the evaporation is carried out at a temperature higher than the culture temperature. In some embodiments, the evaporation is carried out at a temperature higher than 5°C, higher than 10°C, higher than 15°C, higher than 20°C, higher than 25°C or higher than 30°C. In some embodiments, the evaporation is carried out at 5°C to 40°C, 10°C to 35°C, 15°C to 30°C. In some embodiments, the evaporation is carried out at about 20°C to about 35°C. In some embodiments, if there is more than one solvent, the evaporation temperature can be maintained at a first temperature until the first solvent evaporates, and then changed to a second temperature.

[0146] In some embodiments, the evaporation can be performed at different temperatures. In some embodiments, the evaporation is performed at 1 atmosphere. In some embodiments, the evaporation is performed at less than 1 atmosphere.

[0147] In some embodiments, the removal of the solvent is performed by filtration. For example, in some embodiments, the solvent is removed using a membrane or a semipermeable membrane. In some embodiments, when a semipermeable membrane is used, the solvent is replaced by a different solvent, wherein the PP-001 forms crystals in the different solvent.

[0148] In some embodiments, the solvent is removed by lyophilization.

[0149] Pharmaceutical composition

[0150] The disclosure provides a pharmaceutical composition comprising a polymorph of PP-001 described herein (e.g., Form A or Form B). In some embodiments, the disclosure provides a pharmaceutical composition comprising Form A of the polymorph of PP-001 and a pharmaceutically acceptable excipient, carrier, or diluent.

[0151] In some embodiments, the term "pharmaceutically acceptable" excipient, carrier, diluent or ingredient refers to a substance suitable for human and / or animal use without excessive adverse side effects (e.g., toxicity, irritation and allergy), i.e., with a reasonable benefit / risk ratio.

[0152] In some embodiments, the pharmaceutical compositions described herein may include other therapeutically active substances.

[0153] In some embodiments, the pharmaceutical composition of the present invention is formulated for parenteral administration, including formulations for intravenous, arterial, intramuscular, subcutaneous, peritoneal, vitreous and transdermal administration. In some embodiments, the pharmaceutical composition of the present invention is formulated for topical, oral, sublingual, enteral, nasal, oral or inhaled administration.

[0154] In some embodiments, the pharmaceutical composition comprising the polymorph of the present invention is formulated in the form of pills, tablets, capsules, suppositories, syrups, lozenges, eye drops or liquid preparations. The formulations of pills, tablets and hard gelatin capsules may contain excipients known to the skilled person.

[0155] In some embodiments, the present disclosure provides a method of preparing a pharmaceutical composition, the method comprising combining Form A of the polymorph of PP-001 with one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0156] In some embodiments, the present disclosure provides a kit comprising Form A (or Form B) of a polymorph of PP-001 and a container. In some embodiments, the container is a vial, a packet, a pouch, a prefilled syringe, an ampoule, or a capsule.

[0157] Treatment

[0158] In some embodiments, pharmaceutical composition as used herein, the term "effective amount" refers to the amount of therapeutic agent used to treat, alleviate or prevent the target disease or condition, or the amount that exhibits a detectable therapeutic or preventive effect. The exact effective amount for the subject depends on the subject's size and health, the nature and extent of the condition, and the selected therapeutic agent and / or combination of therapeutic agents. Therefore, it is useless to specify the exact effective amount in advance. However, for a given situation, routine experiments can be used to determine the effective amount, which can be determined by a clinician.

[0159] The present disclosure provides a method for treating, preventing or ameliorating a disease or condition in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of Form A of the polymorph of PP-001 to the subject.

[0160] In some embodiments, the disease, disorder or condition benefits from inhibition or reduction of the activity of DHODH.

[0161] In some embodiments, the disease, disorder or condition is an inflammatory disease, disorder or condition; an acute immune disease, disorder or condition; an autoimmune disease, disorder or condition; a disease, disorder or condition caused by abnormal or malignant cell proliferation; or an infectious disease, disorder or condition.

[0162] In some embodiments, the disease, disorder or condition includes but is not limited to fibrosis, uveitis, rhinitis, asthma or arthropathy, particularly arthropathy, all forms of rheumatic acute immune events and conditions, such as sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, stroke, reperfusion injury, central nervous system injury, allergic conditions, graft-versus-host and host-versus-graft disorders, Alzheimer's disease, fever, restenosis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease. These immune events also include the intended modulation and suppression of the immune system; all types of autoimmune diseases, especially rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, multiple sclerosis, insulin-dependent diabetes and non-insulin-dependent diabetes as well as systemic lupus erythematosus, lupus nephritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease and other chronic inflammatory diseases, chronic diarrhea; skin diseases such as psoriasis, progressive retinal atrophy and various infections, including opportunistic infections.

[0163] In some embodiments, the disease, disorder or condition is malignant cell proliferation, such as all forms of hematological cancer and solid cancer. Therefore, the polymorphic forms according to the present invention and the compositions prepared therefrom can be generally used for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death, or inducing systemic changes in metabolism, such as changes in sugar, lipid or protein metabolism. They can also be used to support cell generation, including blood cell growth and generation (hematopoietic effect) after cell depletion or destruction caused by, for example, toxic agents, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune disorders, anemia, etc., or provide therapeutic control of tissue generation and degradation, and therapeutic modification of cell and tissue maintenance and blood cell homeostasis.

[0164] In some embodiments, the polymorphs of PP-001 used in the methods of treatment as described herein may be prophylactic or therapeutic. In the methods of treatment, the polymorphs and compositions of the present invention may be administered in combination with other therapeutic agents.

[0165] In some embodiments, the dosage used in therapeutic dosage can vary within a wide range and be adapted to the individual conditions in each individual case. For the above uses, the appropriate dosage will vary depending on the mode of administration, the specific condition to be treated and the desired effect.

[0166] Example

[0167] Example 1 - Properties of PP-001

[0168] The general test properties of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001) are shown in Table 8 below.

[0169] Table 8. Characteristics of PP-001

[0170]

[0171] Example 2 - Obtaining Crystalline PP-001 from Amorphous PP-001

[0172] Preparation and solubility of amorphous PP-001. PP-001 was treated with increasing aliquots of solvent until a maximum of 60 vol (1800 μl) was added to the HPLC vial.

[0173] The resulting solution was filtered under positive pressure using a PTFE syringe filter to remove any remaining solid particles. The solution was then flash frozen in a dry ice / acetone bath and lyophilized overnight to remove the solvent. The solid isolated after lyophilization was analyzed and characterized by XRPD. The XRPD curve of amorphous PP-001 is shown in Figure 1. Figure 2C shown.

[0174] The remaining suspension was subjected to aging cycles between 25° C. and 50° C. (4 hours per cycle) or was stored isothermally at room temperature overnight. The samples were separated under positive pressure and analyzed by XRPD.

[0175] The results of the freeze-drying solvent evaluation are as follows Figure 5 shown.

[0176] like Figure 5 As shown, PP-001 is soluble in THF:water (70:30) and 1,4-dioxane. All other tested solvents and solvent mixtures formed opaque solutions or suspensions that were not suitable for lyophilization. These suspensions were subjected to aging cycles from 25°C to 50°C (4 hours per cycle) or were aged overnight at room temperature. The suspended solids were then separated and the wet cake was analyzed by XRPD. Form A was obtained for ACN / water (1:1), DCM and tert-butanol / water. For pure tert-butanol, a solution was obtained after the aging cycle. It was slowly evaporated to produce Form B.

[0177] For crystallization of amorphous PP-001, P-001 (3.0 g) was treated with 20 vol (60 ml) of THF: water (70:30) and stirred at room temperature until a clear solution was obtained. The solution was filtered under positive pressure using a PTFE syringe filter to remove any residual solid particles. The solution was then aliquoted (600 μl / vial) into individual HPLC vials. The HPLC vials were then flash frozen in a dry ice / acetone bath and lyophilized overnight to remove the solvent, leaving a white powdery solid (approximately 30 mg / vial). A vial representing the batch was then analyzed by XRPD to confirm that the material was amorphous after lyophilization. When not in use, the samples were stored at -20°C. Samples were used for subsequent polymorphism studies as needed.

[0178] Crystallization method. The following isothermal ripening technique and ripening cycles between room temperature and 50°C were used to generate crystalline material and analyzed by XRPD. In addition, an antisolvent addition screen was performed.

[0179] Preparation of amorphous materials

[0180] P-001 (3.0 g) was treated with 20 vol (60 ml) of THF: water (70: 30) and stirred at room temperature until a clear solution was obtained. The solution was filtered under positive pressure using a PTFE syringe filter to remove any residual solid particles. The solution was then aliquoted (600 μl / bottle) into individual HPLC sample bottles. The HPLC sample bottles were then flash frozen in a dry ice / acetone bath and lyophilized overnight to remove the solvent, leaving a white powdery solid (approximately 30 mg / bottle). The vials representing the batch were then analyzed by XRPD to confirm that the material was amorphous after lyophilization. When not in use, the samples were stored at -20°C. Samples were used for subsequent polymorphism studies as needed.

[0181] Polymorph screening procedure 2 (5°C isothermal ripening)

[0182] Amorphous PP-001 (approximately 30 mg, batch #2) was treated with aliquots of solvent up to a maximum of 15 vol (450 μl) at 5°C, 300 rpm while maintaining the suspension. Observations were then recorded. The samples were aged at 5°C for 24 hours. After further observations were made, the samples were processed as follows:

[0183] • For suspensions, take an aliquot (approximately 30 μl) and perform XRPD analysis while still wet. For any new spectrum, the sample was dried at room temperature before reanalyzing.

[0184] • For samples that have formed a solution, add up to 10 vol (1500 μl) of antisolvent at room temperature.

[0185] Solids showing any new profiles were subsequently extracted using an SPE cartridge and frit under positive pressure filtration. The samples were dried at ambient conditions for at least one night before further characterization.

[0186] The results of aging amorphous materials at 5°C are as follows Fig. 6A and 6B shown.

[0187] Upon ripening at 5°C, most solvents remained in suspension. DMSO froze at 5°C as expected. The sample was heated back to 25°C and excess ACN was added as an antisolvent to promote precipitation. However, the sample remained a solution and was not investigated further. 1,4-Dioxane partially froze but remained a mobile slurry. For THF:water (50%), a viscous solid formed upon addition of the solvent. All samples were analyzed by wet analysis in an attempt to capture any possible metastable solvate forms. However, upon analysis, the vast majority of the material obtained was either Form A or Form B (see Fig. 6A and 6B ).

[0188] Form A was obtained from ethyl acetate, MIBK, IPA, MEK, 1-propanol, acetone, ethanol, ACN, methanol, water, methanol:water (3%) and (5%), ethanol:water (5%), acetone:water (5%) and (10%), and THF:water (50%). Form B was obtained from ether, propyl acetate, isopropyl acetate, TBME, 1,4-dioxane, toluene, chloroform, THF:heptane (1:1), and the current process solvent IPA:water (5% and 25% water). Another new spectrum was obtained from heptane, represented by spectrum 3 ( Figure 7 ).

[0189] Polymorph Screening Procedure 3 (Temperature Cycling)

[0190] Amorphous PP-001 (approximately 30 mg, batch #2) was treated with aliquots of solvent up to a maximum of 20 vol (600 μl) at 25°C, 300 rpm while maintaining the suspension. Observations were then recorded. The sample was then subjected to a maturation cycle between room temperature and 50°C (4 hours per cycle) for 24 hours. After further observations were made, the sample was processed as follows:

[0191] • For suspensions, take an aliquot (approximately 30 μl) and perform XRPD analysis while still wet. For any new spectrum, the sample was dried at room temperature before reanalyzing.

[0192] • For samples that have formed a solution, add up to 1 volume equivalent (150 μl) of antisolvent at room temperature.

[0193] Solids showing any new profiles were subsequently extracted using an SPE cartridge and frit under positive pressure filtration. The samples were dried at ambient conditions for at least one night before further characterization.

[0194] The results of the aging cycle of amorphous materials are as follows Fig. 8A and 8B shown.

[0195] As in the case of ripening at 5°C, most solvents remained in suspension. Ether did not play a role as the experimental temperature exceeded the boiling point of the solvent. Solutions were obtained from acetone:water (5%) after ripening, but additional water (150ul) was added to obtain a suspension. Volatile solvents (acetone and ethyl acetate) produced clear solutions with solid material accumulating above the solvent line. The material was resuspended periodically with a spatula until screening was completed. Form B was obtained from n-heptane, TBME, toluene chloroform. Form B was also obtained from acetone:water (5%) after the addition of an anti-solvent.

[0196] The remaining suspensions all gave Form A. Interestingly, when acetone:water (5%) was added with an antisolvent (final ratio was approximately 1:1 acetone:water) Form B was obtained, and acetone:water (10%) gave Form A. This is also in contrast to previous screens where both 5% and 10% acetone:water gave Form A. The results may be kinetically driven, where rapid nucleation (i.e., by rapid addition of antisolvent) favored Form B. This was further investigated in subsequent screens. No additional spectra were obtained from this screen. The current process solvent (IPA:water) gave Form A upon maturation.

[0197] Polymorph screening procedure 4 (50°C isothermal ripening)

[0198] Amorphous PP-001 (approximately 30 mg, batch #2) was treated with aliquots of solvent up to a maximum of 15 vol (450 μl) at 50°C, 300 rpm while maintaining the suspension. Observations were then recorded. The samples were aged at 50°C for 24 hours. After further observations were made, the samples were processed as follows:

[0199] • For suspensions, take an aliquot (approximately 30 μl) and perform XRPD analysis while still wet. For any new spectrum, the sample was dried at room temperature before reanalyzing.

[0200] • For samples that form a solution, add up to 3 vol (450 μl) of antisolvent at 50°C.

[0201] Solids showing any new profiles were subsequently extracted using an SPE cartridge and frit under positive pressure filtration. Samples were dried at ambient conditions for at least one night before further characterization.

[0202] The results of aging amorphous materials at 50°C are as follows Fig.9A and 9B shown.

[0203] As with the ripening cycle screening, ether did not play a role as the experimental temperature exceeded the boiling point of the solvent. Suspensions were maintained in most of the tested solvents. From the suspension, Form B was obtained from n-heptane, TBME, toluene and isopropyl acetate. However, in the extraction with isopropyl acetate, this material converted to Form A. All other suspensions gave Form A. Solutions were obtained only from acetone:water (5%). About 150 μl of water was added at 50°C to obtain a suspension. A sample was immediately collected and analyzed by XRPD, which matched the XRPD pattern of Form B. The sample was then isothermally ripened with the other samples. After ripening, the sample was analyzed again and showed that it had converted to Form A. This result is consistent with previous screening, in which the nucleation of Form B can be converted to Form A with ripening.

[0204] Acetone:water (10%) was initially opaque, but after a few days of aging, a solution was obtained. The sample was removed from the heat source and precipitated at room temperature using ACN as an antisolvent to isolate Form A. The current process solvent (IPA:water 13:5) will give Form A after aging.

[0205] Polymorph Screening Procedure 5 (Antisolvent Addition)

[0206] PP-001 (approximately 30 mg, batch #1) was treated with an aliquot of solvent at room temperature and stirred until a solution was obtained or a maximum of 80 vol (2.4 ml) was reached. Observations were then recorded. If the sample did not dissolve at room temperature, the suspension was heated to 50°C to promote dissolution. Antisolvent (up to 5 v / v equivalents) was added to all solutions to promote precipitation at temperature.

[0207] For the suspension, an aliquot was taken for XRPD analysis of the precipitate of the material. The suspension was then left to mature overnight at temperature. A second aliquot was then taken for XRPD analysis.

[0208] The solution was cooled from 25°C to 5°C at a rate of 0.1°C / min and kept at 5°C overnight. Any remaining solution was evaporated at room temperature.

[0209] The suspension was then extracted using an SPE cartridge and frit under positive pressure filtration. A sample of the filter cake was taken for analysis. The sample was dried at ambient conditions for at least one night and then reanalyzed by XRPD.

[0210] The results of the anti-solvent addition polymorph screening are as follows Fig.10 shown.

[0211] Water, heptane and toluene were used as antisolvents and various solvents were selected to dissolve PP-001. In some cases, dissolution was only achieved at elevated temperatures. Once dissolution occurred, antisolvent was added up to 5 volume equivalents. Suspensions were obtained in all water samples and in most heptane samples, indicating that these two solvents were the most effective antisolvents. Aliquots were extracted from all suspensions within 1 hour after the addition of the antisolvent, and a second aliquot was then extracted after 24 hours of maturation. Diffraction was difficult to observe from the aliquots (due to the dilution effect and therefore the high solvent volumes used).

[0212] For those samples where the diffraction was sufficiently pronounced, Form B was observed to be present in all samples. After ripening, a transition to Form A was observed in all samples except THF / heptane. This result again supports the idea that the formation of Form B may be kinetically driven. It is therefore recommended to carefully control the supersaturation during any crystallization process. The raw materials were separated and Form B was obtained from IPA / water, ethyl acetate / heptane and THF / heptane. The remaining suspension gave Form A. The samples with toluene as the antisolvent did not precipitate. IPA / heptane also did not precipitate. These samples were cooled to 5°C overnight in an attempt to promote nucleation, but remained in solution. Therefore, the samples were evaporated slowly. In all cases, Form B was obtained.

[0213] Summary of Crystal Polymorph Screening

[0214] In most cases, polymorph screening with amorphous PP-001 resulted in the isolation of crystalline material. Specifically, the formation of Form A and Form B was most prevalent. Another unique XRPD pattern was obtained from heptane at 5°C. The conditions for all polymorph screening experiments (except antisolvent addition) used to generate each pattern are summarized in Table 9.

[0215] Table 9. Summary of materials for polymorph screening using amorphous input materials

[0216]

[0217]

[0218] As can be seen in Table 9, Form A is the most prevalent pattern overall, while Form B generally increases at lower temperatures. Solvents: Heptane, TBME, Toluene, and Chloroform also favor Form B at higher temperatures. At 5 °C, heptane produces a new pattern 3. Note that the current process solvent IPA / water also shows a preference for Form B at low temperatures, but Form A at high temperatures. In addition, some samples were initially characterized as Form B, but then converted to Form A upon further ripening. This is particularly noteworthy as the basis for antisolvent crystallization.

[0219] For antisolvent addition, a transition from Form B to Form A was observed in several solvent / antisolvent mixtures. This result supports the idea that the formation of Form B may be kinetically driven.

[0220] Example 3: X-ray powder diffraction

[0221] The following method was used for XRPD.

[0222] X-ray powder diffraction. The identification of Form A and Form B in a given sample is determined by analyzing the sample using X-ray powder diffraction (XRPD). The XRPD diffraction curves of Form A and Form B of PP-001 are shown in Figure 2A and 2B The following XRPD experimental protocol was used for these studies:

[0223] 1. Bruker AXS C2GADDS

[0224] XRPD diffractograms were collected on a Bruker AXS C2GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a Vantec-500 2D area detector. The X-ray optics consisted of a single Goebel It consists of a multilayer mirror and a 0.3mm pinhole collimator.

[0225] The beam divergence angle (i.e., the effective size of the X-ray beam on the sample) was about 4 mm. The θ-θ continuous scanning mode was adopted, the sample-detector distance was 20 cm, and the effective 2θ range was 1.5°-32.5°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data acquisition and analysis was GADDS for Win7 / XP and Diffrac Plus EVA, respectively.

[0226] Non-ambient conditions. For variable temperature (VT-XRPD) experiments, samples were placed on an Anton Paar DHS900 hot stage at ambient conditions. The samples were then heated to the appropriate temperature at 20°C / min and then held isothermally for 1 minute before data collection. Samples were prepared and analyzed on silicon wafers mounted on the hot stage using thermal paste. Silicon wafers were mounted on the hot stage using thermal paste, samples prepared and analyzed.

[0227] 2. Bruker AXS D8Advance

[0228] XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, then a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit, then through a Lynxeye detector. The software used for data acquisition and analysis was Diffrac Plus XRDCommander and Diffrac Plus EVA, respectively.

[0229] Samples were run under ambient conditions as flat plate samples using powder as received. Samples were prepared on polished zero-background (510) silicon wafers by gently pressing on a flat surface or loading into a cutting chamber. Samples were rotated on their own plane.

[0230] Details of the standard Pharmorphix data collection method are:

[0231] · Angular range: 2° to 42° 2θ

[0232] Step size: 0.05°2θ

[0233] Acquisition time: 0.5 sec / step (total acquisition time: 6:40 min.

[0234] 3. PANalyticEmpyrean

[0235] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, a 4 mm mask and a 0.04 radian Soller slit were used on the incident beam with a focusing lens. A PIXcel3D detector with a receiving slit and a 0.04 radian Soller slit was placed on the diffracted beam. The software used for data collection was X'Pert DataCollector using X'Pert Operator Interface. The collected data were analyzed and presented using Diffrac Plus EVA or HighScore Plus.

[0236] Samples were prepared and analyzed in transmission mode in metal or microwell 96-well plates. X-ray transparent film was used between the metal plates on the metal well plates and powders (approximately 1-2 mg) were used as received. Microwell plates were used to separate and analyze solids in suspension by adding small amounts of suspension directly to the plate before filtering under a light vacuum.

[0237] The scanning method of the metal plate adopts angular axis scanning, while the scanning method of the microplate adopts 2θ scanning.

[0238] Details of the standard screening data collection method are:

[0239] · Angular range: 2° to 32° 2θ

[0240] Step size: 0.0130°2θ

[0241] Acquisition time: 12.75 seconds / step (total acquisition time is 2.07 minutes)

[0242] Non-ambient conditions. For variable temperature (VT-XRPD) experiments, samples were prepared and analyzed in Anton Paar chrome-plated sample holders with silicon wafer inserts. A 10°C / min heating / cooling rate was used and the isothermal hold was for 2 minutes before the measurement began. The measurement parameters were carried out according to the standard screening data acquisition method (see above for details). The measurements were carried out at the following temperatures: 25°C, 170°C, 180°C, 190°C, 200°C when heating and 170°C, 140°C and 25°C when cooling. This cycle was repeated once.

[0243] Example 4. Solubility and XRPD of PP-001

[0244] PP-001 (approximately 20 mg, batch #1) was treated with increasing aliquots of solvent until a clear solution was obtained or a maximum of 80 vol (1600 μl) of solvent was added. After each addition of solvent, the sample was placed at 25°C, 300 rpm for 3 minutes and observations were recorded. Where possible, the sample was heated to 50°C and further observations were made. Solutions at 25°C or 50°C were cooled to 5°C at a rate of 0.1°C / min, 300 rpm and maintained overnight. Any suspension at 50°C was subjected to an aging cycle between room temperature / 50°C (4 hours per cycle). Depending on the solvent, solvents that were not suitable for heating to 50°C or cooling to 5°C were evaporated, antisolvents were added at room temperature, or aging was performed at room temperature.

[0245] After 24 hours, the lid was removed and the solution was evaporated at room temperature at 5 °C. The evaporated sample was dried before analysis. The remaining suspension was placed under certain conditions for 3 days and then extracted using SPE cartridges and frits under positive pressure filtration.

[0246] A sample from the filter cake was analyzed by XRPD while the remaining sample was allowed to dry overnight at room temperature (DS-2045-08-XX-W). After drying overnight, any new patterns were analyzed by XRPD to determine if any changes in crystalline form had occurred.

[0247] The results of the solubility and solvent selection evaluation are as follows Figure 3A and 3B shown.

[0248] from Figure 3A and 3B As can be seen, 15 tested solvents have good solubility at 25 °C (dissolution volume <80 vol). In general, higher solubility is observed in aprotic polar solvents such as THF, DMSO and acetone. The mobile suspension or partially dissolved sample was subsequently heated to 50 °C (for solvents with sufficiently high boiling points). Clear solutions were obtained at 50 °C in IPA, 1-propanol, ACN, methanol:water (3%), methanol:water (5%), ethanol:water (5%), IPA:water (5%) and IPA:water (25%). The results show that in many solvent systems, PP-001 shows a significant solubility variation curve with temperature. The remaining solvents, heptane, toluene, chloroform and water, remained suspensions. Therefore, these solvents may be suitable antisolvents.

[0249] Crystal polymorph screening. After preliminary solubility assessment, the samples were used as input material for crystalline polymorph screening. Figure 3A and 3B As shown, the samples were subjected to various experimental conditions. The samples kept in suspension at 50°C were subjected to aging cycles between 25°C and 50°C (4 hours per cycle) overnight. The samples formed into solutions at 25°C or 50°C were cooled to 5°C at a rate of 0.1°C / min and left at 5°C overnight. Separately, 1,4-dioxane (freezing point 11°C) was evaporated at room temperature, and DMSO (freezing point 19°C) was added with an antisolvent (water) at room temperature. Ether (boiling point 35°C) was aged at room temperature.

[0250] After aging overnight, any samples that remained in solution at 5°C were slowly evaporated at room temperature until dry. The remaining suspensions were left under the desired conditions for 3 days before the solids were extracted. Any solids obtained were isolated and initially analyzed by XRPD. The results of this analysis are summarized in Figure 4A and 4B middle.

[0251] The XRPD patterns of samples isolated from most solvents were consistent with that of Form A. For samples that formed solutions, slow evaporation resulted in the formation of a new pattern that matched the reference provided by Form B (characterized in previous studies). Form B was isolated from isopropyl acetate, TBME, 1,4-dioxane, THF, and THF:water (10%). A mixture of Form A and Form B was obtained by evaporation from acetone / water. Addition of an antisolvent to DMSO resulted in the isolation of only amorphous material. Insufficient material was recovered from acetone and methanol / water (3%) for analysis. The remaining samples contained C1-C5 alcohols (ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol or isopentanol), C1-C5 ketones (methyl ethyl ketone, methyl isobutyl ketone, acetone) or C1-C5 acetates (methyl acetate, ethyl acetate, propyl acetate, butyl acetate or amyl acetate), forming Form A. No other new spectra were obtained during this screening process. Further characteristics of Form B can be found in Example 5.

[0252] Example 4 - Characteristics of Form A

[0253] Further characteristics of Form A of PP-001 are described below, and its characteristics are summarized in Table 10 below.

[0254] X-ray powder diffraction. XRPD studies were performed as described in Example 1. The XRPD pattern of Form A of PP-001 is shown in Figure 2A The 2θ values ​​(with relative intensity) of Form A are shown in Table 10 below.

[0255] Table 10. XRPD data of Form A of PP-001

[0256]

[0257]

[0258] Differential Scanning Calorimetry (DSC). DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. Typically, 0.5-3 mg of each sample was placed in a pinhole aluminum pan and heated from 25°C to 250°C at a rate of 10°C / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0259] Modulated temperature DSC was performed with a base heating rate of 2°C / min and temperature modulation parameters of ±0.636°C (amplitude) every 60 seconds (cycle).

[0260] The instrument control software was Advantage and Thermal Advantage for the Q series, and data analysis used Universal Analysis or TRIOS.

[0261] DSC showed a small endothermic onset at 177.6°C (20 J / g) with some tailing, and a second sharp endothermic onset at 227.9°C (108 J / g), which probably corresponds to melting. The first endothermic event was further investigated by VT-XRPD and thermal analysis and is discussed further below (Example 4). TGA data showed no weight loss prior to degradation (above 230°C), which is consistent with unsolvated material as seen with proton NMR analysis.

[0262] Polarized light microscopy (PLM) and scanning electron microscopy (SEM). For PLM analysis, samples were analyzed on a Leica LM / DM polarized light microscope and image capture was performed using a digital camera. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a cover slip. Samples were observed with appropriate magnification and partially polarized light coupled with a lambda pseudocolor filter. Images were captured using StudioCapture or Image ProPlus software.

[0263] For SEM analysis, data were collected on a Phenom Pro scanning electron microscope. A small sample was mounted on an aluminum stub using conductive double-sided tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 s).

[0264] PLM and SEM images (Figures 11A and 11B, respectively) show that the sample consists of a mixture of large plate-like crystals and smaller flake-like crystals of similar breadth and width (up to about 200 μm). The surface of the larger crystals is scattered with smaller flake-like crystals. Ion chromatography was used to confirm the absence of anions or cations.

[0265] Gravimetric Vapor Sorption (GVS). Adsorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer and controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 °C by the instrument controller. Humidity was controlled by a mixed dry and wet nitrogen flow with a total flow rate of 200 ml / min.

[0266] Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0-100% RH) located near the sample. A microbalance continuously monitored the sample's weight change (mass relaxation) as a function of %RH (accuracy ±0.005 mg).

[0267] Typically, 5-30 mg of sample was placed in a peeled mesh stainless steel basket under ambient conditions. Samples were loaded and unloaded at 40% RH and 25°C (typical room conditions). The moisture adsorption isotherm (two scans per complete cycle) was determined as described below. The standard isotherm was determined at 25°C in the range of 0-90% RH at intervals of 10% RH. Typically, a double cycle (4 scans) was performed. Data analysis was performed in Microsoft Excel using the DVS analysis suite. The data are shown in Table 11 below.

[0268] Table 11. SMS DVS Intrinsic experimental method

[0269] parameter Numeric Adsorption-Scan 1 40-90 Desorption, adsorption-scan 2 90-0、0-40 Interval (%RH) 10 Scan times 4 Flow rate (ml / min) 200 Temperature(℃) 25 Stability (℃ / min) 0.2 Adsorption time (hours) 6 hours timeout Number of cycles 2

[0270] After the isotherm determination was completed the samples were recovered and reanalyzed by XRPD.

[0271] GVS analysis showed that between 0 and 90% RH, the mass adsorption gradually increased by 0.12 wt%, equivalent to 0.03 mol water, with no obvious hysteresis ( Fig.12 ). The kinetic images showed some oscillations throughout the run, but this was thought to be due to very low mass changes from the humidity cycles. The sample was considered non-hygroscopic and showed no changes by XRPD analysis after GVS.

[0272] Chemical purity was determined by HPLC. Purity analysis was performed using OpenLAB software on an Agilent HP1100 / Infinity II 1260 Series system equipped with a diode array detector. Full method details are provided in Table 12:

[0273] Table 12. Chemical purity determined by HPLC

[0274]

[0275] HPLC showed that the purity of the material was 99.6% ( Fig. 12A ). After 8 days of accelerated storage at 40°C / 75%RH, XRPD and HPLC analysis showed no change in the sample ( Fig. 12B ). After 8 days of accelerated storage at 25°C / 97%RH and HPLC analysis, the samples showed no change ( Fig. 12C ), but a small peak was obtained at 8.1 2θ angle, and the small peak disappeared at 17.6 2θ angle ( Fig.13A The sample was stored for an additional 22 days (30 days in total) and reanalyzed by XRPD, which revealed Form A, lacking the additional peaks previously observed ( Fig. 13B). Therefore, sample contamination on the instrument was likely the cause of the additional peaks at the first 8-day time point, rather than accidental formation or degradation.

[0276] Thermodynamic water solubility. The water solubility is determined by suspending enough compound in the relevant medium to make the maximum final concentration of the parent free state of the compound>10mg / ml. The suspension is balanced for 24 hours at 25°C on a Heidolph microplate oscillator set at 750rpm. The pH of the saturated solution is then measured, and the suspension is filtered with a C-type glass fiber filter (particle retention 1.2μm) and appropriately diluted. HPLC is used to quantify the standard solution of about 0.15mg / ml in DMSO. Different volumes of standard, diluted and undiluted sample solutions are injected. Solubility is calculated using peak area, which is determined by integrating the peak found at the same retention time as the main peak in the standard injection. The data are shown in Table 13 below.

[0277] Table 13. HPLC method for solubility determination

[0278]

[0279] Its thermodynamic solubility was determined to be 0.76 mg / ml in fasting state simulated intestinal fluid (FaSSIF). The XRPD of the remaining solid did not change much, but some additional peaks corresponding to NaCl could be seen.

[0280] Table 14. Characteristic data of Form A of PP-001.

[0281]

[0282]

[0283] Example 5 - Thermal studies of Form A

[0284] Form A is characterized as a stable anhydrous form. However, the additional thermal event at 177.6°C requires further analysis to determine whether a crystalline form change has occurred. Form A was subjected to DSC analysis at different heating rates (5°C / min, 10°C / min, 20°C / min, and 50°C / min), DSC cycles (from 25°C to 205°C, from 205°C to 25°C, and from 25°C to 250°C at a rate of 10°C / min), and MDSC. In addition, the sample was subjected to VT-XRPD processing up to 200°C. The results are summarized in Table 15.

[0285] Table 15. Thermal analysis results of Form A of PP-001

[0286]

[0287]

[0288] The purpose of the variable heating rate experiment was to be able to isolate the endothermic event at approximately 180°C to demonstrate shape change by variable temperature (VT)-XRPD. From the results in Table 15, when the heating rate was varied from 5°C / min to 50°C / min, apart from some artifacts noted in the 20°C / min and 50°C / min runs, little change was observed prior to the onset of this endotherm ( Figures 14A-14D ). In all cases, the event is still present, with the same visible tailing effect. The most interesting finding is the decomposition of another sharp endothermic / exothermic event before melting, which is only seen with faster heating of 20°C / min and 50°C / min (onset at 222.5°C and 224.7°C, respectively), suggesting that there may be additional polymorphic changes before the main melting. However, the closeness of the sample melts (about 227°C-228°C) makes it difficult to probe further without specialized equipment.

[0289] Regarding the first endotherm at about 177°C, DSC cycles were used to further probe this event. In this case, a small endotherm started at 178.2°C (19 J / g) in the first heating cycle, consistent with previous DSC runs. Upon cooling (205°C to 25°C), a small exotherm was observed with an onset temperature of 159.4°C (10 J / g). In the second heating cycle (25°C to 250°C), a small endotherm was again observed with an onset temperature of 177.1°C (12 J / g), followed by a sharp endotherm at 228.2°C (103 J / g), consistent with a melt. This analysis indicates that the endothermic event at 177°C is a reversible transition.

[0290] In the melt-quench-cool measurement, the sample was cooled rapidly after melting and a Tg of 36.4°C was measured upon reheating. This was followed by a double exotherm starting at 86.9°C (29 J / g) and a second endotherm observed at 196.7°C (15 J / g). Figures 15A-15B ).

[0291] Example 6 - Characteristics of Form B of PP-001

[0292] Preparation of Form B of PP-001. Amorphous PP-001 (1 g) was placed in 10 vol (10 ml) toluene. The suspension was matured overnight at 5°C, 300 rpm. An aliquot of about 20 μl was taken and subjected to XRPD to monitor solid phase transformation. The solid was extracted using Buchner filtration. The residual material was extracted using x2 1 mL cold (5°C) toluene washes. The mixed solids were dried under vacuum for more than 1 hour. Yield = 697.41 mg, 69.7%.

[0293] Characteristics of Form B. Form B of PP-001 was characterized by XRPD, DSC, PLM, SEM, HPLC and GVS analysis using the same procedures described in Example 3.

[0294] The DSC curve shows a sharp exotherm at 225.8℃ (92J / g) Fig.16 ). PLM and SEM images showed that the particles were a series of spherical agglomerates (about 50 μm to 100 μm in diameter) composed of small (<10 μm) plate-like crystals ( Figures 17A-17B HPLC analysis showed that the sample maintained a high purity of 99.5% ( Fig.18A ). Accelerated storage at 40°C / 75%RH and 25°C / 97%RH for 7 days showed no observable changes in XRPD in either case. After storage, HPLC purity was found to be 99.6% and 99.4%, respectively ( Figures 18B-18C The isotherm plot of GVS analysis showed that between 0 and 90% RH, the mass adsorption gradually increased by 0.10 wt%, which is equivalent to 0.03 mol water ( Fig.19 ). There was a small hysteresis between adsorption and desorption. The sample was unchanged by XRPD analysis after GVS. The GVS results showed that Form B was non-hygroscopic and stable to variable humidity. The results of these studies are summarized in Table 16 below.

[0295] Table 16. Characteristics of Form B of PP-001

[0296]

[0297]

[0298] The XRPD study of Form B was conducted according to the previously described Example 1. The XRPD curve of Form B of PP-001 is as follows: Figure 2B As shown, the 2θ values ​​of Form B are shown in Table 17 below.

[0299] Table 17. XRPD data of Form B of PP-001

[0300] Position [°2θ] Relative strength [%] 5.2 90.4 13.4 3.8 14.2 36.7 14.9 71 15.6 25.5 16.2 7.5 17.6 100 18.0 16.2 19.3 23.9 20.0 9 20.9 90.8 22.0 17.3 23.5 17.l 24.0 22.6 24.3 15.9 24.9 69.3 25.4 79.5 26.1 15.3 26.4 22.2 27.0 25.3 27.3 24.3 28.2 29.7 28.6 23.5 29.1 8.6

[0301] Additional thermal studies were performed using the magnification of Form B, where the DSC heating rate was varied from 5°C / min to 50°C / min, as performed for Form A in Example 4. The results are shown in Tables 18 and 18 below. Figures 20A-20C An overview is given in .

[0302] Table 18. Thermal characteristics of Form B of PP-001

[0303]

[0304] Example 7 - Thermodynamic Stability Analysis

[0305] The aim of this work was to investigate the stability order of Form A and Form B at scale by competitive slurrying of the materials in a range of solvents at 5 °C, 25 °C and 50 °C. In addition, the thermodynamic solubility and IDR of the two forms were compared in the selected media.

[0306] Aliquot (1 ml) of the suggested solvent into HPLC vials and equilibrate at 5°C, 25°C and 50°C at 300 rpm. Add increasing amounts of PP-001 to each vial until a sustained suspension is observed at the desired temperature. Allow the saturated solution to equilibrate overnight.

[0307] About 300 mg of Form B (prepared as described in previous Example 5) and Form A were added to 20 ml scintillation vials. The sample bottles were turbulently mixed for more than 2 hours to ensure that the mixture was uniform. A mixture of about 30 mg of Form A and Form B was added to a series of HPLC sample bottles. The sample bottles were placed at 5°C, 25°C and 50°C, 300 rpm. The previously prepared suspension was filtered directly into each sample bottle through a PTFE syringe to suspend the prepared crystal mixture in a saturated solution of the target solvent. Polymorph conversion was studied by taking 30-50 μl aliquots of the suspension and analyzing them by XRPD.

[0308] The results of competitive slurrying of Form A and Form B are as follows: Figure 21-23 shown and in Fig.24 Summarized in .

[0309] from Fig.24 It can be seen that Form A is obtained under all solvent and temperature tests. The results show that Form A is the preferred form in the solvent system and temperature range studied. It is worth noting that IPA and IPA / water mixtures show some solvent evaporation at high temperatures, with solids on one side above the solvent line of the sample bottle and a clear solution. In order to confirm that there is no misdetection, additional solid crystal mixtures (Form A + Form B) were added to these samples and allowed to mature for another 24 hours. In each case, the suspension was observed to persist 24 hours after adding more solid mixtures. An aliquot was taken for analysis (DS-2045-48-XX-B, total time 5 days). XRPD confirmed that only Form A was present.

[0310] In addition to competitive slurrying, thermodynamic solubility assays were performed in FaSSIF medium for both Form A and Form B, as well as IDR in pH 7.4 phosphate buffer. The results are shown in Table 19. Full reports for both assays can be found in Appendix 2 - Analytical Services Reports.

[0311] Table 19. Thermodynamic stability and intrinsic dissolution rate (IDR) of Form A and Form B

[0312]

[0313] The results in Table 19 show that both crystalline forms have very low water solubility (<1 mg / ml) and slow dissolution rate (<0.1 g / min / cm 2 ). In the thermodynamic solubility assay and IDR assay, Form A exhibited lower solubility and slower dissolution rate than Form B. The results were consistent with the competitive slurry assay, indicating that Form A is a thermodynamically more stable form.

[0314] The flowchart based on the experiment described in this paper is as follows Fig.25 Form B and Spectrum 3 were fully characterized and both were successfully scaled up. Analysis showed that Form B is a non-solvated anhydrous form suitable for thermodynamic stability studies with Form A. Spectrum 3 is a non-stoichiometric heptane solvate that is unstable and can be converted to Form B. Fig.16 Most solvents and conditions were shown to produce crystallization of Form B or Form A. The only exception was the ripening of amorphous material in heptane at 5 °C, which produced Spectrum 3. The features of Spectrum 3 indicate that the solvate is unstable and will convert to Form B under high humidity or heating / drying.

[0315] Both Form A and Form B are stable anhydrous forms of PP-001, however, competitive slurrying of Form A and Form B indicated that Form A was the preferred form for all conditions and solvents tested. Therefore, Form A is likely the most thermodynamically favorable and is the form recommended for further expansion. The results of the competitive slurrying are consistent with the results of the thermodynamic solubility and IDR assays, where the solubility of Form A is lower than that of Form B, indicating that Form A is the more stable form. Finally, another high temperature form (Spectrum 4) was observed by heating Form A above 175°C. The transition from Form A to Spectrum 4 is reversible and is only visible at high temperatures. Based on the thermal data collected for Form A and Form B, theoretically, a transition from Form A to Spectrum 4 occurs upon heating to melt the sample, followed by a transition from Spectrum 4 to Form B. However, a direct determination of this transition could not be observed due to the close proximity of the thermal event to the melting point. In terms of crystallization process development, pattern 4 is unlikely to be the polymorph of interest because of the high temperatures required to achieve pattern 4.

[0316] Example 7-Crystallization Development of Form A of PP-001

[0317] Form A of PP-001 was selected for crystallization development because it was found to be the most thermodynamically stable form.

[0318] The strategy for crystallization development was to select Class III crystallization solvents from previously performed solubility assessments (Example 1). The solubility curves of Form A in these solvent / antisolvent mixtures were then obtained and the data were regressed using DynoChem to generate a solubility model for Form A at solvent composition and temperature.

[0319] Small-scale (1 g) crystallization was then performed based on the generated solubility model to evaluate the validity of the model and the crystallization kinetics of Form A in the solvent mixture. Finally, the optimal process at the 1 g scale was scaled up to the 5 g scale and monitored using PAT (Process Analytical Technology) to evaluate the process stability of overhead stirring at the multi-gram scale.

[0320] Method 1: 1 g of Form A of PP-001 was dispensed into 20 ml scintillation vials. On this basis, a stirring bar was added and 11.2 vol IPA (11.2 ml) and 1.2 vol H2O (1.2 ml) were added. The resulting suspension was heated to 65°C under magnetic stirring at 500 rpm using a Polar Bear (Cambridge ReactorDesigns heat / cool block) to obtain a clear solution.

[0321] The solution was cooled to 58°C (Ssat ratio 1.2) and 5 wt% PP-001 Form A seeds (5 wt%, 50 mg) were added. The seed retention was observed and the suspension was stirred for 1 hour. The suspension was then cooled to 5°C at a rate of 0.1°C / min and then placed isothermally overnight.

[0322] The suspension was then isolated by filtration, suction dried for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0323] Method 2: 1 g of Form A of PP-001 was dispensed into 20 ml scintillation vials. On this basis, a stirring bar was added and 11.2 vol IPA (11.2 ml) and 1.2 vol H2O (1.2 ml) were added. The resulting suspension was heated to 65°C under magnetic stirring at 500 rpm using a Polar Bear (Cambridge ReactorDesigns heat / cool block) to obtain a clear solution.

[0324] The solution was cooled to 58°C (Ssat ratio 1.2) and 5 wt% PP-001 Form A seeds (5 wt%, 50 mg) were added. The seed retention was observed and the suspension was stirred for 1 hour. Then 7 vol H2O (7 ml) was injected over 2 hours using a syringe pump. The suspension was then cooled to 5°C at a rate of 0.1°C / min and then left isothermally overnight.

[0325] The suspension was then isolated by filtration, suction dried for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0326] Method 3: 1 g of Form A of PP-001 was dispensed into 20 ml scintillation vials. On this basis, a stirring bar was added and 6.4 vol acetone (6.4 ml) and 0.6 vol H2O (0.6 ml) were added. The resulting suspension was heated to 40°C using a Polar Bear (Cambridge ReactorDesigns heat / cool block) with magnetic stirring at 500 rpm to obtain a clear solution.

[0327] The solution was cooled to 30°C (Ssat ratio 1.2) and 5 wt% PP-001 Form A seeds (5 wt%, 50 mg) were added. The seed retention was observed and the suspension was stirred for 1 hour. Then 3 vol H2O (3 ml) was injected over 2 hours using a syringe pump. The suspension was then cooled to 5°C at a rate of 0.1°C / min and then left isothermally overnight.

[0328] The suspension was then isolated by filtration, suction dried for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0329] Method 4: 1 g of Form A of PP-001 was dispensed into 20 ml scintillation vials. On this basis, a stirring bar was added and 4.2 vol acetone (4.2 ml) and 0.33 vol H2O (0.33 ml) were added. The resulting suspension was heated to 50°C using a Polar Bear (Cambridge ReactorDesigns heat / cool block) with magnetic stirring at 500 rpm to obtain a clear solution.

[0330] The solution was cooled to 40°C (Ssat ratio 1.2) and 5 wt% PP-001 Form A seeds (5 wt%, 50 mg) were added. The seed retention was observed and the suspension was stirred for 1 hour. Then 3 vol H2O (3 ml) was injected over 2 hours using a syringe pump. The suspension was then cooled to 5°C at a rate of 0.1°C / min and then left isothermally overnight.

[0331] The suspension was then isolated by filtration, suction dried for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0332] result The characterization results of the solids isolated from the 1 g scale experiments are shown in Table 20. In all four executions, dissolution of Form A of PP-001 was observed at the dissolution temperature identified using the DynoChem model, and the persistence of seeds was observed at the seeding temperature. These observations support the accuracy of the generated solubility model. High purity (99.8% by HPLC) and low residual solvent content (e.g., 1.3% by volume) were obtained in all four experiments performed. 1 H-NMR confirmed) of pure phase Form A. This material was obtained in different yields, with process 2 (IPA / water) giving the highest recovery (88.7%). Based on the solubility model, each process theoretically yielded more than 90%. The difference between the obtained and predicted yields can be explained by the crystal growth rate of Form A in the solvent mixture, in all cases the solution was still supersaturated at the solid phase separation point, indicating slow growth kinetics.

[0333] Table 20. 1g scale-up experimental results

[0334]

[0335] Compared to the provided Form A, in each of the four solids isolated from the 1 g experiment, an additional peak at 11°-14° was observed in the XRPD pattern in the 2q range ( Fig.26 and Fig. 27 ). These peaks are consistent between samples and have low amplitudes. PLM examination of the sample Form A provided showed that it consisted of large plates with a diameter of approximately 100 μm ( Fig.28). However, the particles obtained from the scale-up consisted of much smaller particles with a diameter of about 10μm. When preparing samples for XRPD measurements, they are flattened on a sample holder. The geometry of large plates (such as those in the supplied material) means that when flattened, they are generally oriented with their largest faces parallel to the sample holder. This means that certain planes of the crystal are presented to the incident X-rays at a lower frequency than others, resulting in an apparently smaller number of peaks in the XRPD pattern, an effect known as preferred orientation. The orientation of smaller plates (such as sample (JH-2045-62-04)) is more likely to be randomly distributed during sample preparation, presenting more crystal planes to the incident X-rays, resulting in an XRPD pattern with more peaks. To assess whether the additional peaks observed in the XRPD pattern of the 1g scaled-up sample were caused by preferred orientation, a sample of the supplied material was remeasured using a larger sample holder. Using a larger sample holder allows the crystals to be positioned in more directions, thereby measuring more reflections. The XRPD pattern of the supplied material measured using the large holder is shown in Figure 2. Fig.29 The XRPD pattern shows additional peaks seen in the 1 g scaled-up sample, indicating that these reflections are present in the Form A crystals.

Claims

1. A polymorph, wherein the polymorph is a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, as shown in general formula I: in, The polymorphs are: Form A comprising an X-ray powder diffraction (XRPD) comprising three or more 2-theta values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.2; or Form B comprises an X-ray powder diffraction (XRPD) comprising three or more 2θ values ​​selected from 14.9±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.

2.

2. The polymorph according to claim 1, wherein The polymorph is Form A.

3. The polymorph according to claim 2, wherein: The polymorph comprises four or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.

2.

4. The polymorph according to claim 2, wherein The polymorph comprises five or more 2θ values ​​selected from 14.8±0.2, 15.6±0.2, 16.5±0.2, 19.6±0.2, 20.8±0.2, 25.6±0.2, and 26.1±0.

2.

5. The polymorph according to claim 2, wherein Form A includes the XRPD pattern shown in Figure 2A.

6. The polymorph according to claim 2, further comprising one or more characteristics selected from the group consisting of: a.DSC spectrum (5°C / min) contains an endothermic onset temperature of 178.3±1.0°C and a second endothermic onset temperature of 227.3±1.0°C; b.DSC spectrum (10°C / min) includes an endothermic onset temperature of 177.6±1.0°C and an endothermic onset temperature of 227.9±1.0°C; c.DSC spectrum (20°C / min) including an endothermic onset temperature of 178.5±1.0°C, endothermic onset temperatures of 222.5±1.0°C and 224.3±1.0°C, and a subsequent endothermic onset temperature of 227.8±1.0°C; d.DSC spectrum (50°C / min) containing double endothermic onset temperatures of 88.0±1.0°C and 92.6±1.0°C, a second endothermic onset temperature of 180.5±1.0°C, a sharp endothermic onset temperature / exothermic onset temperature of 224.7±1.0°C, and an endothermic onset temperature of 229.5±1.0°C; e. melt-quench-cool (MDSC) comprising an endothermic onset temperature of 177.7±1.0°C and an endothermic onset temperature of 227.8±1.0°C; or f. VT-XRPD pattern with observable changes at 200°C.

7. The polymorph according to claim 1, wherein The polymorph is Form B.

8. The polymorph according to claim 7, wherein The polymorph comprises four or more 2θ values ​​selected from 14.8±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.

2.

9. The polymorph according to claim 7, wherein: The polymorph comprises five or more 2θ values ​​selected from 14.8±0.2, 17.6±0.2, 19.3±0.2, 20.9±0.2, 24.0±0.2, 24.9±0.2, and 25.4±0.

2.

10. The polymorph according to claim 7, wherein Form B includes the XRPD pattern shown in Figure 2B.

11. A pharmaceutical composition comprising Form A or Form B of a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; and a pharmaceutically acceptable excipient, carrier or diluent.

12. A kit comprising Form A or Form B of a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; and a container.

13. A method for preparing a crystalline form A of a polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, the method comprising: a) obtaining a sample comprising 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; b) dissolving the sample in (a) in a solvent comprising a C1-C5 alcohol, a C1-C5 ketone or a C1-C5 acetate solvent at 20° C. to 60° C. to form a solution; and c) removing the solvent from the solution to obtain Form A of the polymorph.

14. The method according to claim 13, wherein: The C1-C5 alcohol is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol or isopentanol.

15. The method according to claim 13, wherein: The C1-C5 ketone is selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) or acetone.

16. The method according to claim 13, wherein: The C1-C5 acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate or pentyl acetate.

17. The method according to claim 13, wherein: The solution is greater than 80% C1-C5 alcohol, C1-C5 ketone or C1-C5 acetate.

18. The method according to claim 13, wherein: The solution contains 0% to 20% water.

19. The method according to claim 13, wherein: The solution contains 0% to 10% water.

20. The method according to any one of claims 13 to 19, wherein: After the dissolution in (b), the solution is cooled to a culture temperature of 1°C to 10°C and maintained for a period of time.

21. The method according to claim 20, wherein: Cooling to the culture temperature is performed at a rate of about 0.02°C / min to about 1°C / min until the culture temperature is reached.

22. The method according to claim 20, wherein: Cooling to the culture temperature is performed at a rate of about 0.05°C / min to about 0.5°C / min until the culture temperature is reached.

23. The method according to any one of claims 20 to 22, wherein: The period of time for the incubation temperature is from about 1 hour to about 48 hours.

24. The method according to any one of claims 20 to 22, wherein: The period of time for the incubation temperature is from about 6 hours to about 18 hours.

25. The method according to any one of claims 13 to 24, wherein: The removal of the solvent is carried out by evaporation.

26. The method according to any one of claims 13 to 24, wherein: The removal of the solvent was performed by filtration.

27. The method according to claim 25, wherein: The evaporation occurs at about 20°C to about 35°C.

28. A method for treating, preventing or ameliorating a disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of Form A of the polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid.

29. A method of preparing a pharmaceutical composition, the method comprising combining Form A of the polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid with one or more pharmaceutically acceptable excipients, diluents or carriers.

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