Solid form of Tafamidis and method for manufacturing the same

Abstract

The present invention describes a crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and a method for preparing the same. The crystalline form is further suitable as an intermediate for preparing the crystalline form 1, crystalline form 4 and crystalline form M, which have improved stability and purity.

Description

Technical Field

[0001] The present invention relates to crystals of tafamidis and a method for producing the same.

Background Art

[0002] 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis) is a drug used to delay the loss of sensory nerve function in adults with the life-threatening but relatively rare disease of familial amyloidotic polyneuropathy associated with genetic mutations of the transthyretin (TTR) gene, and for the treatment of heart diseases (cardiomyopathies) caused by transthyretin-mediated amyloidosis (ATTR-CM).

[0003] In May 2019, the US Food and Drug Administration approved two separate formulations for oral administration (one containing tafamidis (Vyndamax®) and one containing tafamidis meglumine (Vyndaqel®)) to treat cardiomyopathy in adults with wild-type or genetic transthyretin-mediated amyloidosis (ATTR-CM) and to reduce cardiovascular mortality and cardiovascular-related hospitalizations.

[0004] As is generally known, the active ingredient can exist as an amorphous or different crystal forms (polymorphs), either as a pure compound or in a form in which molecules of water (hydrate) or another solvent (solvate) are present in the crystal structure. In the case of hydrates and solvates, the ratio between the number of molecules of the active ingredient and the number of molecules of water or solvent can vary, resulting in different solid compounds. In particular, an amorphous solid consists of an irregular arrangement of molecules and does not possess a distinguishable crystal lattice.

[0005] Certain solid compounds may possess properties that differ from or are more advantageous than those of other crystalline transformations. These include, but are not limited to, packing properties such as molar volume and density, thermodynamic properties such as melting point, glass transition temperature and solubility, kinetic properties such as dissolution rate, surface properties such as wettability and interfacial tension, handling and filtration properties. Variations in any of these properties can affect the chemical and pharmaceutical processing of the compound, and in many cases, certain solids may be more suitable than others for pharmaceutical and medical use, or for producing other polymorphic forms in high yield and good purity.

[0006] 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid was first described in WO2004 / 056315 (filed December 19, 2003), where tafamidis is disclosed as compound (19), obtained as a white solid by final separation of the acid by preparative TLC. WO2016 / 38500 discloses various crystalline forms of tafamidis (6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole, namely Crystal 1, Crystal 2 (THF solvate), Crystal 4, Crystal 6, and amorphous form.

[0007] As used herein, “Tafamidis crystal 4” refers to the form described in WO2016 / 38500, characterized by a powder X-ray diffraction pattern that includes peaks at diffraction angles (2θ) of 15.9, 16.9, and optionally 18.0, 24.1, and 27.3 (all ±0.2). As used herein, “Tafamidis crystal 1” refers to a form described in WO2016 / 38500, characterized by a powder X-ray diffraction pattern that includes a peak at a diffraction angle (2θ) of 28.6 and further includes other peaks at 15.4, 16.5, 20.2, 23.5, 26.7, and 29.0 (all ±0.2).

[0008] WO2013 / 038351 describes anhydrous crystal I, also called crystal M, which is a solid API crystal present in the drug Vyndaqel, specifically the N-methyl-D-glucamine (meglumine) salt of tafamidis, as reported in the EPAR-public assessment report issued by the European Medicine Agency (EMA) on September 22, 2011, and has a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 10.7, 11.8, and 13.3 (all ±0.2, using Cu Kα1 radiation).

[0009] Angewandte Chemie Int. Ed. 2003, 42, 2758-2761 describes a method for obtaining tafamidis by vacuum concentration of a flash column chromatography fraction (4.9:95:0.1 MeOH:CH2Cl2:AcOH). According to the information provided during the EP3191461 test, the solid thus obtained is amorphous and converts to crystalline form 4 after storage at 70°C and 75% relative humidity for one week. Various solid forms of tafamidis, including adducts with formic acid, trifluoroacetic acid, and acetic acid, are described in WO2019 / 175263.

[0010] WO2020 / 232325 relates to tafamidis and describes amorphous form, crystalline form I (obtained by exposure of amorphous form to water vapor for 30-33 days, or as a hydrate from THF / water), crystalline form II (obtained from 2-methyl THF by crush cooling, or by slow evaporation of the solvent over 7 days), crystalline forms III and IV (solvates with acetic acid), and crystalline form V (solvate with anhydrous or methanol). Crystals I, II, III, and IV are converted to crystalline form 4 by drying in a vacuum dryer at 100-160°C, as disclosed in Examples 16-20 of WO2020 / 232325.

[0011] Crystal 1 is thermodynamically stable at room temperature, as reported in the application history of the European corresponding application WO2016 / 38500, while Crystal 4 is more stable at high temperatures, as reported above. The methods for producing crystals 1 and 4 of tafamidis and crystal M of tafamidis meglumine described in the literature cited above relate to laboratory-scale tests (10 mg to 1 to 1.5 grams) and it is clear that they have not been demonstrated to be suitable for large-scale production. There is a need for alternative, reliable, and easily industrializable methods for producing tafamidis polymorphic crystals, particularly crystals 1 and 4, and tafamidis meglumine salts of their polymorphic crystal M, which are forms of tafamidis present in the pharmaceutical product Vyndaqel®. [Overview of the project] [Problems that the invention aims to solve]

[0012] The object of the present invention is to provide a novel crystalline form of tafamidis that is suitable for large-scale production and suitable for conversion into other crystalline forms and salts of tafamidis, or, if necessary, directly incorporated into pharmaceutical dosage forms. [Means for solving the problem]

[0013] The above objective is achieved, in one embodiment, by the present invention relating to a novel crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis) (hereinafter also referred to as the α-type), wherein the substantially pure and stable crystalline form is characterized by an XRPD profile that, when collected using copper Kα line (λ=1.5418 Å), includes at least one peak at 9.6, 13.5, 16.3, 18.2, 20.4 and 27.5°(2θ).

[0014] In another embodiment, the present invention relates to a method for producing the crystalline α-type of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. In a further embodiment, the present invention relates to the use of the α-form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid for producing solids of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and its salts or adducts, excluding the α-form. In another embodiment, the present invention relates to a pharmaceutical formulation comprising the α-form of the above-mentioned 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. [Brief explanation of the drawing]

[0015] [Figure 1] Figure showing an exemplary X-ray powder diffractogram (XRPD) of solid α of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. [Figure 2] This figure shows a comparison of the XRPD patterns of the α-form (lower curve) and crystalline form 4 (upper curve) of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. [Figure 3] This figure shows the differential scanning calorimetry (DSC) curve of solid α-form 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (11 mg; 30-300°C; 10°C / min). [Figure 4] This figure shows the thermogravimetric analysis (TGA) curve of the solid α-form (5°C / min, 30-300°C) of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. [Figure 5] A figure showing the infrared (IR) spectrum of the solid α-form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. [Figure 6] This figure shows a comparison of XRPD patterns for the α-form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid during stability testing, obtained in open vials at room temperature and 80% relative temperature (RH) on days 0, 8, 15, and 4 weeks. [Figure 7]Comparison of XRPD patterns for the α-form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid during stability testing, showing those obtained on day 0, day 8, day 15, and at 4 weeks at 40 °C and 75% relative humidity (RH) in an open vial. [Figure 8] Comparison of XRPD patterns for crystal form 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid during stability testing, showing those obtained on day 0, 1 month, 3 months, and 6 months at 40 °C and 75% relative humidity (RH). [Figure 9] Comparison of XRPD patterns for crystal form 1 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid maintained under storage conditions, showing those obtained at 0 months and 8 months in a sealed vial. [Figure 10] Comparison of XRPD patterns for crystal form 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid maintained under storage conditions, showing those obtained at 0 months and 10 months in a sealed vial. [Figure 11] Comparison of XRPD patterns for meglumine salt of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid during stability testing, showing those obtained on day 0, 1 month, 3 months, and 6 months at 40 °C and 75% relative humidity (RH). [Figure 12] Figure showing a comparison of XRPD patterns for crystal form 1 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and crystal form 4 obtained from the repetition of Example 2 of WO2016 / 038500.

Mode for Carrying Out the Invention

[0016] All terms used in this application shall be understood in their ordinary meanings known in the relevant technical field, unless otherwise specified. The term "about" includes the range of experimental error that may typically occur when making measurements, for example, ±5% or ±2% or ±1%. The term "mass" defines a combination of substrates, reagents, solvents, and products on which physical or chemical transformations are performed.

[0017] The term "excipient" means any substance contained in the final pharmaceutical form other than the active ingredient, which may generally not be therapeutically effective by itself. Excipients are essential for the administration of the active substance as they enable the delivery of the drug to the target site. Excipients are generally referred to as raw materials added to the composition of a pharmaceutical preparation for the purpose of facilitating administration and giving a shape for preserving the active ingredient. Furthermore, they contribute to characterizing the pharmaceutical preparation from the viewpoints of appearance, stability, biopharmaceutical profile, and acceptability by patients.

[0018] Unless otherwise indicated, in the context of the present invention, the percentage and amount of a particular component in a composition shall refer to the weight of said component relative to the total weight of the composition. Unless otherwise indicated, in the context of the present invention, the designation that a composition "comprises" one or more other components / elements means that, in addition to those specifically listed, the indicated component / element must be present in the composition, and other components may be present but not necessarily. In other words, the designation that a composition "comprises" one or more components does not exclude the composition from consisting of or being essentially composed of the listed components.

[0019] As used herein, the term "substantially pure" with respect to a particular crystal means that the crystal contains less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, and even more preferably less than 1% by weight of any other physical form of the compound. As used herein, the designation that compound or composition A is “pure” or “completely free” of other substances (or “consisting of” other substances) means that, within the detection range of the instrument or method used, it is impossible for any substance other than the specifically indicated substance to be detected in A.

[0020] As used herein, the terms “compound or composition A is essentially free of other substances” or “essentially composed of A” mean that any other substances, if present, can only be detected in trace amounts using analytical methods and techniques known to those skilled in the art. Unless otherwise indicated, in the context of the present invention, a range of values ​​indicated for a particular parameter, such as the weight of a component in a mixture, includes an upper and lower limit to the range. For example, if the weight or volume content of component A in the mixture is indicated as "X~Y", the content of A may be X, Y, or an intermediate value.

[0021] "Polymorphically stable" means that when the crystals of the present invention are stored (I) at 70°C and under reduced pressure for at least 1 hour (preferably 5 hours, more preferably 10 hours, and even more preferably 12 hours), (II) at 60°C for at least 1 day (preferably 5 days, more preferably 10 hours, and even more preferably 15 days), (III) at 40°C and 75% relative humidity (RH) for at least 1 day (preferably 8 days, more preferably 15 hours, even more preferably 1 month, and advantageously 6 months), and / or at room temperature and 80% or less relative humidity (RH) for at least 5 days (preferably 1 month, more preferably 8 months, and even more preferably 10 months), they do not show any signs of conversion to different crystals, as assessed by the absence of peaks in an X-ray powder diffractogram (XRPD).

[0022] "Chemically stable" means that the solid of the present invention does not decompose when stored under stress conditions, for example, (I) at least 70°C and under reduced pressure for at least 1 hour (preferably 5 hours, more preferably 10 hours, and even more preferably 12 hours), (II) at 60°C for at least 1 day (preferably 5 days, more preferably 10 days, and even more preferably 15 days), (III) at 40°C and 75% relative humidity (RH) for at least 1 day (preferably 8 days, more preferably 15 days, even more preferably 1 month, and advantageously 6 months), and / or at room temperature and 80% or less relative humidity (RH) for at least 5 days (preferably 1 month, more preferably 8 months, and even more preferably 10 months).

[0023] "No decomposition" means that HPLC analysis of the sample does not show a significant decrease in purity with respect to the formation of new impurities and an increase in the content of existing profiles relative to the initial profile (e.g., an area increase of less than 0.1%). The “storage conditions” for 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and its salts mean that all forms should be stored in a sealed container at room temperature, atmospheric pressure, and a relative humidity (RH) of 80% or less.

[0024] The "Type A" container used in stability testing refers to a transparent, double-walled polyethylene bag with a zip closure, collected in a plastic (HPDE) drum. "Type B" refers to an additional stabilizing container consisting of a zip-closure transparent double polyethylene bag inserted into a heat-sealed quadruple-layer aluminum bag. Room temperature refers to a temperature range of 15–25°C, as reported in the European Pharmacopoeia. Unless otherwise specified, data related to peaks in the XRPD pattern are intended to be within the range of common instrumental uncertainties, typically ±0.2°(2θ), when collected using copper Kα lines (λ=1.5418Å).

[0025] In one embodiment, the present invention provides a crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid, referred to as the α-type, characterized by an XRPD profile that includes at least one peak at 9.6, 13.5, 16.3, 18.2, 20.4 and 27.5°(2θ)(±0.2) when collected using a copper Kα line (λ = 1.5418 Å). Preferably, the crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid is further characterized in that its XRPD profile contains at least one peak among 5.3, 6.4, 12.3, 19.3, 22.8 and 23.5°(2θ).

[0026] As a non-restrictive example, a complete list of peaks in a typical alpha-type XRPD pattern is provided below (I / I0 = relative intensity): [Table 1]

[0027] In a preferred embodiment, the present invention has a DSC profile similar to that shown in Figure 3, i.e., an exothermic transition in the range of about 135 to about 165°C and an endothermic transition with a peak at 287±2°C, and / or a TGA profile representing the thermal behavior shown in Figure 4 and / or 1695, 1573, 1547, 1437, 1420, 1298, 1276, 882, 862, 772, 745, 725, 678, 665, 534 cm². -1 The above-mentioned crystalline α-type is further characterized by an IR spectrum having at least one of the following.

[0028] As reported in Figures 7 and 8, the α-type according to the present invention was found to be chemically and physically stable, in that it does not alter its polymorphic crystalline structure, and its chemical purity does not decrease even when stored at different humidity levels for several weeks at 15-60°C. This characteristic allows the α-type of tafamidis according to the present invention to be used as an intermediate to produce other crystalline forms of tafamidis (e.g., crystalline form 1 or crystalline form 4 described in WO2016 / 38500) or salts, such as meglumine salt, in a manner suitable for large-scale production.

[0029] In another embodiment, the present invention provides a method for producing the crystalline α-type of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid described above, i. Dissolving 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, and mixtures thereof; ii. Adding the solution obtained in step i to a reverse solvent selected from the group consisting of hexane, heptane, and mixtures thereof; iii. A step of separating the obtained solid; This relates to the manufacturing method, including the manufacturing method.

[0030] Preferably, in the α-type manufacturing method, the solvent used to dissolve 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in step i is tetrahydrofuran. Preferably, in the above-mentioned method for producing the α-type, the reverse solvent used in step ii is heptane. In a preferred embodiment, the weight / volume ratio of tafamidis / solvent in the method according to the present invention is 1:5 to 1:30, more preferably 1:18 to 1:28. In a preferred embodiment, the solvent / reverse solvent volume / volume ratio in the method according to the present invention is 1:1 to 1:5, preferably 1:1.5 to 1:3.5. In a preferred embodiment, step i in the method according to the present invention is carried out at a temperature of 30 to 80°C, more preferably 40 to 70°C or 55 to 65°C. In a preferred embodiment, step ii in the method according to the present invention is carried out at -30 to 25°C, more preferably -20 to 20°C or -15 to 10°C.

[0031] In one embodiment, the present invention relates to the use of the crystalline α-form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid for producing a solid of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a salt or adduct thereof, excluding the α-form. Preferably, the present invention relates to the production of crystalline form 1 or 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid from solid α-type. More preferably, the present invention relates to the production of a crystalline form 1 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid using a solid α-form as an intermediate, wherein the α-form is suspended in a high-boiling point solvent, such as 1,3,5-trimethylbenzene, xylene, or chlorobenzene at a temperature of 100°C to 140°C for 1 to 24 hours, more preferably at a temperature of 125°C to 135°C for 15 to 20 hours. The resulting suspension is maintained under stirring at the same temperature range for about 24 hours, preferably about 17 hours, then cooled to 20 to 25°C and filtered using conventional techniques. The filtered solid is washed with the same solvent used in the reaction and dried under vacuum at 45 to 50°C for about 1 to about 24 hours, preferably about 10 to about 18 hours.

[0032] Advantageously, the present invention relates to the production of a crystalline 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid using a solid α-type as an intermediate, wherein the drying of the α-type is carried out under vacuum at a temperature of 100°C to 150°C for about 1 to about 24 hours, more preferably at a temperature of 125°C to 135°C for about 1 to about 20 hours, and preferably about 10 to about 16 hours.

[0033] Crystals 1 and 4 of tafamidis obtained according to the present invention were found to be substantially pure crystals obtained using a suitable and scalable process. The crystals are chemically and physically stable, and in particular, they do not change their XPRD patterns or show decomposition when held under storage conditions. Furthermore, analysis of a first set of stability data makes it possible to demonstrate that crystal 4 is chemically and physically stable when stored for several months at 40°C and 75% relative humidity (RH).

[0034] In contrast, solid tafamidis obtained by reproducing the prior art method, for example, Example 2 of WO2016 / 038500, which is reported as a non-limiting example in the experimental portion, on a multi-gram scale, was found to contain a detectable amount of crystalline material other than crystalline material 4 shown in Figure 12. In a preferred embodiment, the present invention relates to the production of a salt of tafamidis, preferably a meglumine salt of tafamidis, starting from solid α-form of tafamidis.

[0035] Preferably, the tafamidis meglumine salt is obtained by suspending the α-form in a mixture of water and a solvent selected from the group consisting of methyl, ethyl, propyl, and isopropyl alcohols at 20–25°C. More preferably, the α-form is suspended in a mixture of isopropyl alcohol and water in a volume ratio ranging from about 3:1 to about 6:1, preferably 5:1. Meglumine is then added and the resulting suspension is heated until completely dissolved. After cooling the resulting solution to 10–15°C for about 1–5 hours, preferably about 1–2 hours, the tafamidis meglumine salt is recovered by conventional filtration techniques, washed with the same solvent mixture used in the reaction, and dried under vacuum at about 45–50°C for about 1–20 hours, preferably about 10–16 hours. The first set of stability data shows that the tafamidis meglumine salt is obtained in substantially pure and stable polymorphic crystals M according to the present invention.

[0036] In one embodiment, the present invention provides a pharmaceutical formulation comprising crystalline α-type of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid and at least one optionally selected excipient.

[0037] The following embodiments are provided to illustrate specific embodiments of the present invention, without the intention of limiting the scope of the invention. The equipment and methods used to characterize the crystals obtained in the examples are as follows:

[0038] X-ray powder diffraction (XRPD) analysis was performed on a Bruker D8 Advance X-ray powder diffractometer at approximately 25°C and ambient humidity (e.g., 25-35%) using a Cu Kα tube (40kV, 40mA, λ=1.5418Å) equipped with a linear Lynxeye XE-T position-sensitive detector set 250mm from the sample as the X-ray source. A nickel filter (0.0125mm thick) was attached to the primary beam. Data acquisition was performed in coupled mode, with θ-θ configuration over an angular range of at least 3°2θ to 40°2θ, and with a scanning step of 0.02°. The fine powder sample was placed in a flat, thin layer within a 12mm × 0.2mm cavity of a silicon low-background plate fixed on a sample holder adapted to the autosampler position. The instrument was pre-calibrated using NIST SRM 1976b. Data acquisition was performed using Bruker Diffraction Measurement Center software; data refinement was performed using Crystal Impact Match! or Bruker Diffrac. EVA software.

[0039] Differential Scanning Calorimetry (DSC): DSC testing was performed using a Mettler-Toledo DSC1 Stare System. Indium was used for calibration. Accurately weighed samples (3–5 mg) were placed in an open aluminum vented pan and heated at a rate of 10°C / min under a nitrogen purge of 80 mL / min. The range from 30°C to 300°C was investigated.

[0040] TGA analysis was performed using a Perkin-Elmer Pyris 1 TGA at a scanning rate of 5°C / min, within a thermal range of 30–300°C, and under a nitrogen stream. Approximately 5 mg of powder was loaded into the platinum crucible of the thermobalance. Fourier Transform Infrared Analysis (FT-IR): FT-IR analysis was performed using a Spectrum Two FTIR Spectrophotometer equipped with Universal Attenuation Total Reflectance (ATR) and Spectrum 10™ software. Measurements were taken at 4000–450 cm². -1 Within a range of 4.0cm -1 This was achieved by performing 16 scans with a resolution of [resolution value].

[0041] Tafamidis used in the experiment is prepared according to the procedures described in the prior art, for example, according to the procedure reported in roc. Natl. Acad. Sci USA, Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade, 2012 June, 109(24), 9629-34. [Examples]

[0042] Example 1 Manufacturing of Taffamidis α type. Tafamidis (10 g) was dissolved in tetrahydrofuran (220 mL) at 60-65°C. The resulting solution was filtered through a diatomaceous earth (Hyflo®) bed. The filtrate was heated to 60-65°C, and the resulting clear solution was added dropwise to heptane (730 mL) cooled to -15 / -10°C. The resulting suspension was maintained at the same temperature under stirring for 1-2 hours, and then filtered. The solid was dried under vacuum at 45-50°C for 16 hours and analyzed by XRPD. Tafamidis α was obtained. Yield: 8.5g

[0043] Example 2 Manufacturing of Tafamidis crystal 4 8.5 g of tafamidis α-type obtained according to the procedure of Example 1 was dried under vacuum at 130°C for 2 hours. The resulting solid was analyzed by XRPD. Tafamidis was obtained as a substantially pure crystalline material 4, as shown in Figure 10 (initial data). The obtained tafamidis crystal 4, when stored in a sealed vial under storage conditions for 10 months, does not change its XRPD pattern, as shown in Figure 10. Yield: 8.5g

[0044] Example 3 Manufacturing of Tafamidis crystal 1 Tafamidis α-type (3 g) was suspended in 1,3,5-trimethylbenzene (mesitylene) (30 mL) and heated to 130-135°C. The resulting suspension was maintained at the same temperature under stirring for 17 hours, then cooled to 20-25°C and filtered. The solid was washed with mesitylene (5 mL), dried under vacuum at 45-50°C for 16 hours, and analyzed by XRPD. Tafamidis was obtained as a substantially pure crystalline material 1, as shown in Figure 9 (initial data). The obtained tafamidis crystal 1, when stored in a sealed vial under storage conditions for 8 months, does not change its XRPD pattern, as shown in Figure 9. Yield: 3g

[0045] Example 4 Manufacturing of Tafamidismeglumine (crystal M) Tafamidis α-type (10 g) was suspended in a 5:1 mixture of isopropyl alcohol and water (300 mL) at 20–25°C. Meglumine (6.8 g, 1.07 equivalents) was added, and the resulting suspension was dissolved at 80°C. The resulting solution was slowly cooled to 10–15°C. The resulting suspension was maintained at the same temperature under stirring for 1–2 hours, and then filtered. The solid was washed with the same solvent mixture (15 mL), dried under vacuum at 45–50°C for 16 hours, and analyzed by XRPD. Tafamidis meglumine was obtained in substantially pure crystalline form M, as shown in Figure 11 (initial data). Yield: 14.9g

[0046] Example 5 Preparation of Tafamidis crystal 4 from wet α-type Tafamidis (15 kg) was dissolved in tetrahydrofuran (375 L) at 55-60°C. The resulting solution was filtered through a diatomaceous earth (Hyflo®) bed. The filtrate was heated to 55-60°C, and the resulting clear solution was added dropwise to heptane (750 mL) cooled to -15 / -10°C. The resulting suspension was maintained at the same temperature with stirring for 1-2 hours, and then filtered. The solid was dried under vacuum at 120-125°C for several hours until complete conversion to crystalline form 4 was achieved. Yield: 14.2 kg

[0047] Comparative Example 6: Production of Tafamidis Crystal 4 (Reproduction of Example 2 of WO2016 / 038500 on a multigram scale) Tafamidis crystal 1 (5 g) was suspended in tetrahydrofuran (200 mL), and the mixture was heated at 75°C. The hot solution was filtered through a preheated 0.2 μm nylon filter and placed in a container cooled in an ice / water bath containing toluene (670 mL). The resulting solution was stored overnight in a refrigerator (-10 / -15°C). The obtained solid was filtered and dried under vacuum. The solid analyzed by XRPD (Figure 12) demonstrates that this experimental procedure, performed on a multigram scale, yielded tafamidis of polymorph 4 containing polymorph 1. Yield: 2g

[0048] Example 7: Stability Test [7a.α type] Store vials containing 100 mg each of the α-type of the present invention under the following conditions (RH refers to relative humidity): - Room temperature (RT) and 80% RH, open vial - 40°C and 75% RH, open vial We evaluated arbitrary changes in the crystalline structure using X-ray powder diffractograms (XRPD), and measured chemical purity using HPLC. Samples were analyzed before storage (initial data), at 8 days, 15 days, and 4 weeks. X-ray powder diffractograms (XRPDs) recorded four weeks later showed no signs of conversion to different α-type crystals, as reported in Figures 6 and 7. HPLC analysis shows that the α-type of the present invention does not exhibit a significant decrease in purity with respect to the formation of new impurities and an increase in the content of already present impurities compared to the initially obtained profile.

[0049] [7b. Crystal obtained from α-type 4] 700 mg of tafamidis crystal 4 obtained according to the present invention is stored under the following conditions (RH refers to relative humidity): - 40°C and 75% RH, Type A container. We evaluated arbitrary changes in the crystalline structure using X-ray diffractograms (XRPDs), and measured chemical purity using HPLC. Samples were analyzed before storage (initial data), and after 1 month, 3 months, and 6 months. The X-ray powder diffractogram (XRPD) recorded six months later showed no signs of conversion to a different crystalline form, as reported in Figure 8. HPLC analysis shows that the α-type of the present invention does not exhibit a significant decrease in purity with respect to the formation of new impurities and an increase in the content of already present impurities compared to the initially obtained profile.

Claims

1. Crystals of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid, characterized by an XRPD profile containing peaks at 9.6, 13.5, 16.3, 18.2, 20.4 and 27.5° (2θ) when collected using copper Kα (λ = 1.5418 Å).

2. The crystalline form of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid according to claim 1, characterized in that the XRPD profile further includes at least one peak among 5.3, 6.4, 12.3, 19.3, 22.8 and 23.5° (2θ).

3. A crystalline 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid according to claim 1, characterized by a DSC profile having an exothermic transition in the range of 135°C to 165°C and an endothermic transition with a peak at 287±2°C.

4. A method for producing crystalline 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid according to any one of claims 1 to 3: i. The step of dissolving 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof; ii. Adding the solution obtained in step i to a reverse solvent selected from the group consisting of hexane, heptane, or a mixture thereof; iii. A step of separating the obtained solid; A manufacturing method that includes this.

5. The production method according to claim 4, wherein the solvent used to dissolve 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in step i is tetrahydrofuran.

6. The manufacturing method according to claim 4, wherein the reverse solvent used in step ii is heptane.

7. Use of crystalline 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid according to any one of claims 1 to 3 for producing a solid of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a salt or adduct thereof, excluding the α-type.

8. The use according to claim 7 for producing a pure crystalline form 1 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid.

9. The use according to claim 7 for producing pure crystalline 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid.

10. The use according to claim 7 for producing a pure crystalline form M of the meglumine salt of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid.

11. A pure crystalline form 4 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid, wherein the term "pure" means that the crystalline form 4 is not contaminated with the crystalline form 1 of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The aforementioned crystalline body 4.

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