Polymorphs of dihydroorotate dehydrogenase (DHOD) inhibitors.

Abstract

The present disclosure provides polymorphs of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, and methods for making such polymorphs. The present disclosure further provides pharmaceutical compositions and kits comprising the polymorphs of the invention, and methods for 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'-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001), and methods for making such polymorphs. The present disclosure further provides pharmaceutical compositions and kits comprising the polymorphs of the invention, and methods for treating, preventing, or ameliorating a disease or condition comprising administering the polymorphs of the invention. [Background technology]

[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), shown below as Formula I, is a potent DHODH inhibitor. [ka]

[0003] See, for example, US 7,365,094, US 8,354,433 and US 9,795,590, which are incorporated herein by reference. PP-001 has application in the treatment of diseases and conditions associated with DHOD activity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] US7,365,094 [Patent Document 2] US8,354,433 [Patent Document 3] US9,795,590 Summary of the Invention

[0005] In some embodiments, the present disclosure relates to a polymorph of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, as shown below in Formula I: [ka]

[0006] In some embodiments, the polymorph is Form A comprising an X-ray powder diffraction (XRPD) comprising 3 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 3 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.

[0007] In some embodiments, the polymorph is Form A. In some embodiments, the polymorph is Form A and comprises a 2θ value of 4 or greater 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 a 2θ value of 5 or greater 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 the XRPD pattern depicted in FIG. 2A.

[0008] In some embodiments, the polymorph is Form A; a DSC spectrum (5°C / min) with an endotherm onset at 178.3 ± 1.0°C and a second endotherm onset at 227.3 ± 1.0°C; b DSC spectrum (10 °C / min) with endothermic onset at 177.6 ± 1.0 °C and endothermic onset at 227.9 ± 1.0 °C; c. DSC spectrum (20°C / min) with an endothermic onset at 178.5±1.0°C, and endothermic onsets at 222.5±1.0°C and 224.3±1.0°C, followed by an endothermic onset at 227.8±1.0°C; d. DSC spectrum (50°C / min) containing double endothermic onsets at 88.0±1.0°C and 92.6±1.0°C, a second endothermic onset at 180.5±1.0°C, a sharp endothermic / exothermic onset at 224.7±1.0°C, and an endothermic onset at 229.5±1.0°C; e. Melt-quench-cool (MDSC) with an endothermic onset of 177.7 ± 1.0 °C and an endothermic onset of 227.8 ± 1.0 °C; or f. VT-XRPD pattern with observable changes at 200±1.0℃ The present invention includes one or more features selected from the following:

[0009] In some embodiments, the polymorph is Form B. In some embodiments, the polymorph is Form B and comprises 4 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 5 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 the XRPD pattern shown in FIG. 2B.

[0010] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising polymorphic Form A or Form B of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0011] In some embodiments, the present disclosure relates to a kit comprising polymorphic Form A or Form B of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid and a container.

[0012] In some embodiments, the present disclosure provides a method for preparing polymorphic Form A 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′-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; 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 c) removing the solvent from the solution to obtain polymorphic Form A. The present invention relates to a method comprising the steps of:

[0013] In some embodiments, the C1-C5 alcohol is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 2-pentanol, or isopentanol. In some embodiments, the C1-C5 ketone is selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), or acetone.

[0014] In some embodiments, the C1-C5 acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, or pentyl acetate.

[0015] In some embodiments, the solution is greater than 80% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, hi some embodiments, the solution contains 0%-20% water.

[0016] In some embodiments, after dissolving in (b), the solution is cooled to an incubation temperature of 1° C. to 10° C. over a period of time. In some embodiments, cooling to the incubation temperature is at a rate of about 0.02° C. / min to about 1° C. / min until the incubation temperature is reached. In some embodiments, cooling to the incubation temperature is at a rate of about 0.05° C. / min to about 0.5° C. / min until the incubation temperature is reached.

[0017] In some embodiments, the time period to reach the incubation temperature is about 1 hour to about 48 hours, In some embodiments, the time period to reach the incubation temperature is about 6 hours to about 18 hours.

[0018] In some embodiments, the solvent is removed by evaporation. In some embodiments, the solvent is removed by filtration. In some embodiments, the evaporation is performed at about 20°C to about 35°C.

[0019] In some embodiments, the present invention relates to a method of treating, preventing or ameliorating a disease or condition in a subject in need of such treatment, the method comprising administering to the subject a pharma- ceutical effective amount of polymorphic Form A of 3-(2,3,5,6-tetrafluoro-3′trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid.

[0020] In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition, the method comprising combining polymorphic Form A of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid with one or more pharma- ceutically acceptable excipients, diluents, or carriers. [Brief description of the drawings]

[0021] [Figure 1]FIG. 1 shows the chemical structure of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001). [Figure 2A] FIG. 1 shows the X-ray powder diffraction (XRPD) profiles of PP-001 Form A, Form B, an overlay of Forms A and B, and amorphous PP-001, respectively. [Figure 2B] FIG. 1 shows the X-ray powder diffraction (XRPD) profiles of PP-001 Form A, Form B, an overlay of Forms A and B, and amorphous PP-001, respectively. [Figure 2C] FIG. 1 shows the X-ray powder diffraction (XRPD) profiles of PP-001 Form A, Form B, an overlay of Forms A and B, and amorphous PP-001, respectively. [Figure 2D] FIG. 1 shows the X-ray powder diffraction (XRPD) profiles of PP-001 Form A, Form B, an overlay of Forms A and B, and amorphous PP-001, respectively. [Figure 3A] FIG. 1 shows the results of solubility evaluation of PP-001 in various solvent systems and treatments. [Figure 3B] FIG. 1 shows the results of solubility evaluation of PP-001 in various solvent systems and treatments. [Figure 4A] FIG. 1 provides the results of crystalline polymorph screening of PP-001 using the solvent systems and treatments indicated. [Figure 4B] FIG. 1 provides the results of crystalline polymorph screening of PP-001 using the solvent systems and treatments indicated. [Diagram 5] FIG. 1 shows the results of a solubility screen of amorphous PP-001 using the solvents and treatments indicated. [Figure 6A] FIG. 1 provides observations and results upon aging amorphous PP-001 at 5° C. using the indicated solvents. [Figure 6B] FIG. 1 provides observations and results upon aging amorphous PP-001 at 5° C. using the indicated solvents. [Figure 7]FIG. 1 shows overlaid XPRD profiles of PP-001 Form A and Form B, and "Pattern 3" obtained by aging amorphous PP-001 with heptane at 5° C. [Figure 8A] FIG. 1 provides observations and results of temperature cycling maturation of amorphous PP-001 using the indicated solvents. [Figure 8B] FIG. 1 provides observations and results of temperature cycling maturation of amorphous PP-001 using the indicated solvents. [Figure 9A] FIG. 1 provides observations and results upon aging of amorphous PP-001 at 50° C. using the indicated solvents. [Figure 9B] FIG. 1 provides observations and results upon aging of amorphous PP-001 at 50° C. using the indicated solvents. [Figure 10] FIG. 1 provides observations and results from anti-solvent polymorph screening using the solvents and conditions indicated. [Figure 11A] FIG. 1 shows PP-001 Form A polymorph crystals using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM). [Figure 11B] FIG. 1 shows PP-001 Form A polymorph crystals using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM). [Figure 12] FIG. 1 shows the Gravimetric Vapor Sorption (GVS) isotherm of PP-001 Form A. [Figure 12A] FIG. 1 shows HPLC profiles of (A) PP-001 form A starting material, (B) PP-001 form A after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form A after 8 days of storage at 25° C. / 97% relative humidity. [Figure 12B] FIG. 1 shows HPLC profiles of (A) PP-001 form A starting material, (B) PP-001 form A after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form A after 8 days of storage at 25° C. / 97% relative humidity. [Figure 12C]FIG. 1 shows HPLC profiles of (A) PP-001 form A starting material, (B) PP-001 form A after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form A after 8 days of storage at 25° C. / 97% relative humidity. [Figure 13A] FIG. 1 shows overlaid XPRD profiles of PP-001 starting material, and PP-001 form A after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form A after 8 days of storage at 25° C. / 97% relative humidity. [Figure 13B] FIG. 1 shows overlaid XPRD profiles of PP-001 starting material, and PP-001 form A after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form A after 8 days of storage at 25° C. / 97% relative humidity. [Figure 14A] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form A at (A) 5° C. / min, (B) 10° C. / min, (C) 20° C. / min, and (D) 50° C. / min. [Figure 14B] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form A at (A) 5° C. / min, (B) 10° C. / min, (C) 20° C. / min, and (D) 50° C. / min. [Figure 14C] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form A at (A) 5° C. / min, (B) 10° C. / min, (C) 20° C. / min, and (D) 50° C. / min. [Figure 14D] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form A at (A) 5° C. / min, (B) 10° C. / min, (C) 20° C. / min, and (D) 50° C. / min. [Figure 15A] FIG. 1 shows the results of a DSC melt / quench cooling analysis of PP-001 Form A. [Figure 15B] FIG. 1 shows the results of a DSC melt / quench cooling analysis of PP-001 Form A. [Figure 16] FIG. 1 shows TGA and DSC analysis of PP-001 form B. [Figure 17A]FIG. 1 shows PP-001 Form B polymorph crystals using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM). [Figure 17B] FIG. 1 shows PP-001 Form B polymorph crystals using (A) polarized light microscopy (PLM) and (B) scanning electron microscopy (SEM). [Figure 18A] FIG. 1 shows HPLC profiles of (A) PP-001 form B starting material, (B) PP-001 form B after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form B after 8 days of storage at 25° C. / 97% relative humidity. [Figure 18B] FIG. 1 shows HPLC profiles of (A) PP-001 form B starting material, (B) PP-001 form B after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form B after 8 days of storage at 25° C. / 97% relative humidity. [Figure 18C] FIG. 1 shows HPLC profiles of (A) PP-001 form B starting material, (B) PP-001 form B after 8 days of storage at 40° C. / 75% relative humidity, and (C) PP-001 form B after 8 days of storage at 25° C. / 97% relative humidity. [Figure 19] FIG. 13 shows the GVS isotherm of PP-001 form B. [Figure 20A] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form B at (A) 5° C. / min, (B) 20° C. / min, and (C) 50° C. / min. [Figure 20B] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form B at (A) 5° C. / min, (B) 20° C. / min, and (C) 50° C. / min. [Figure 20C] FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of PP-001 form B at (A) 5° C. / min, (B) 20° C. / min, and (C) 50° C. / min. [Figure 21] FIG. 1 shows an overlay of XRPD (DS-2054-47) of PP-001 form A, PP-001 form B, and a mixture of PP-001 forms A and B. [Figure 22]FIG. 1 shows an XRPD overlay of aliquot samples taken during competitive slurrying of PP-001 Forms A and B after 5 days. [Diagram 23] FIG. 13 shows the XRPD of PP-001 form B after thermodynamic solubility measurements. [Figure 24] FIG. 1 provides a summary of the results of competitive slurrying of PP-001 Forms A and B. [Diagram 25] FIG. 1 shows a diagram depicting different polymorphic forms of PP-001. [Figure 26] FIG. 1 shows XRPD analysis of 1 g crystallization scale-up of PP-001 Form A. [Figure 27] FIG. 1 shows a comparison of XRPD profiles of PP-001 form A as supplied and PP-001 form A crystallized using four crystallization methods. [Figure 28] FIG. 16 shows a comparison of PLM images of PP-001 Form A starting material and PP-001 Form A crystals after 1 g scale-up crystallization. [Figure 29] FIG. 1 shows the XRPD profile of PP-001 form A crystallized using a large recess sample holder. [Diagram 30] FIG. 1 shows an overlay of the crystal structures of Forms A and B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present disclosure relates to polymorphic forms of the dihydroorotate dehydrogenase (DHODH) inhibitor 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)thiophene-2-carboxylic acid, processes for their preparation, pharmaceutical compositions containing same, and their use for the treatment and prevention of diseases, particularly diseases in which it is advantageous to inhibit dihydroorotate dehydrogenase (DHODH).

[0023] Different polymorphic forms of a given compound, such as PP-001, may have different properties, such as solubility, dissolution rate, suspension stability, grinding stability, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration performance, drying, density, melting point, degradation stability, stability against phase change to other forms, color, and even chemical reactivity. More importantly, in some embodiments, different forms of a small molecule compound, such as PP-001, may alter its dissolution, dissolution performance, pharmacokinetics, and bioavailability, which may affect the efficacy and safety performance of the drug in some cases.

[0024] In particular, in some embodiments, the crystalline form of PP-001 may affect its dissolution, in vivo absorption, and thereby affect its clinical therapeutic efficacy and safety to some extent. In some embodiments, the crystalline form of PP-001 may be crucial for drug quality control. The present disclosure relates to polymorphic forms of PP-001 and compositions and kits thereof, methods of making polymorphic forms of PP-001, and methods of treating, preventing, or ameliorating a disease, disorder, or condition by administering a therapeutically effective amount of a polymorphic form of PP-001.

[0025] This disclosure provides novel polymorphic forms of PP-001. This application describes the chemical and physical properties of these polymorphic forms and discloses methods for making these polymorphic forms.

[0026] A list of abbreviations used throughout this specification is provided in Table 1.

[0027] Table 1. List of abbreviations [Table 1]

[0028] TIFF2025508023000004.tif80167

[0029] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meaning commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more. As used herein, "another" or "further" may mean at least a second or more.

[0030] Throughout this application, the term "about" is used to indicate that a value includes the inherent error variation of the method / device being used to determine the value or the variation that exists between test subjects. Typically, the term "about" is meant to encompass a variation of less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, depending on the context.

[0031] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or where the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers only to alternatives and "and / or."

[0032] As used herein, the terms "comprising" (and any variation or form of "comprising", such as "comprise" and "comprises"), "having" (and any variation or form of "having", such as "have" and "has"), "including" (and any variation or form of "including", such as "includes" and "include"), or "containing" (and any variation or form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment described herein can be practiced with respect to the salts, methods, and / or kits of the disclosure. Additionally, the methods of the disclosure can be accomplished using the salts and / or kits of the disclosure.

[0033] Use of the term "for example" and its corresponding abbreviation "eg" (whether italicized or not) means that the specific terms described are representative examples and embodiments of the present disclosure that are not intended to be limited to the specific examples referenced or cited, unless expressly stated otherwise.

[0034] As used herein, "between" refers to a range that includes both ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any number that falls within the range between x and y.

[0035] In the case of characteristic diffraction peaks expressed in two-theta (2θ) angles, the term "about" means that the recited value does not vary by more than 0.2°, e.g., for about X°, it means X±0.2°, preferably X±0.1°. Thus, in some embodiments, any of the 2θ angles described herein can be ±0.1.

[0036] The term "room temperature" as used herein generally refers to 4°C to 30°C, 18°C ​​to 22°C, 19°C to 21°C, or 20±5°C.

[0037] The present disclosure provides polymorphs of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001) in various crystalline forms, such as Form A, Form B, as well as in an amorphous form.

[0038] In some embodiments, PP-001 is polymorph Form A. In some embodiments, the term "Form A" refers to a polymorph of PP-001 comprising an X-ray powder diffraction (XRPD) comprising 3 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.

[0039] In some embodiments, the Form A polymorph of PP-001 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 14.8±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 15.6±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 16.5±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 19.6±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 20.8±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 25.6±0.2 and two other 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 has an X-ray powder diffraction (XRPD) spectrum comprising a 2θ value of 26.1±0.2 and two other 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.

[0040] In some embodiments, the Form A polymorph of PP-001 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 14.8±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 15.6±0.2 and three other 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 of 16.5±0.2 and three other 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 of 19.6±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 20.8±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 25.6±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 26.1±0.2 and three other 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.

[0041] In some embodiments, polymorph form A comprises 4 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, polymorph form A comprises 5 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.

[0042] In some embodiments, polymorph form A comprises 6 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, polymorph form A 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 PP-001 form A is shown in FIG. 2A. One of ordinary skill in the art would know how to determine the predominant 2θ values ​​from an XRPD pattern.

[0043] In some embodiments, polymorph Form A can be determined by measuring the endothermic onset of the polymorph by differential scanning calorimetry (DSC). In some embodiments, the DSC spectrum can be determined at various rates, such as, for example, 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 various rates, such as, for example, 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 various rates, such as, for example, 30°C / min to 70°C / min, 40°C / min to 60°C / min, or 50°C / min.

[0044] In some embodiments, any of the DSC endothermic onset temperatures described herein can be ±1.0° C. In some embodiments, any of the DSC endothermic onset temperatures described can be ±0.5° C., ±0.2° C., or ±0.1° C. Thus, for example, if Form A is described as having a DSC spectrum that includes an endothermic onset at about 178.3° C. at 5° C. / min, it is considered to 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.

[0045] In some embodiments, Form A comprises a DSC spectrum (5° C. / min) with an endothermic onset at about 175° C. to about 180° C., such as about 178° C. to about 179° C., such as at 178.3° C., or such as at 178.3° C.±0.1. In some embodiments, Form A comprises a DSC spectrum (5° C. / min) with a second endothermic onset at about 225° C. to about 230° C., such as about 227° C. to about 228° C., such as at 227.3° C., or such as at 227.3° C.±0.1.

[0046] In some embodiments, Form A comprises a DSC spectrum (10° C. / min) with an endothermic onset at about 175° C. to about 180° C., such as 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) with an endothermic onset at about 225° C. to about 230° C., such as about 227° C. to about 228° C., such as 227.9° C., or such as 227.9° C.±0.1.

[0047] In some embodiments, Form A comprises a DSC spectrum (20°C / min) with an endothermic onset at about 175°C to about 180°C, such as 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 an additional endothermic onset at about 220°C to about 225°C, such as 222.5°C, and about 221°C to about 226°C, such as 224.3°C, or such as 224.3°C±0.1. In some embodiments, Form A comprises an additional endothermic onset at about 225°C to about 230°C, such as 227.8°C, or such as 227.8°C±0.1.

[0048] In some embodiments, Form A comprises a DSC spectrum (50° C. / min) comprising a double endotherm onset at about 85° C. to about 90° C., such as 88.0° C., and at about 90° C. to about 95° C., such as 92.6° C., or such as 92.6° C.±0.1. In some embodiments, the endotherm onset is about 178° C. to about 182° C., such as 180.5° C., or such as 180.5° C.±0.1, the endotherm / exotherm onset is about 221° C. to about 226° C., such as 224.7° C., or such as 224.7° C.±0.1, and the endotherm onset is about 227° C. to about 231° C., such as 229.5° C., or such as 229.5° C.±0.1.

[0049] In some embodiments, Form A exhibits a DSC spectrum at one or more of the rates described above, for example, at rates of 5° C. / min, 10° C. / min, 20° C. / min, and / or 50° C. / min.

[0050] In some embodiments, any of the polymorphs having melt-quench-cool (MDSC) endothermic onset temperatures described herein can be ±1.0° C. In some embodiments, any of the listed MDSC endothermic onset temperatures can be ±0.5° C., ±0.2° C., or ±0.1° C. Thus, for example, if Form A is described as having an MDSC spectrum that includes an endothermic onset at about 178.3° C., this could 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., etc.

[0051] In some embodiments, the Form A polymorph has a melt-quench-cool (MDSC) with an endothermic onset at about 175° C. to about 180° C., such as 177.7° C., or such as 177.7° C.±0.1, and an endothermic onset at about 225° C. to about 230° C., such as 227.8° C., or such as 227.8° C.±0.1.

[0052] In some embodiments, the Form A polymorph comprises a variable temperature XRPD (VTXRPD) pattern with an observable change between about 190°C and about 210°C, for example, 200°C.

[0053] In some embodiments, the disclosure provides a crystalline polymorph Form A of PP-001 characterized by one or more of the crystal structure parameters set forth in Table 2.

[0054] Table 2: Crystal structure parameters of PP-001 polymorph form A [Table 2]

[0055] TIFF2025508023000006.tif201163

[0056] The dimensions of the unit cell are defined by three parameters: the length of the sides of the cell, the relative angles between the sides, and the volume of the cell. The lengths of the sides of the unit cell are defined by a, b, and c. The relative angles of the sides of the cell are defined by α, β, and γ. The embodiments of the present invention further include PP-001 polymorph Form A having atomic positions of all atoms relative to the origin of the unit cell as set forth in Tables 3 and 4. Tables 3 and 4 list the atomic coordinates as well as bond length and bond angle parameters of PP-001 Form A as set forth herein. These parameters define the atomic arrangement in the crystal structure of PP-001 Form A as set forth herein.

[0057] Table 3: Atomic coordinates of PP-001 polymorph form A (x10 4 ) and the equivalent isotropic displacement parameter (A 2 ×10 3 ) [Table 3]

[0058] Table 4: Bond lengths [Å] and angles [°] of PP-001 polymorph form A [Table 4]

[0059] TIFF2025508023000009.tif255147

[0060] TIFF2025508023000010.tif142168

[0061] The DSC, GVS, PLM, SEM, and HPLC characterization of PP-001 Form A is described and illustrated in more detail in Example 3 below, and the thermal studies of Form A are described in more detail in Example 4.

[0062] In some embodiments, the polymorph of PP-001 is Form B. In some embodiments, Form B comprises an X-ray powder diffraction (XRPD) comprising 3 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.

[0063] In some embodiments, the Form B polymorph of PP-001 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 14.9±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 17.6±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 19.3±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 20.9±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 24.0±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 24.9±0.2 and two other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 25.4±0.2 and two other 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.

[0064] In some embodiments, the Form B polymorph of PP-001 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 14.9±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 17.6±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 19.3±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 20.9±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 24.0±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 24.9±0.2 and three other 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 has an X-ray powder diffraction (XRPD) comprising a 2θ value of 25.4±0.2 and three other 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.

[0065] In some embodiments, the polymorph of Form B comprises 4 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 of Form B comprises 5 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 of Form B comprises 6 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 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.

[0066] 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 PP-001 Form B is shown in Figure 2B.

[0067] In some embodiments, the disclosure provides a crystalline polymorph Form A of PP-001 characterized by one or more of the crystal structure parameters set forth in Table 5.

[0068] Table 5: Crystal structure parameters of PP-001 polymorph form B [Table 5]

[0069] TIFF2025508023000012.tif197170

[0070] Embodiments of the present invention further include PP-001 polymorph Form B having atomic positions of all atoms relative to the origin of the unit cell as set forth in Tables 6 and 7.

[0071] Tables 6 and 7 list the atomic coordinates and bond length and bond angle parameters of PP-001 Form B described herein, which define the atomic arrangement in the crystal structure of PP-001 Form B described herein.

[0072] Table 6. Atomic coordinates of PP-001 polymorph form B (×10 4 ) and the equivalent isotropic displacement parameter (A 2 x10 3 ) [Table 6]

[0073] Table 7: Bond lengths of PP-001 polymorph form B [ Å ] and bond angle [°] [Table 7]

[0074] TIFF2025508023000015.tif255154

[0075] TIFF2025508023000016.tif131169

[0076] In some embodiments, the DSC, GVS, PLM, SEM, and HPLC characteristics of PP-001 Form B are discussed in more detail below in Example 5.

[0077] Methods for producing polymorphs In some embodiments, the disclosure provides a method for preparing polymorphic Form A. In some embodiments, the disclosure provides a method for preparing polymorphic Form A 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 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 (c) removing the solvent from the solution to obtain the polymorphic Form A.

[0078] The present disclosure provides that polymorphic form A is formed by dissolving PP-001 in a lower alkyl solvent, such as C1-C5 alcohol, C1-C5 ketone, and C1-C5 acetate, followed by crystallization by removal of the solvent. As used herein, the terms "C1-C5 alcohol," "C1-C5 ketone," and C1-C5 acetate refer to any alcohol, ketone, or acetate of 1 to 5 carbon atoms, respectively. In some embodiments, the C1-C5 alkyl is a straight or branched carbon chain. 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 pentyl acetate.

[0079] In some embodiments, PP-001 is dissolved in a solvent to form a solution that is greater than 80% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, greater than 85% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, greater than 90% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, greater than 95% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, greater than 98% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate, or greater than 99% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate.

[0080] In some embodiments, PP-001 is dissolved in a solvent to form a solution, which 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.

[0081] In some embodiments, PP-001 is dissolved in a solvent to form a solution, which 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.

[0082] In some embodiments, PP-001 is dissolved in a solvent to form a solution, which 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.

[0083] In some embodiments, PP-001 forms crystals, e.g., polymorph form A, using a solvent that contains little water. In some embodiments, it contains less than 20% water, less than 15% water, less than 10% water, less than 5% water, or less than 2% water (volume / volume). In some embodiments, PP-001 is dissolved in a solvent to form a solution, the solution containing 0%-20% water, 0%-10% water, 0%-5% water, or 0%-2% water. In some embodiments, PP-001 is dissolved in a solvent to form a solution, the solution containing 0%-1% water. In some embodiments, PP-001 is dissolved in a solvent to form a solution, the solvent being a dehydrated solvent.

[0084] In some embodiments, PP-001 forms crystals comprising a solvent and a small amount of water, such as about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water, such as polymorph form A. In some embodiments, PP-001 forms crystals comprising a solvent and a small amount of water, such as about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water, such as polymorph form A.

[0085] In some embodiments, PP-001 forms crystals comprising C1-C5 alcohols and a small amount of water, such as about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water, such as polymorph form A. In some embodiments, PP-001 forms crystals comprising C1-C5 ketones and a small amount of water, such as about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water, such as polymorph form A. In some embodiments, PP-001 forms crystals comprising C1-C5 acetates and a small amount of water, such as about 1% to about 15%, about 1% to about 10%, about 1% to about 5% water, such as polymorph form A.

[0086] The temperature used to dissolve PP-001 in the solvent can be determined by one of skill in the art and may depend on the concentration of PP-001 in the solvent, as well as the temperature at which dissolution occurs and the duration of dissolution.

[0087] In some embodiments, 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, 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, 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, or 45°C to 50°C, or 50°C to 60°C to form a solution.

[0088] In some embodiments, PP-001 is dissolved in the solvent at less than 10% (w / v), less than 5% (w / v), less than 2% (w / v), less than 1% (w / v), less than 0.5% (w / v), or less than 0.1% (w / v) of the solvent. In some embodiments, the concentration of PP-001 is less than the saturation point for a given solvent and temperature, e.g., if the saturation point of PP-001 for a given solvent and temperature is "X mg / mL", then the concentration of PP-001 is less than "X mg / mL", e.g., less than 20%, less than 50%, or less than 80%.

[0089] In some embodiments, PP-001 dissolved in a solvent forms a solution, which is cooled to the incubation temperature. In some embodiments, the incubation temperature is maintained for a "period of time." In some embodiments, the period 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, greater than 2 days, or greater than 3 days. In some embodiments, the period of time to reach the incubation 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.

[0090] In some embodiments, the incubation temperature is from about 1° C. to about 10° C. for a period of time. In some embodiments, the incubation temperature is from about 2° C. to about 8° C., from about 3° C. to about 7° C., or from about 4° C. to about 6° C. for a period of time.

[0091] In some embodiments, the temperature change from the lysis temperature to the incubation temperature can be performed over a defined period of time, i.e., a rate of change or temperature over a given time. In some embodiments, the cooling from the lysis temperature to the incubation temperature is at a rate of about 0.02° C. / min to about 1° C. / min until the temperature is reached. In some embodiments, the cooling to the incubation temperature is at a rate of about 0.05° C. / min to about 0.5° C. / min until the incubation temperature is reached. In some embodiments, the cooling to the incubation temperature is at a rate of about 0.1° C. / min to about 0.3° C. / min until the incubation temperature is reached.

[0092] In some embodiments, after the incubation temperature is held for a period of time, the solvent is removed and the PP-001 is crystallized. In some embodiments, the crystallization process can be initiated using seed crystals or other starting compositions. In some embodiments, the solvent is removed and the polymorph is allowed to form over a period of time, i.e., over the removal time. One of skill in the art will appreciate that as the concentration of the solvent decreases, the concentration of PP-001 will increase until the crystallization process is initiated. One of skill in the art will also appreciate that many factors can affect the removal time, for example, the amount of solvent removed, the type of solvent removed, temperature, pressure, etc., affect the solvent removal time.

[0093] 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, greater than 2 days, greater than 3 days, greater than 4 days, greater than 5 days, or greater than 6 days.

[0094] In some embodiments, the solvent is removed by evaporation. One skilled in the art will appreciate that the evaporation rate is determined by many factors, including but not limited to the type of solvent, temperature, and pressure. In some embodiments, the evaporation is performed at the incubation temperature. In some embodiments, the evaporation temperature can vary, e.g., change over time. In some embodiments, the evaporation temperature is constant. In some embodiments, the evaporation is performed at a temperature higher than the incubation temperature. In some embodiments, the evaporation is performed at above 5°C, above 10°C, above 15°C, above 20°C, above 25°C, or above 30°C. In some embodiments, the evaporation is performed at 5°C to 40°C, 10°C to 35°C, 15°C to 30°C. In some embodiments, the evaporation is performed at about 20°C to about 35°C. In some embodiments, when multiple solvents are present, the evaporation temperature can be maintained at a first temperature until the first solvent is evaporated, and then changed to a second temperature.

[0095] In some embodiments, the distillation can be carried out at various temperatures. In some embodiments, the distillation is carried out at 1 atmosphere. In some embodiments, the distillation is carried out at less than 1 atmosphere.

[0096] In some embodiments, the removal of the solvent is accomplished by filtration. For example, in some embodiments, the solvent is removed using a membrane or semi-permeable membrane. In some embodiments, when a semi-permeable membrane is used, the solvent is exchanged for a different solvent in which PP-001 forms crystals.

[0097] In some embodiments, the solvent is removed by lyophilization.

[0098] Pharmaceutical Compositions The present disclosure provides pharmaceutical compositions comprising a polymorph of PP-001 as described herein, such as Form A or Form B. In some embodiments, the present disclosure provides pharmaceutical compositions comprising polymorph Form A of PP-001 and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0099] In some embodiments, the term "pharmacologically acceptable" excipient, carrier, diluent, or ingredient refers to a substance suitable for use in humans and / or animals without undue side effects (such as toxicity, irritation, and allergies), i.e., with a reasonable benefit / risk ratio.

[0100] In some embodiments, the pharmaceutical compositions described herein can include other therapeutically active substances.

[0101] In some embodiments, the pharmaceutical compositions of the invention are formulated for parenteral administration, such as intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intravitreal, and transdermal administration. In some embodiments, the pharmaceutical compositions of the invention are formulated for topical, oral, sublingual, enteral, nasal, buccal, or inhalation administration.

[0102] In some embodiments, pharmaceutical compositions comprising the polymorphs of the present invention are formulated in the form of pills, tablets, capsules, suppositories, syrups, lozenges, eye drops, or liquid formulations. Pill, tablet, and hard gelatin capsule formulations may contain excipients known to those skilled in the art.

[0103] In some embodiments, the disclosure provides a process for preparing a pharmaceutical composition comprising combining polymorphic Form A of PP-001 with one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0104] In some embodiments, the disclosure provides a kit comprising polymorphic Form A (or Form B) of PP-001 and a container. In some embodiments, the container is a vial, packet, sachet, pre-filled syringe, ampoule, or capsule.

[0105] Treatment method In some embodiments, the pharmaceutical composition, as used herein, the term "effective amount" refers to an amount of a therapeutic agent to treat, ameliorate or prevent a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The exact effective amount for a subject will depend on the subject's size and health, the nature and extent of the condition, and the therapeutic agent and / or combination of therapeutic agents selected. Thus, it is not useful to pre-specify the exact effective amount. However, for a particular condition, the effective amount can be determined using routine experimentation, which can be determined by the clinician.

[0106] The present disclosure provides a method of treating, preventing or ameliorating a disease or condition in a subject in need of treatment, comprising administering to the subject a pharma- ceutical effective amount of polymorphic Form A of PP-001.

[0107] In some embodiments, the disease, disorder or condition is one which benefits from inhibiting or reducing the activity of DHODH.

[0108] 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.

[0109] 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 rheumatism, acute immunological events and disorders such as sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, stroke, reperfusion injury, CNS disorders, allergic diseases, graft-versus-host and host-versus-graft disorders, Alzheimer's disease, fever, restenosis, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcomatosis, bone resorption diseases, etc. These immunological events include the desired regulation and suppression of the immune system; autoimmune diseases of all kinds, in particular rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, multiple sclerosis, insulin-dependent and non-insulin-dependent diabetes mellitus, and systemic lupus erythematosus, lupus nephritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease and other chronic inflammation, chronic diarrhea; skin diseases such as psoriasis, progressive retinal atrophy, and infectious diseases of all kinds, including opportunistic infections.

[0110] In some embodiments, the disease, disorder, or condition is malignant cell proliferation, such as all forms of hematological and solid cancers. Thus, the polymorphs according to the invention and compositions prepared therewith are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation, and cell death, or for inducing systemic changes in metabolism, such as changes in sugar, lipid, or protein metabolism. They can also be used to support cell production, including growth and production of blood cells (pro-hematopoietic effect) following cell depletion or destruction caused, for example, by toxic substances, radiation, immunotherapy, growth deficiencies, malnutrition, malabsorption, immune dysregulation, anemia, etc., or to provide therapeutic control of tissue production and degradation, as well as therapeutic correction of cell and tissue maintenance and blood cell homeostasis.

[0111] In some embodiments, the polymorphs of PP-001 used in the treatments described herein can be prophylactic or therapeutic. In the treatments described, the polymorphs and compositions of the invention can be administered in combination with other therapeutic agents.

[0112] In some embodiments, the dosage used for treatment can vary within wide limits and should be adapted to the particular symptoms in each individual case. In the above applications, the appropriate dosage will vary depending on the method of administration, the particular symptoms being treated, and the effect desired. EXAMPLES

[0113] Example 1 - Properties of PP-001 The investigated characteristics of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001) are shown in Table 8 below.

[0114] Table 8. Characteristics of PP-001 [Table 8]

[0115] Example 2 - Crystallization of PP-001 from amorphous PP-001 Preparation and solubility of amorphous PP-001 PP-001 was treated with increasing amounts of solvent until a maximum of 60 volumes (1800 μL) had been added to the HPLC vial.

[0116] The sample formed a solution and was positive pressure filtered using a PTFE syringe filter to remove any remaining solid particles. The solution was then flash frozen in a dry ice / acetone bath and freeze-dried overnight to remove the solvent. The solid isolated after freeze-drying was analyzed and characterized by XRPD. The XRPD profile for amorphous PP-001 is shown in Figure 2C.

[0117] The remaining suspension was either subjected to aging cycles from 25°C to 50°C (4 h per cycle) or held isothermal at room temperature overnight. Samples were separated under positive pressure and analyzed by XRPD.

[0118] The results of the solvent evaluation for lyophilization are shown in FIG.

[0119] As shown in Figure 5, PP-001 was shown to be soluble in THF:water (70:30) and 1,4-dioxane. All other solvents and solvent mixtures tested 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 overnight at room temperature. The suspended solids were then isolated and the wet cakes were analyzed by XRPD. In the case of ACN / water (1:1), DCM and t-BuOH / water, Form A was obtained. In the case of pure t-BuOH, a solution was obtained after the aging cycle, which was subjected to slow evaporation, thereby obtaining Form B.

[0120] For crystallization of amorphous PP-001, P-001 (3.0 g) was treated with 20 volumes (60 mL) of THF:water (70:30) and stirred at room temperature until a clear solution was obtained. The solution was positive pressure filtered using a PTFE syringe filter to remove residual solid particles. The solution was then aliquoted into individual HPLC vials (600 μL / vial). 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 representative of the batch was then analyzed by XRPD to confirm that the material was amorphous after lyophilization. Samples were stored at -20°C when not in use. Samples were used for subsequent polymorphism studies as needed.

[0121] Crystallization method Using the following isothermal aging technique and aging cycles from room temperature to 50°C, crystalline material was produced and analyzed by XRPD. In addition, antisolvent addition screening was also performed.

[0122] Preparation of amorphous materials PP-001 (3.0 g) was treated with 20 volumes (60 mL) of THF:water (70:30) and stirred at room temperature until a clear solution was obtained. The solution was positive pressure filtered using a PTFE syringe filter to remove any remaining solid particles. The solution was then aliquoted into individual HPLC vials (600 μL / vial). 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 representative of the batch was then analyzed by XRPD to confirm that the material was amorphous after lyophilization. Samples were stored at -20°C when not in use. Samples were used for subsequent polymorphism studies as needed.

[0123] Polymorph Screening Procedure 2 (5°C Isothermal Aging) Amorphous PP-001 (approximately 30 mg, batch #2) was treated with solvent in small portions up to 15 volumes (450 μL) at 5° C. and 300 rpm while maintaining a suspension. Observations were then recorded. Samples were aged for 24 hours at 5° C. Further observations were made and samples were treated as follows:

[0124] For suspensions, a small sample (approximately 30 μL) was taken and subjected to XRPD analysis while still wet. For new patterns, the sample was reanalyzed after drying at room temperature.

[0125] For samples that formed solutions, they were treated with up to 10 times the volume (1500 μL) of antisolvent at room temperature.

[0126] Solids showing new patterns were then extracted using SPE cartridges and frits under positive pressure filtration. Samples were allowed to dry under ambient conditions for at least overnight before further characterization.

[0127] The aging results for the amorphous material at 5° C. are shown in FIGS. 6A and 6B.

[0128] When aged at 5°C, most solvents remained in suspension. DMSO froze at 5°C as expected. This sample was heated back to 25°C and excess ACN was added as an anti-solvent in an attempt to encourage precipitation. However, the sample remained in solution and was not investigated further. 1,4-Dioxane partially froze but maintained a fluid slurry. In the case of THF:water (50%), a gummy solid formed upon addition of the solvent. All samples were analyzed in the wet state in an attempt to capture any possible metastable solvate forms. However, upon analysis, the majority of the resulting material was either Form A or Form B. (See Figures 6A and 6B).

[0129] Form A was obtained from ethyl acetate, MIBK, IPA, MEK, 1-propanol, acetone, EtOH, ACN, MeOH, water, MeOH:water (3%) and (5%), EtOH:water (5%), acetone:water (5%) and (10%), and THF:water (50%). Form B was obtained from diethyl 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 pattern, called Pattern 3, was obtained from heptane (Figure 7).

[0130] Polymorph Screening Procedure 3 (Temperature Cycling) Amorphous PP-001 (approximately 30 mg, batch #2) was treated with solvent in small aliquots up to 20 volumes (600 μL) at 25° C. and 300 rpm while maintaining a suspension. Observations were then recorded. The sample was then subjected to 24 hour aging cycles between room temperature and 50° C. (4 hours per cycle). Further observations were made and the sample was treated as follows:

[0131] For suspensions, a small sample (approximately 30 μL) was taken and subjected to XRPD analysis while still wet. For new patterns, the sample was allowed to dry at room temperature and then reanalyzed.

[0132] For samples that formed solutions, they were treated with up to 1 volume equivalent (150 μL) of antisolvent at room temperature.

[0133] Solids showing new patterns were then extracted using SPE cartridges and frits under positive pressure filtration. Samples were allowed to dry under ambient conditions at least overnight for further characterization.

[0134] The results of the maturation cycle of the amorphous material are shown in Figures 8A and 8B.

[0135] Most solvents maintained a suspension, as did the aging at 5°C. Diethyl ether was not used because the experimental temperature exceeded the boiling point of the solvent. After aging, solutions were obtained from acetone:water (5%), but additional water (150 μL) was added to obtain a suspension. Volatile solvents (acetone and ethyl acetate) gave clear solutions with solid material accumulating above the solvent line. The material was periodically resuspended using a spatula until sieving was complete. Form B was obtained from n-heptane, TBME, toluene chloroform. Form B was also obtained from acetone:water (5%) after addition of anti-solvent.

[0136] All remaining suspensions gave Form A. Interestingly, after addition of anti-solvent to 5% acetone:water (final ratio of approx. 1:1 acetone:water) Form B was obtained, whereas 10% acetone:water gave Form A. This was also in contrast to previous screening where both 5% and 10% acetone:water gave Form A. This result was likely driven by kinetics, where rapid nucleation (i.e., rapid addition of anti-solvent) favors Form B. This was further explored in subsequent screening. No other patterns emerged from this screening. The current process solvent (IPA:water) was shown to give Form A after aging.

[0137] Polymorph screening procedure 4 (isothermal maturation at 50°C) Amorphous PP-001 (approximately 30 mg, batch #2) was treated with solvent in small portions up to 15 volumes (450 μL) at 50° C. and 300 rpm while maintaining a suspension. Observations were then recorded. The sample was aged at 50° C. for 24 hours. Further observations were made and the sample was treated as follows:

[0138] For suspensions, an aliquot (approximately 30 μL) was taken and subjected to XRPD analysis while still wet. For new patterns, the sample was reanalyzed after drying at RT.

[0139] For samples that formed solutions, they were treated with up to three times the volume (450 μL) of antisolvent at 50°C.

[0140] Solids showing new patterns were then extracted using SPE cartridges and frits under positive pressure filtration. Samples were allowed to dry under ambient conditions for at least overnight before further characterization.

[0141] The results of aging the amorphous material at 50° C. are shown in FIGS. 9A and 9B.

[0142] As with the aging cycle screen, diethyl ether was not performed because the experimental temperature exceeded the boiling point of the solvent. A suspension was maintained in most of the solvents tested. From the suspension, form B was obtained from n-heptane, TBME, toluene, and isopropyl acetate. However, upon extraction of the isopropyl acetate, this transformed to form A. All other suspensions gave form A. A solution was obtained only from acetone:water (5%). Approximately 150 μL of water was added at 50° C. to obtain a suspension. A sample was immediately taken and analyzed by XRPD, which matched the XRPD pattern of form B. The sample was then isothermally aged with the other samples. After aging, the sample was analyzed again and showed a transformation to form A. This result was consistent with the previous screen that nucleation of form B could transform to form A with aging.

[0143] Acetone:water (10%) was initially opaque but after aging for several days gave a solution. This sample was removed from the heat source and treated with ACN as an anti-solvent and allowed to precipitate at room temperature to isolate Form A. The current process solvent (IPA:water 13:5) was shown to give Form A after aging.

[0144] Polymorph Screening Procedure 5 (Antisolvent Addition) PP-001 (approximately 30 mg, batch #1) was treated with small aliquots of solvent at room temperature under stirring until a solution was obtained or a maximum of 80 volumes (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 aid in dissolution. Antisolvent was added (up to 5 volume equivalents) to all solutions to aid in precipitation at temperature.

[0145] For the suspension, a small sample was taken for XRPD analysis for precipitation of material. The suspension was then left to age at temperature overnight. A second small sample was then taken for XRPD analysis.

[0146] The solution was cooled from 25°C to 5°C at 0.1°C / min and held at 5°C overnight. The remaining solution was evaporated at room temperature.

[0147] The suspension was then extracted by positive pressure filtration using an SPE cartridge and frit. A sample of the wet cake was taken for analysis. The sample was then allowed to dry at room temperature at least overnight before being reanalyzed by XRPD.

[0148] The results of antisolvent addition polymorphism screening are shown in FIG.

[0149] Water, heptane, and toluene were targeted as antisolvents, and the selected solvents were used to dissolve PP-001. In some cases, dissolution was only achieved at elevated temperatures. Once dissolution was achieved, antisolvent was added up to 5 volume equivalents. Suspensions were achieved in all water samples and most heptane samples, suggesting that these two were the most effective antisolvents. Small samples were taken from all suspensions within 1 hour after antisolvent addition, followed by a second small sample after aging for 24 hours. It was difficult to observe diffraction from the small sample (due to the dilution effect of the large amount of solvent used).

[0150] For samples where diffraction was sufficient, the presence of Form B was observed in all samples. After aging, a transition to Form A was observed in all samples except THF / heptane. This again supports the idea that the formation of Form B may be kinetically driven. Therefore, careful control of supersaturation during the crystallization process is recommended. Upon isolation of the material, Form B was obtained from IPA / water, ethyl acetate / heptane, and THF / heptane. The remaining suspensions gave Form A. Samples treated with toluene as antisolvent did not precipitate. IPA / heptane also did not precipitate. These samples were cooled to 5°C overnight in an attempt to induce nucleation, but remained in solution. Therefore, the samples were instead subjected to slow evaporation of the solvent. Form B was obtained in all cases.

[0151] Summary of Polymorph Screening In most cases, polymorphism screening using amorphous PP-001 resulted in the isolation of crystalline material. In particular, the formation of Form A and Pattern B was most common. Additional unique XRPD patterns were obtained from heptane at 5 °C. The conditions for all polymorphism screening experiments (excluding antisolvent addition) used to generate each pattern are summarized in Table 9.

[0152] Table 9. Summary of materials obtained from polymorph screening using amorphous input material [Table 9]

[0153] TIFF2025508023000019.tif39170

[0154] As can be seen from Table 9, overall Form A was the most prevalent pattern, with Form B prevalent at lower temperatures. Solvents: heptane, TBME, toluene, and chloroform also tend to favor Form B at higher temperatures. At 5°C, heptane gives novel pattern 3. Of note, the current process solvent, IPA / water, also tends to favor Form B at lower temperatures, but Form A at higher temperatures. Additionally, some samples were initially characterized as Form B, but then transitioned to Form A upon further aging. This was noted to be the basis for anti-solvent crystallization in particular.

[0155] Upon antisolvent addition, a transition from form B to form A was observed in some solvent / antisolvent mixtures, supporting the idea that the formation of form B may be kinetically promoted.

[0156] Example 3 - X-ray powder diffraction The following method was used for XRPD.

[0157] X-ray powder diffraction The identity of Form A and Form B in a given sample was determined by analysis of the sample using X-ray powder diffraction (XRPD). The XRPD diffraction profiles of PP-001 Forms A and B are shown in Figures 2A and 2B, respectively, and are described in further detail below. The following XRPD protocol was utilized in this study:

[0158] 1. Bruker AXS C2 GADDS XRPD diffractograms were collected on a Bruker AXSC2GADDS diffractometer using CuKα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a Vantec-500 two-dimensional area detector. The X-ray optics consisted of a single Göbel multilayer mirror coupled with a 0.3 mm pinhole collimator.

[0159] The beam divergence, i.e., the effective size of the X-ray beam on the sample, was about 4 mm. A θ-θ continuous scan mode was employed with a sample-detector distance of 20 cm, resulting in an effective 2θ range of 1.5°–32.5°. Typically, the sample was exposed to the X-ray beam for 120 s. The software used for data collection and analysis were GADDS and Diffrac Plus EVA for Win7 / XP, respectively.

[0160] Non-ambient conditions. For variable temperature (VT-XRPD) experiments, samples were mounted on an Anton Paar DHS 900 hot stage at ambient conditions. The samples were then heated at 20°C / min to the appropriate temperature and then held isothermal for 1 min before data collection. Samples were prepared and analyzed on silicon wafers mounted on the hot stage using thermally conductive paste.

[0161] 2. Bruker AXS D8 Advance XRPD diffractograms were collected on a Bruker D8 diffractometer using CuKα radiation (40 kV, 40 mA) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passes through an 8.0 mm receiving slit with a 2.5° Soller slit followed by a Lynxeye detector. The software used for data collection and analysis were Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0162] Samples were tested under ambient conditions as flat specimens using the as-received powder. Samples were prepared on polished zero background (510) silicon wafers by lightly pressing onto a flat surface or packing into a cut cavity. The sample was rotated within its own plane.

[0163] Details of the standard Pharmorphix data collection method are as follows.

[0164] Range: 2~42°2θ Step size: 0.05° 2θ Acquisition time: 0.5 seconds / step (total acquisition time: 6 minutes 40 seconds)

[0165] 3. PANalytic Empyrean XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using CuKα radiation (45 kV, 40 mA) in transmission geometry. The incident beam used a 0.04 rad Soller slit with a 0.5° slit, a 4 mm mask, and a focusing mirror. A PIXcel3D detector placed on the diffracted beam was fitted with a receiving slit and a 0.04 rad Soller slit. The software used for data collection was X′Pert Data Collector using the X′Pert Operator Interface. Data were analyzed and displayed using Diffrac Plus EVA or HighScore Plus.

[0166] Samples were prepared and analyzed in metal or Millipore 96-well plates in transmission mode. X-ray transparent film was used between metal sheets on metal well plates, and powders (approximately 1-2 mg) were used as received. Millipore plates were used to separate and analyze solids from suspensions by adding a small amount of suspension directly to the plate and then filtering under light vacuum.

[0167] The gonioscan axis was used in the scan mode for metal plates, and 28 scans were used for Millipore plates.

[0168] Details of standard screening data collection methods are as follows:

[0169] Angle range: 2°~32° 2θ Step size: 0.0130° 2θ Acquisition time: 12.75 seconds / step (total acquisition time: 2.07 minutes)

[0170] Non-ambient conditions. For variable temperature (VT-XRPD) experiments, samples were prepared and analyzed in an Anton Paar chrome-plated sample holder with a silicon wafer insert. A heating / cooling rate of 10°C / min was used with a 2 minute isothermal hold before the measurement began. Measurement parameters followed the standard screening data collection method (detailed above). Measurements were taken at 25, 170, 180, 190, 200°C for heating and 170, 140, 25°C for cooling. This cycle was repeated once.

[0171] Example 4. Solubility and XRPD of PP-001 PP-001 (approximately 20 mg, batch #1) was treated with increasing amounts of solvent until a clear solution or up to 80 volumes (1600 μL) of solvent had been added. After each solvent addition, the sample was left at 25° C., 300 rpm for approximately 3 minutes before observations were recorded. When possible, samples were heated to 50° C. for further observations. Solutions at 25° C. or 50° C. were cooled to 5° C. at 0.1° C. / min, 300 rpm, and held overnight. Suspensions at 50° C. were subjected to room temperature / 50° C. age cycles (4 hours per cycle). Solvents not suitable for heating to 50° C. or cooling to 5° C. were subjected to evaporation, anti-solvent addition at room temperature, or room temperature ageing, depending on the solvent.

[0172] After 24 hours, the solution was removed from the 5°C solution and evaporated at room temperature. The evaporated samples were dried and analyzed. The remaining suspension was left for 3 days and then extracted by positive pressure filtration using an SPE cartridge and frit.

[0173] A sample from the wet cake was analyzed by XRPD and the remaining sample was allowed to dry at room temperature overnight (DS-2045-08-XX-W). After drying overnight, the new pattern was analyzed by XRPD to determine if there had been a change in shape.

[0174] The results of the solubility and solvent selectivity evaluation are shown in Figures 3A and 3B.

[0175] As can be seen from Figures 3A and 3B, good solubility (<80 vol) was observed in 15 of the solvents tested at 25°C. In general, higher solubility was observed in aprotic polar solvents such as THF, DMSO and acetone. Samples that were fluid suspensions or showed partial dissolution were then heated to 50°C (for solvents with sufficiently high boiling points). Clear solutions were obtained at 50°C in IPA, 1-propanol, ACN, MeOH:water (3%), MeOH:water (5%), EtOH:water (5%), IPA:water (5%) and IPA:water (25%). This result suggests that PP-001 shows a significant solubility curve with respect to temperature in a number of solvent systems. The remaining solvents, heptane, toluene, chloroform and water, remained suspensions. Thus, these solvents may be suitable poor solvents.

[0176] Polymorph ScreeningAfter initial solubility evaluation, the samples were used as input for polymorph screening. Various experimental conditions were run on the samples as shown in Figures 3A and 3B. Samples kept as suspensions at 50°C were cycled for overnight maturation between 25°C and 50°C (4 hours per cycle). Samples that formed solutions at 25°C or 50°C were cooled to 5°C at 0.1°C / min and held at 5°C overnight. 1,4-dioxane (freezing point 11°C) was distilled off at room temperature and DMSO (freezing point 19°C) was subjected to anti-solvent (water) addition, respectively. Diethyl ether (boiling point 35°C) was aged at room temperature.

[0177] After overnight aging, the samples that remained in solution at 5 °C were allowed to slowly evaporate to dryness at room temperature. The remaining suspension was allowed to stand under the desired conditions for 3 days before the solid was extracted. The resulting solid was isolated and initially analyzed by XRPD. The results of this analysis are summarized in Figures 4A and 4B.

[0178] XRPD patterns of samples isolated from most solvents were consistent with Form A. For samples that did form a solution, slow evaporation produced new patterns consistent with the supplied Form B standard (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 from evaporation of acetone / water. Upon addition of anti-solvent to DMSO, only amorphous material was isolated. Not enough material was recovered for analysis from acetone and MeOH / water (3%). The remaining samples, containing 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 pentyl acetate), resulted in Form A. No other new patterns were obtained during this screen. Further characterization of Form B is in Example 5.

[0179] Example 4 - Characterization of Form A PP-001 Form A was further characterized as follows, and its properties are summarized in Table 10 below.

[0180] X-Ray Powder Diffraction. XRPD testing was performed as described above in Example 1. The XRPD pattern of PP-001 Form A is shown in Figure 2A, and the 2θ values ​​(with relative intensities) for Form A are shown in Table 10 below.

[0181] Table 10. PP-001 form AXRPD data [Table 10]

[0182] 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 heated from 25°C to 250°C at 10°C / min in an aluminum pan with a pinhole. Dry nitrogen was purged over the sample at 50 mL / min.

[0183] Temperature modulated DSC was performed using a base heating rate of 2°C / min and temperature modulation parameters of ±0.636°C (amplitude) every 60 s (period).

[0184] The instrument control software was Advantage for Q Series and Thermal Advantage and data were analyzed using Universal Analysis or TRIOS.

[0185] DSC showed a small endotherm onset at 177.6° C. (20 J / g) with some tailing, and a second sharp endotherm onset at 227.9° C. (108 J / g) likely corresponding 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 decomposition (above 230° C.), which is consistent with the material being nonsolvated, which is consistent with the proton NMR analysis.

[0186] Polarized Light Microscopy (PLM) and Scanning Electron Microscopy (SEM). For PLM analysis, samples were analyzed with a Leica LM / DM polarizing microscope equipped with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without immersion oil and covered with a glass slip. Samples were observed at appropriate magnification and partially polarized light in combination with a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0187] For SEM analysis, data were collected on a Phenom Pro scanning electron microscope. A small sample was attached to an aluminum stub using conductive double-sided adhesive tape. A thin layer of gold was applied using a sputter coater (20 mA, 120 s).

[0188] PLM and SEM images (Figures 11A and 11B, respectively) showed that the sample consisted of a mixture of larger plate-like crystals of similar breath and width (up to about 200 μm) and smaller flake-like crystals. The surfaces of the larger crystals were peppered with smaller flake-like crystals. Ion chromatography was used to confirm the absence of anions or cations.

[0189] Gravimetric Vapor Sorption (GVS) Adsorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software. Sample temperature was maintained at 25 °C by instrument controls. Humidity was controlled by a mixed flow of dry and humid nitrogen, with a total flow rate of 200 mL / min.

[0190] Relative humidity was measured with a calibrated Rotronic probe (dynamic range 1.0–100% RH) placed close to the sample. The weight change of the sample (mass relaxation) as a function of %RH was constantly monitored with a microbalance (accuracy ±0.005 mg).

[0191] Typically, 5-30 mg of sample was placed into a tared mesh stainless steel basket under ambient conditions. Samples were loaded and removed at 40% RH and 25°C (representative room conditions). Moisture sorption isotherms were run as outlined below (2 scans per complete cycle). Standard isotherms were run at 25°C over the 0-90% RH range, with 10% RH intervals. Typically, duplicate cycles (4 scans) were run. Data analysis was performed in Microsoft Excel using the DVS Analysis Suite. Data is presented in Table 11 below.

[0192] Table 11. SMSDVS-specific experimental methods [Table 11]

[0193] Samples were collected after completion of the isotherm and reanalyzed by XRPD.

[0194] GVS analysis showed a gradual mass increase of 0.12 wt%, equivalent to 0.03 moles of water, from 0 to 90% RH, without any noticeable hysteresis (Figure 12). The kinetic plot shows some oscillations during the run, but this is likely due to very small mass changes with humidity cycling. The sample was considered non-hygroscopic and showed no change in XRPD after GVS.

[0195] Determining Chemical Purity by HPLC Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full details of the method are provided in Table 12 below.

[0196] Table 12. HPLC methods for chemical purity determination [Table 12]

[0197] HPLC showed the material to be 99.6% pure (Figure 12A). Accelerated storage at 40°C / 75%RH for 8 days revealed the sample to be unchanged by XRPD and HPLC (Figure 12B). Accelerated storage at 25°C / 97%RH for 8 days revealed the sample to be unchanged by HPLC (Figure 12C), however a small peak at 8.1 2θ angle was gained and a small peak loss at 17.6 2θ angle was observed (Figure 13A). The sample was left for an additional 22 days (30 days storage total) and reanalyzed by XRPD, appearing as Form A and lacking the additional peaks previously observed (Figure 13B). Thus, it is believed that contamination of the sample on the instrument from the previous 8 days, rather than a change in form or degradation, is the likely cause of the additional peaks.

[0198] thermodynamic water solubility Aqueous solubility was determined by suspending sufficient compound in an appropriate vehicle to give a maximum final concentration of the parent free form of the compound of ≥ 10 mg / mL. The suspension was equilibrated for 24 hours at 25°C in a Heidolph plate shaker set at 750 rpm. The pH of the saturated solution was then measured and the suspension was filtered through a glass fiber C filter (particle retention 1.2 μm) and diluted appropriately. Quantitation was performed by HPLC against a standard solution of approximately 0.15 mg / mL in DMSO. Different volumes of standard, diluted and undiluted sample solutions were injected. Solubility was calculated using peak areas determined by integration of the peaks observed at the same retention time as the main peak in the standard injection. The data are shown in Table 13 below.

[0199] Table 13. HPLC methods for solubility measurements [Table 13]

[0200] The thermodynamic solubility was measured to be 0.76 mg / mL in fasting stimulated intestinal fluid (FaSSIF). The XRPD of the residual solid was largely unchanged, although some additional extra peaks corresponding to NaCl can be seen.

[0201] Table 14. Characterization data for PP-001 Form A [Table 14]

[0202] Example 5 - Thermal testing of Form A Form A is characterized as a stable anhydrous form. However, an additional thermal event at 177.6° C. required further analysis to determine if a morphological change occurred. Form A was subjected to DSC analysis at different ramp rates (5, 10, 20, 50° C. / min), DSC cycles (25 to 205° C., 205 to 25° C., 25 to 250° C. at 10° C. / min), and MDSC. Additionally, samples were subjected to VTXRPD up to 200° C. The results are summarized in Table 15.

[0203] Table 15: Thermal analysis results of PP-001 Form A [Table 15]

[0204] The purpose of the experiments varying the heating rate was to isolate the endothermic event at approximately 180 °C so that the shape change could be demonstrated by variable temperature (VT)-XRPD. From the results in Table 15, little change was observed before the onset of this endotherm when varying the ramp rate from 5 to 50 °C / min, except for some artifacts identified in the 20 and 50 °C / min runs (Figures 14A-14D). In all cases, the event remained present and the same tailing effect was seen. The most interesting finding was the resolution of an additional sharp endothermic / exothermic event before the melt, which was only seen with the faster heating at 20 and 50 °C / min (onset at 222.5 and 224.7 °C, respectively), suggesting that there may be an additional shape change before the main melt. However, the closeness of the melting points of the samples (approximately 227-228 °C) makes it difficult to investigate this further without specialized equipment.

[0205] For the first endotherm at approximately 177°C, a DSC cycle was performed to further investigate this event. In this case, the first heating cycle showed a small endotherm beginning at 178.2°C (19 J / g), which was consistent with the previous DSC run. Upon cooling (205 to 25°C), a small exotherm was observed with an onset at 159.4°C (10 J / g). Upon the second heating cycle (25 to 250°C), a small endotherm was again observed with an onset at 177.1°C (12 J / g), followed by a sharp endotherm at 228.2°C (103 J / g) consistent with melting. This analysis is believed to indicate that the endothermic event at 177°C is a reversible transition.

[0206] In the melt-quench-cool measurements, the sample was rapidly cooled after melting and upon reheating a Tg of 36.4 °C was measured, followed by a double exotherm with an onset at 86.9 °C (29 J / g) and a second endotherm observed at 196.7 °C (15 J / g) (Figures 15A-15B).

[0207] Example 6 - Characterization of PP-001 Form B Production of PP-001 Form B. Amorphous PP-001 (1 g) was treated with 10 volumes (10 mL) of toluene. The suspension was aged overnight at 5° C. and 300 rpm. A small sample of approximately 20 μL was taken and subjected to XRPD to monitor the turnover of the solid form. The solid was extracted using Buchner filtration. The residue was extracted using two 1 mL washes of cold (5° C.) toluene. The combined solid was dried under vacuum for >1 h. Yield=697.41 mg, 69.7%.

[0208] Characterization of Form B PP-001 Form B was characterized by XRPD, DSC, PLM, SEM, HPLC, and GVS analyses using the same procedures as described above in Example 3.

[0209] The DSC trace shows a single sharp exotherm at 225.8 °C (92 J / g) (Figure 16). PLM and SEM images show that the particles are a series of spherical agglomerates (approximately 50-100 μm in diameter) that consist of small (<10 μm) plate-like crystals (Figures 17A-17B). HPLC analysis showed that the sample maintained a high purity of 99.5% (Figure 18A). Accelerated storage at 40 °C / 75% RH and 25 °C / 97% RH for 7 days showed no observable changes by XRPD in either case. After storage, the HPLC purity was found to be 99.6% and 99.4%, respectively (Figures 18B-18C). The isotherm plot from the GVS analysis shows a gradual mass uptake of 0.10 wt%, equivalent to 0.03 moles of water, from 0% to 90% RH upon adsorption (Figure 19). There is a small hysteresis between adsorption and desorption. The sample was unchanged by XRPD after GVS analysis. The GVS results indicate that Form B is non-hygroscopic and stable to variable humidity. The results of these tests are summarized in Table 16 below.

[0210] Table 16: Characterization of PP-001 Form B [Table 16]

[0211] XRPD testing on Form B was performed according to the method described above in Example 1. The XRPD profile of PP-001 Form B is shown in Figure 2B, and the 2θ values ​​for Form B are shown in Table 17 below.

[0212] Table 17: PP-001 Form B XRPD Data [Table 17]

[0213] Additional thermal testing was performed using a scale-up of Form B, varying the DSC ramp rate from 5 to 50° C. / min, as was done with Form A in Example 4. The results are shown in Table 18 below and in Figures 20A-20C.

[0214] Thermal characterization of PP-001 form B [Table 18]

[0215] Example 7 - Thermodynamic Stability Analysis The objective of this study was to investigate the stability ordering of scaled-up Forms A and B via competitive slurrying of the materials in a wide range of solvents at 5° C., 25° C., and 50° C. Additionally, the thermodynamic solubility and IDR of the two forms were compared in selected media.

[0216] The proposed solvent was aliquoted (1 mL) into HPLC vials and equilibrated at 5°C, 25°C, and 50°C, respectively, at 300 rpm. Increasing amounts of PP-001 were added to each vial until a persistent suspension was observed at the desired temperature. The saturated solutions were allowed to equilibrate overnight.

[0217] Approximately 300 mg of Form B, prepared as described above in Example 5, and Form A were added to a 20 mL scintillation vial. The vials were mixed by vortexing for at least 2 hours to ensure the mixture was homogenous. Approximately 30 mg of the mixture of Form A and Form B was added to a series of HPLC vials. The vials were placed at 5, 25, and 50 °C at 300 rpm. The previously prepared suspension was filtered directly into each vial with a PTFE syringe, and the prepared mixture of forms was suspended in a saturated solution of the target solvent. Polymorph turnover was investigated by taking small samples of the suspension, 30-50 μL, and analyzing them by XRPD.

[0218] The results of the competitive slurrying of Form A and Form B are shown in FIGS. 21-23 and summarized in FIG.

[0219] As can be seen from FIG. 24, all solvents and temperatures tested yielded Form A. Thus, the results would suggest that Form A is the preferred form under the solvent systems and temperature ranges investigated. Hot IPA and IPA / water mixtures were found to give clear solutions with solids present on the side of the vial above the solvent line, indicating some solvent distillation. To ensure there were no false positive results, additional solid form mixtures (Form A + Form B) were added to these samples, which were then aged for an additional 24 hours. In all cases, a persistent suspension was observed 24 hours after the addition of the additional solid mixture. A small sample was taken for analysis (DS-2045-48-XX-B, total time 5 days). XRPD confirmed the presence of only Form A.

[0220] In addition to competitive slurrying, thermodynamic solubility measurements in FaSSIF medium and IDR in pH 7.4 phosphate buffer were performed for both Form A and Form B. The results are shown in Table 19. A complete report of both measurements can be found in Appendix 2 - Analytical Services Report.

[0221] Table 19. Thermodynamic stability and intrinsic dissolution rate (IDR) of Form A and Form B [Table 19]

[0222] The results in Table 19 show that both forms have very low aqueous solubility (<1 mg / mL) and slow dissolution rates (<0.1 g / min cm 2 ) Thermodynamic solubility and IDR measurements showed that Form A was less soluble and had a slower dissolution rate compared to Form B. This result is consistent with the competitive slurry measurements and suggests that Form A is the more thermodynamically stable form.

[0223] A morphology diagram based on the experiments described herein is shown in Figure 25. Full characterization of Form B and Pattern 3 has been completed and both have been successfully scaled up. Analysis shows that Form B is a non-solvated anhydrous form and is suitable for thermodynamic stability studies with Form A. Pattern 3 is a non-stoichiometric heptane solvate that was found to be unstable and transition to Form B. Figure 16 shows that most solvents and conditions result in crystallization of either Form B or Form A. The only exception is aging of the amorphous material in heptane at 5°C, which results in Pattern 3. Characterization of Pattern 3 showed that the solvate was unstable and transitioned to Form B under high humidity or upon heating / drying.

[0224] Although both Forms A and B are stable anhydrous forms of PP-001, competitive slurrying of Forms A and B revealed that Form A was the preferred form under all conditions and solvents examined. Thus, Form A is likely the most thermodynamically favored and the recommended form for further scale-up. The results of competitive slurrying are consistent with the results of thermodynamic solubility and IDR measurements, where Form A exhibits lower solubility compared to Form B, suggesting that Form A is the more stable form. Finally, an additional high-temperature form (Pattern 4) was observed, obtained by heating Form A above 175 °C. The transition from Form A to Pattern 4 is reversible, and Pattern 4 is only observed at higher temperatures. Based on the thermal data collected for Forms A and B, it is theorized that the transition from Form A to Pattern 4 is followed by a transition from Pattern 4 to Form Bon upon heating the sample until it melts. However, this transition could not be measured directly because the thermal event was close to the melting point. Due to the high temperatures required to reach pattern 4, it is unlikely that pattern 4 is a morphology of concern with regard to developing a crystallization process.

[0225] Example 7 - Crystallization progress of PP-001 Form A PP-001 Form A was selected for crystallization development as it was found to be the most thermodynamically stable form.

[0226] The strategy for crystallization development was to select Class III crystallization solvents from the previously performed solubility assessment (Example 1). Solubility curves of Form A in these solvent / anti-solvent mixtures were then obtained and the data was regression analyzed using DynoChem to generate a solubility model for Form A as a function of both solvent composition and temperature.

[0227] Then, based on the generated solubility model, small-scale (1 g) crystallizations were performed to evaluate the validity of the model and the crystallization kinetics of Form A in the solvent mixture. Finally, the optimized process performed at 1 g scale was scaled up to 5 g scale and monitored by PAT (Process Analytical Technology) to evaluate the process robustness at multi-gram scale with overhead stirring.

[0228] Method 1 1 g of PP-001 Form A was dispensed into a 20 mL scintillation vial. A stir bar was added and 11.2 volumes of IPA (11.2 mL) and 1.2 volumes of HO (1.2 mL) were charged. The resulting suspension was heated to 65° C. with magnetic stirring at 500 rpm using a Polar Bear (heating / cooling block from Cambridge Reactor Designs) to obtain a clear solution.

[0229] The solution was cooled to 58°C (Ssat ratio 1.2) and 5 wt% PP-001 form seeds (5 wt%, 50 mg) were added. The seeds were observed to remain intact and the suspension was stirred for 1 h. The suspension was then cooled to 5°C at a rate of 0.1°C / min and held isothermally overnight.

[0230] The suspension was then isolated by filtration, dried under suction for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0231] Method 21 g of PP-001 Form A was dispensed into a 20 mL scintillation vial. A stir bar was added and 11.2 volumes of IPA (11.2 mL) and 1.2 volumes of H2O (1.2 mL) were charged. The resulting suspension was heated to 65°C with magnetic stirring at 500 rpm using a Polar Bear (Cambridge Reactor Designs heating / cooling block) to obtain a clear solution.

[0232] 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 seeds were observed to remain intact and the suspension was stirred for 1 h. Then, 7 volumes of HO (7 mL) were dosed via syringe pump over 2 h. The suspension was then cooled to 5° C. at a rate of 0.1° C. / min and held isothermal overnight.

[0233] The suspension was then isolated by filtration, dried under suction for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0234] Method 3. 1 g of PP-001 Form A was dispensed into a 20 mL scintillation vial. A stir bar was added and 6.4 volumes of acetone (6.4 mL) and 0.6 volumes of HO (0.6 mL) were charged. The resulting suspension was heated to 40° C. with magnetic stirring at 500 rpm using a Polar Bear (Cambridge Reactor Designs heating / cooling block) to obtain a clear solution.

[0235] 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 seeds were observed to remain intact and the suspension was stirred for 1 h. Then, 3 volumes of HO (3 mL) were dosed via syringe pump over 2 h. The suspension was then cooled to 5° C. at a rate of 0.1° C. / min and held isothermal overnight.

[0236] The suspension was then isolated by filtration, dried under suction for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0237] Method 4. 1 g of PP-001 Form A was dispensed into a 20 mL scintillation vial. A stir bar was added and 4.2 volumes of acetone (4.2 mL) and 0.33 volumes of HO (0.33 mL) were charged. The resulting suspension was heated to 50° C. with magnetic stirring at 500 rpm using a Polar Bear (Cambridge Reactor Designs heating / cooling block) to obtain a clear solution.

[0238] 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 seeds were observed to remain intact and the suspension was stirred for 1 h. Then, 3 volumes of HO (3 mL) were dosed via syringe pump over 2 h. The suspension was then cooled to 5° C. at a rate of 0.1° C. / min and held isothermal overnight.

[0239] The suspension was then isolated by filtration, dried under suction for 30 minutes, and the solid was transferred to a vacuum oven and dried at room temperature overnight.

[0240] Results. Characterization results of the solids isolated from the 1 g scale experiments are shown in Table 20. In all four protocols performed, dissolution of PP-001 Form A was observed at the dissolution temperature identified using the DynoChem model and the seed was observed to be maintained at the seeding temperature. These observations demonstrate the accuracy of the solubility model generated. In all four experiments performed, phase pure Form A was obtained with high purity (99.8% by HPLC) and low residual solvent content ( 1 The resulting product was obtained using process 1 (IPA / water) and process 2 (demonstrated by H-NMR). The material was obtained in various yields, with process 2 (IPA / water) giving the highest recovery (88.7%). Based on the solubility models generated, yields of over 90% were theoretically possible for each process. The difference between the obtained and predicted yields can be explained by the crystal growth rate of Form A in the solvent mixtures; in all cases, the solutions were still supersaturated at the time of solid isolation, indicating a slow growth rate.

[0241] Table 20.1g scale-up experiment results [Table 20]

[0242] In the XRPD patterns of each of the four solids isolated from the 1g experiment, additional peaks were observed in the 2q range 11-14° compared to the as-supplied form A (Figures 26 and 27). These peaks were consistent between samples and were smaller in magnitude. Examination of the PLM of the as-supplied form A sample showed it to be composed of large plates of about 100 μm in diameter (Figure 28). However, the particles obtained from the scale-up were composed of much smaller particles of about 10 μm in diameter. When a sample is prepared for XRPD measurement, it is pressed flat onto a sample holder. The geometry of a large plate (such as that in the supplied material) means that when pressed flat, it will typically be oriented so that its largest face is parallel to the sample holder. This means that some faces of the crystal will be presented at a lower frequency to the incident X-rays than other faces, resulting in fewer peaks being evident 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 and resulting in an XRPD pattern with more peaks. To assess whether the additional peaks observed in the XRPD pattern of the 1g scale-up sample were the result of preferred orientations, a sample of the provided material was re-measured using a larger sample holder. By using a larger sample holder, the crystals can be positioned in more orientations, and therefore more reflections can be measured. The XRPD pattern of the provided material measured using the larger holder is shown in Figure 29. The XRPD pattern displays the additional peaks seen from the 1g scale-up sample, indicating that these reflections are present in Form A crystals.

Claims

1. A polymorph of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid represented by formula I below. 【Chemistry 1】 [where: 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, 19.6±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. It is.]

2. 2. The polymorph of claim 1, wherein the polymorph is Form A.

3. 3. The polymorph of claim 2, wherein the polymorph comprises 4 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. 3. The polymorph of claim 2, wherein Form A comprises the XRPD pattern shown in Figure 2A; 。

5. a. DSC spectrum (5°C / min) with an endotherm onset at 178.3±1.0°C and a second endotherm onset at 227.3±1.0°C; b. DSC spectrum (10°C / min) with an endotherm onset at 177.6±1.0°C and an endotherm onset at 227.9±1.0°C; c. DSC spectrum (20°C / min) with an endotherm onset at 178.5±1.0°C, and endotherm onsets at 222.5±1.0°C and 224.3±1.0°C, followed by an endotherm onset at 227.8±1.0°C; d. DSC spectrum (50°C / min) containing a double endotherm onset at 88.0±1.0°C and 92.6±1.0°C, a second endotherm onset at 180.5±1.0°C, a sharp endotherm / exotherm onset at 224.7±1.0°C, and an endotherm onset at 229.5±1.0°C; e. Melt-quench-cool (MDSC) with an endotherm onset at 177.7±1.0°C and an endotherm onset at 227.8±1.0°C; or f. VT-XRPD pattern with observable changes at 200°C 3. The polymorph of claim 2, further comprising one or more characteristics selected from:

6. 2. The polymorph of claim 1, wherein the polymorph is Form B.

7. 7. The polymorph of claim 6, wherein the polymorph comprises 4 or more 2-theta 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.

8. 7. The polymorph of claim 6, wherein Form B comprises the XRPD pattern shown in Figure 2B; 。

9. 10. A pharmaceutical composition comprising polymorph Form A or Form B of claim 1.

10. 10. A kit comprising polymorph Form A or Form B of claim 1.

11. 1. A method for preparing polymorphic Form A of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, the method comprising: a) obtaining a sample containing 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid; 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 c) removing said solvent from said solution to obtain polymorphic Form A of claim 1. A method comprising:

12. 12. The method of claim 11, wherein the C1-C5 alcohol is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, or isopentanol; the C1-C5 ketone is selected from methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), or acetone; and the C1-C5 acetate is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, or pentyl acetate.

13. 12. The method of claim 11, wherein the solution is greater than 80% C1-C5 alcohol, C1-C5 ketone, or C1-C5 acetate.

14. The method of claim 11, wherein the solution comprises 0% to 20% water.

15. 12. The method of claim 11, wherein after dissolution in (b), the solution is cooled to an incubation temperature of 1°C to 10°C over a period of time.

16. 16. The method of claim 15, wherein cooling to the incubation temperature is at a rate of about 0.02°C / min to about 1°C / min until the incubation temperature is reached.

17. 16. The method of claim 15, wherein the period of time to bring the incubation temperature up is from about 1 hour to about 48 hours.

18. 12. The method of claim 11, wherein the removal of the solvent is carried out by evaporation or filtration.

19. 19. The method of claim 18, wherein the evaporation is carried out at about 20°C to about 35°C.

20. 10. A pharmaceutical composition for treating, preventing or ameliorating a disease or condition comprising a pharmaceutically effective amount of polymorph Form A of claim 1, The pharmaceutical composition, wherein the disease or condition is an inflammatory disease or condition.

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