Solid-state forms of tafamidis

Abstract

The present disclosure relates to solid state forms of tafamidis, methods for their preparation and pharmaceutical compositions thereof.

Description

[Technical field]

[0001] The present disclosure relates to solid state forms of tafamidis, methods for their preparation and pharmaceutical compositions thereof. [Background technology]

[0002] Tafamidis has the chemical name 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. Tafamidis has the following chemical structure:

[0003] [ka]

[0004] has.

[0005] Tafamidis meglumine has the chemical name 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono(1-deoxy-1-methylamino-D-glucitol). Tafamidis meglumine has the following chemical structure:

[0006] [ka]

[0007] has.

[0008] VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) are both capsules for oral administration and contain tafamidis as the active moiety. The US Food and Drug Administration ("FDA") has approved VYNDAQEL and VYNDAMAX for the treatment of cardiomyopathy in adults with wild-type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalizations. The EMA has approved VYNDAQEL for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neuropathy.

[0009] Tafamidis is known from US Pat. No. 7,214,695.

[0010] Solid state forms of tafamidis meglumine are known from U.S. Patent No. 9,249,112, International Publication Nos. WO2017190682 and WO2019175263. Solid state forms of tafamidis are known from U.S. Patent No. 9,770,441, International Publication Nos. WO2020232325 and WO2021001858. International Publication No. WO2021093809 discloses cocrystals of tafamidis.

[0011] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single compound, such as tafamidis, may exist in different crystalline structures and may be characterized by, for example, melting points, thermal behavior (measured, for example, by thermogravimetric analysis "TGA" or differential scanning calorimetry "DSC"), powder X-ray diffraction (PXRD) patterns, infrared absorption fingerprints, Raman absorption fingerprints, and solid-state ( 13 Various polymorphs may occur which have different physical properties, such as different C-NMR spectra. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0012] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may have different properties. Such diversity in the properties of different salts and solid state forms and solvates may be the basis for improving formulations, for example, by facilitating better processing or handling properties, improving dissolution profiles, or improving stability (polymorphic and chemical stability) and shelf life. Such diversity in the properties of different salts and solid state forms may also lead to improvements in the final dosage form, for example if it helps to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to various polymorphs or crystalline forms, which may in turn provide further opportunities to use the diversity in the properties and characteristics of the solid active pharmaceutical ingredient to provide improved products.

[0013] The discovery of new salts, solid state forms and solvates of pharmaceutical products can provide materials with desirable processability, such as ease of handling, ease of processing, storage stability and ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of pharma- ceutically useful compounds can also provide opportunities to improve the performance characteristics (dissolution profile, bioavailability, etc.) of pharmaceutical products. It can broaden the repertoire of materials available to formulation scientists for formulation optimization, for example by providing products with different properties, such as different crystal habits, higher crystallinity, or polymorphic stability, or solubility, flowability, which can result in better processing or handling properties, improved dissolution profile, or improved shelf life of either the drug product during formulation processing or the final pharmaceutical formulation / dosage form. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] U.S. Patent No. 7,214,695 [Patent Document 2] U.S. Patent No. 9,249,112 [Patent Document 3] WO2017190682 No. [Patent Document 4] WO2019175263 No. [Patent Document 5] U.S. Patent No. 9,770,441 [Patent Document 6] WO2020232325 No. [Patent Document 7] WO2021001858 No. [Patent Document 8] WO2021093809 [Patent Document 9] WO2016 / 038500 No. [Non-patent literature]

[0015] [Non-Patent Document 1] Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. Summary of the Invention [Problem to be solved by the invention]

[0016] For at least these reasons, crystalline forms of tafamidis (including solvated forms) that possess desirable properties remain desirable. [Means for solving the problem]

[0017] The present disclosure relates to solid state forms of tafamidis, methods for their preparation, and pharmaceutical compositions comprising the solid state forms.

[0018] The present disclosure also provides for the use of a solid state form of tafamidis described in any embodiment or aspect herein to prepare other solid state forms of tafamidis, tafamidis salts and solid state forms thereof.

[0019] In another embodiment, the disclosure encompasses a solid state form of tafamidis, as described in any embodiment or aspect herein, for use as a medicament, in an embodiment for the treatment of transthyretin-mediated amyloidosis.

[0020] In another embodiment, the present disclosure encompasses a method of treating transthyretin-mediated amyloidosis by use of a solid state form of tafamidis disclosed herein.

[0021] In a further embodiment, the present disclosure further provides for the use of a solid state form of tafamidis described according to any embodiment or aspect herein for the preparation of a pharmaceutical composition or pharmaceutical formulation of tafamidis, wherein the tafamidis in the pharmaceutical composition or pharmaceutical formulation is in solid form, which solid form may be any crystalline or non-crystalline form.

[0022] The present disclosure further provides a pharmaceutical composition comprising a solid state form of tafamidis according to the present disclosure.

[0023] In yet another embodiment, the present disclosure encompasses a pharmaceutical formulation comprising a solid state form of tafamidis, as described in any aspect or embodiment herein, and at least one pharma- ceutically acceptable excipient, in an embodiment for oral administration in the form of a tablet, capsule, or the like.

[0024] The present disclosure encompasses methods of preparing said pharmaceutical formulations of tafamidis by combining at least a solid state form of tafamidis described in any aspect or embodiment of the present disclosure with at least one pharma- ceutically acceptable excipient.

[0025] The solid state forms and pharmaceutical compositions or formulations of solid state forms of tafamidis described herein can be used as medicaments in embodiments for treating transthyretin-mediated amyloidosis.

[0026] The present disclosure also provides a method of treating transthyretin-mediated amyloidosis by administering a therapeutically effective amount of a solid state form of tafamidis of any aspect or embodiment of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, to a subject suffering from or in need of treatment of transthyretin-mediated amyloidosis.

[0027] The present disclosure also provides a use of a solid state form of tafamidis of any aspect or embodiment of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of a medicament for treating transthyretin-mediated amyloidosis. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows the powder X-ray diffraction pattern ("powder XRD" or "PXRD" or "XRPD") of tafamidis form Va. [Diagram 2] FIG. 1 shows the XRPD pattern of tafamidis form V (methanol solvate). [Diagram 3] FIG. 1 shows the XRPD pattern of tafamidis form V (anhydrous). [Figure 4] FIG. 13C NMR of anhydrous form V of tafamidis. [Diagram 5] FIG. 1 shows the XRPD patterns of tafamidis form 4 before and 2 hours after slurrying in PEG400 at room temperature. [Figure 6] FIG. 1 shows the XRPD patterns of tafamidis form Va before and after 7 days of slurrying in PEG400 at room temperature. [Figure 7] FIG. 1 shows the 13C NMR spectrum of tafamidis form Va. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The present disclosure relates to solid state forms of tafamidis, and in embodiments, to crystalline forms of tafamidis, methods for their preparation, and pharmaceutical compositions comprising the solid state forms.

[0030] The solid state forms of tafamidis according to the present disclosure may have advantageous properties selected from at least one of chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability (such as chemical stability with respect to polymorphic conversion and thermal and mechanical stability), stability against dehydration and / or storage stability, lower hygroscopicity, low content of residual solvents, and advantageous processing and handling properties such as compressibility, or bulk density. The advantageous properties may result in better processing or handling properties, improved dissolution profile, or improved shelf life in either the drug product during formulation processing or in the final pharmaceutical formulation / dosage form.

[0031] In particular, Form Va of the present disclosure has been found to have advantageous morphology and small particle size compared to Form 1, for example, as disclosed in U.S. Patent No. 9,770,441. Thus, compared to the long fibrous to needle-like morphology of Form 1, which has a particle size of up to 100 μm, the crystalline Form Va of the present disclosure has significantly shorter needle / rod-like particles, which are significantly smaller and more uniform in particle size distribution (about 5-10 μm particle size). Tafamidis has low aqueous solubility, and therefore particles with smaller size and more uniform particle size distribution are highly advantageous for processing into dosage forms. Thus, Form 1 Tafamidis requires particle size reduction (e.g., by micronization) to achieve the desired particle size distribution and uniformity to increase dissolution. Such processing is not necessary for Form Va, thereby reducing processing time and costs. Furthermore, the fibrous morphology of Form 1 is associated with a higher tendency for particles to stick together, resulting in poor flowability.

[0032] Similarly, Form 6 disclosed in International Publication No. WO2016 / 038500 has large (>100 μm) agglomerated particles with a very broad particle size distribution, which is highly undesirable for pharmaceutical processing.

[0033] Form Va of the present disclosure is also stable to suspension in PEG, which is typically used to formulate tafamidis as a softgel capsule. Form 4 usually converts to form 1 after 2 hours (Figure 5). Form Va of the present disclosure is stable for at least 7 days (Figure 6). Form Va also exhibits better water solubility than Form V, for example, as disclosed in International Publication No. WO2020 / 232325 (2.21 μg / ml vs. 1.47 μg / ml, respectively).

[0034] Crystal forms may be referred to herein as being characterized by the graphical data "shown in" the figures. Such data include, for example, powder X-ray diffractograms and solid-state NMR spectra. As is well known in the art, the graphical data may provide additional technical information (so-called "fingerprints") to further define each solid-state form, which may not necessarily be described by reference to numerical values ​​or peak positions alone. In any event, those skilled in the art will understand that the graphical representation of such data may be subject to small variations in peak relative intensities and peak positions due to factors such as, for example, variations in instrument response and variations in sample concentration and purity, which are well known to those skilled in the art. Nevertheless, those skilled in the art will be able to easily compare the graphical data in the figures herein with the graphical data generated for an unknown crystalline form and will determine whether the two sets of graphical data are characteristic of the same crystalline form or of two different crystalline forms. Thus, crystalline forms of tafamidis and salts thereof referred to herein as being characterized by graphical data "shown in" a figure are understood to include any crystalline form of tafamidis and salts thereof characterized by graphical data having such minor variations as would be known to one of skill in the art compared to the figures herein.

[0035] A solid state form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of any other solid state (or polymorphic) form. As used herein in this context, the phrase "substantially free of any other form" shall be understood to mean that the solid state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other form of the subject compound as measured, for example, by PXRD. Thus, solid state forms of tafamidis and tafamidis salts described herein as being substantially free of any other solid state forms will be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% (w / w) of the subject solid state forms of tafamidis and / or tafamidis salts. Thus, in some embodiments of the present disclosure, the described solid state forms of tafamidis and / or tafamidis salts may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other solid state forms of the same tafamidis and / or tafamidis salts.

[0036] As used herein, unless otherwise indicated, the PXRD peaks reported herein are those of CuK α line, λ=1.541874 Å. Also as used herein, unless otherwise stated, PXRD measurements are taken at 25° C.±3° C.

[0037] As used herein, the term "isolated" with respect to the solid state forms of tafamidis of the present disclosure corresponds to a solid state form of tafamidis that is physically separated from the reaction mixture in which it is formed.

[0038] An item, such as a reaction mixture, may be characterized herein as being at or capable of coming to "room temperature" (often abbreviated as "RT"). This means that the temperature of the item is close to or the same as the temperature of the space, such as the room or fume hood in which the item is placed. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. A process or step may be referred to herein as being carried out "overnight". This refers to a time period for the process or step that extends, for example, overnight, during which the process or step is not actually observed. This time period is about 8 to about 20 hours, or about 10 to about 18 hours, in embodiments about 16 hours.

[0039] The term "solvate" as used herein, and unless otherwise specified, refers to a crystalline form that incorporates a solvent into the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate can be present in either stoichiometric or non-stoichiometric amounts.

[0040] Crystalline hydrates, as evidenced by water analysis by Karl Fischer (KF) titration or by TGA analysis of the product, are believed to have formed as a result of water introduced from the atmosphere in which the material was processed, or by traces of water present in solvents in contact with the material, or by a combination of these factors.

[0041] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to herein as a number of "volumes" or "vol" or "V". For example, a material may be referred to as being suspended (or dissolved) in 10 volumes (or 10 vol or 10 V) of a solvent. In this context, this expression is understood to mean milliliters of solvent per gram of material suspended (or dissolved), so suspending (or dissolving) 5 grams of material in 10 volumes of a solvent would use an amount of 10 milliliters of solvent per gram of material suspended (or dissolved), or 50 mL of solvent in this example. In other contexts, the term "v / v" may be used to indicate the number of volumes of solvent added to a liquid mixture, based on the volume of that mixture. For example, adding methyl tert-butyl ether (MTBE) (1.5 v / v) to 100 ml of a reaction mixture indicates that 150 mL of MTBE has been added.

[0042] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

[0043] As used herein, crystalline form V of tafamidis refers to the crystalline form described in International Publication No. WO2020232325. In particular, crystalline form V of tafamidis, as used herein, can be characterized by a PXRD pattern having peaks at 6.0, 19.9, 20.6, 23.9, and 29.2 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form V of tafamidis may be characterized by a PXRD pattern having peaks at 6.0, 19.9, 20.6, 23.9 and 29.2 degrees 2-theta ± 0.2 degrees 2-theta, and also one, two, three or four additional peaks at 17.8, 25.8, 27.3 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta, particularly a PXRD pattern having peaks at 6.0, 17.8, 19.9, 20.6, 23.9, 25.8, 27.3, 29.2 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form V of tafamidis may be characterized by a PXRD pattern substantially as shown in Figure 3. Crystalline Form V of tafamidis is preferably anhydrous.

[0044] Alternatively or additionally, tafamidis Form V may alternatively or additionally be a solid state tafamidis having peaks at 171.5, 161.0, 149.1, 144.7, 131.0±0.2 ppm. 13 C NMR spectrum and / or solid state with absolute chemical shift differences of the following 62.1, 51.6, 39.6, 35.2, 21.5 ± 0.1 ppm from the reference peak at 109.5 ppm ± 0.2 ppm. 13 Tafamidis Form V may alternatively or additionally be characterized by a solid-state NMR spectrum substantially as shown in FIG. 13 The tafamidis crystalline form V as defined above, and preferably the anhydrous crystalline form V as defined above, can be used as a starting material for preparing tafamidis form Va.

[0045] As used herein, tafamidis methanol solvate is as defined in WO2020 / 232325 and can be prepared, for example, according to Example 15 of WO2020 / 232325. The tafamidis methanol solvate can be characterized by a PXRD pattern substantially as shown in Figure 2. Anhydrous tafamidis can be prepared by the methods described herein or by drying the tafamidis methanol solvate at elevated temperature in a vacuum oven.

[0046] The present disclosure provides a crystalline form of tafamidis, designated Form Va, which is characterized by an X-ray powder diffraction pattern with peaks at 13.3, 16.3, and 19.7 degrees 2-theta ± 0.2 degrees 2-theta. This crystalline form of tafamidis may be further characterized by an X-ray powder diffraction pattern with any one, two, three, four, or five additional peaks selected from 5.8, 9.5, 13.7, 20.0, and 28.8 degrees 2-theta ± 0.2 degrees 2-theta. In embodiments, this crystalline form of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, and 28.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0047] Alternatively, crystalline form Va of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta, and may be further characterized by an X-ray powder diffraction pattern with one, two, three, four, five or six additional peaks selected from 23.3, 23.4, 23.7, 25.1 and 26.6 degrees 2-theta ± 0.2 degrees 2-theta. In embodiments, tafamidis crystalline form Va may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, 23.3, 23.4, 23.7, 25.1, and 26.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Alternatively, the crystalline form of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 13.3, 16.3, and 19.7 degrees 2-theta ± 0.1 degrees 2-theta. The crystalline form of tafamidis may be further characterized by an X-ray powder diffraction pattern with any one, two, three, four, or five additional peaks selected from 5.8, 9.5, 13.7, 20.0, and 28.8 degrees 2-theta ± 0.1 degrees 2-theta. In embodiments, the crystalline form of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, and 28.8 degrees 2-theta ± 0.1 degrees 2-theta.

[0049] Alternatively, crystalline form Va of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0 and 28.8 degrees 2-theta ± 0.1 degrees 2-theta, and may be further characterized by an X-ray powder diffraction pattern with one, two, three, four, five or six additional peaks selected from 23.3, 23.4, 23.7, 25.1 and 26.6 degrees 2-theta ± 0.1 degrees 2-theta. In embodiments, crystalline form Va of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, 23.3, 23.4, 23.7, 25.1, and 26.6 degrees 2-theta ± 0.1 degrees 2-theta. Alternatively, the crystalline form of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 13.3, 16.3, and 19.7 degrees 2-theta. This crystalline form of tafamidis may be further characterized by an X-ray powder diffraction pattern with any one, two, three, four, or five additional peaks selected from 5.8, 9.5, 13.7, 20.0, and 28.8 degrees 2-theta. In embodiments, the crystalline form of tafamidis may be characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0 and 28.8 degrees 2-theta.

[0050] Alternatively, crystalline Form Va of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, and 28.8 degrees 2-theta, and may be further characterized by an X-ray powder diffraction pattern with one, two, three, four, five, or six additional peaks selected from 23.3, 23.4, 23.7, 25.1, and 26.6 degrees 2-theta. In embodiments, crystalline Form Va of tafamidis may be characterized by an X-ray powder diffraction pattern with peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, 23.3, 23.4, 23.7, 25.1, and 26.6 degrees 2-theta.

[0051] In any aspect or embodiment, the most intense peak of crystalline form Va is at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) degrees 2-theta, or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) degrees 2-theta. In any aspect or embodiment, the peak at 5.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 15-60% relative to the most intense peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 9.5 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 2 to 10% relative to the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 4 to 20% relative to the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, if the peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) is the most intense peak (100%), then the peak at 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 50% to 100% (up to and including) of the most intense peak. In any aspect or embodiment, the peak at 16.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 10 to 40% of the intensity of the most intense peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).In any aspect or embodiment, the peak at 19.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity between 10 and 40% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, if the peak at 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) is the strongest peak (100%), then the peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity between 60% and 100% (not including the upper limit) of the strongest peak. In any aspect or embodiment, the peak at 23.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4 to 20% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.4 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4 to 30% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4 to 25% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 25.1 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4 to 20% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).In any aspect or embodiment, the peak at 26.6 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4 to 20% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 28.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 2 to 10% of the strongest peak at either 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) or 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).

[0052] In any aspect or embodiment, the peak at 5.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 39±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 9.5 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 4±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 9±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 82±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 16.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 23±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 19.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 25±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 11±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.4 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 12±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).In any aspect or embodiment, the peak at 23.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 13±10% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 25.1 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 10±10% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 26.6 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 9±10% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 28.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4±10% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).

[0053] In any aspect or embodiment, the peak at 5.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 39±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 9.5 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 4±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has an intensity of 9±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 82 ± 5% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 16.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 23 ± 5% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 19.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 25 ± 5% of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 11 ±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.4 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 12 ±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).In any aspect or embodiment, the peak at 23.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 13±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 25.1 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 10±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 26.6 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 9±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 28.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4±5% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).

[0054] In any aspect or embodiment, the peak at 5.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has 39% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 9.5 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has 4% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta), if present, has 9% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 13.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 82% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 16.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 23% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 19.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 25% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.3 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 115% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 23.4 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 12% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).In any aspect or embodiment, the peak at 23.7 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 13% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 25.1 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 10% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 26.6 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has 9% of the intensity of the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta). In any aspect or embodiment, the peak at 28.8 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta) has an intensity of 4% relative to the strongest peak at 20.0 (optionally ±0.2 degrees 2-theta or ±0.1 degrees 2-theta).

[0055] In any aspect or embodiment, tafamidis crystalline form Va is characterized by an XRPD pattern having the following 2-theta values ​​and relative intensities:

[0056] [Table 1]

[0057] Alternatively or in addition to any of the above embodiments, tafamidis crystalline form Va may be a solid-state crystalline form having peaks at 161.8, 145.3, 132.5, 126.0, 120.3±0.2 ppm. 13 C NMR spectrum and / or solid state with chemical shift differences of 91.8, 75.3, 62.5, 56.0, and 50.3 ± 0.1 ppm between the reference peak at 70.0 ± 0.2 ppm and the reference peak at 70.0 ± 0.2 ppm. 13Alternatively or in addition to any of the above embodiments, crystalline form Va of tafamidis may be characterized by a solid-state NMR spectrum having peaks at 34.6, 62.4, 70.0, 73.4, 110.1, 120.3, 124.0, 124.8, 126.0, 127.7, 132.56, 136.7, 145.3, 149.3, 161.8, and 172.3±0.2 ppm. 13 C NMR spectrum or solid state substantially as shown in FIG. 13 It may be characterized by C NMR spectrum.

[0058] In any aspect or embodiment, tafamidis crystalline form Va is characterized by an XRPD pattern substantially as shown in FIG.

[0059] In any aspect or embodiment, tafamidis crystalline form Va may be a hydrate.

[0060] In any aspect or embodiment, tafamidis crystalline form Va may contain about 1% to about 8% (w / w) water, about 2% to about 7% (w / w) water, about 2% to about 7.5% (w / w) water, about 3% to about 7% (w / w) water, about 5% to about 6.5% (w / w) water, about 5.5% to about 6% (w / w) water, about 1% to about 6% (w / w), about 2% to about 6% (w / w), about 3% to about 6% (w / w), about 4% to about 6% (w / w), about 5% to about 6% (w / w), about 5.5% to about 6% (w / w), or about 6% (w / w) water.

[0061] In any aspect or embodiment, crystalline form Va of tafamidis may be substantially free of any other crystalline form of tafamidis.

[0062] In any aspect or embodiment, crystalline form Va of tafamidis may contain less than about 20% (w / w), less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w), or less than about 0% of any other crystalline form of tafamidis, preferably as measured by XRPD.

[0063] In any aspect or embodiment, crystalline Form Va of tafamidis may be substantially free of any non-crystalline forms of tafamidis.

[0064] In any aspect or embodiment, crystalline Form Va of tafamidis may contain less than about 20% (w / w), less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w), or about 0% of any amorphous form of tafamidis, preferably as measured by XRPD.

[0065] In any aspect or embodiment, tafamidis crystalline form Va may contain less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w), or about 0% of any solvated organic solvent in the crystalline structure.

[0066] Further aspects of the disclosure include a method for preparing a crystalline form of tafamidis as defined in any aspect or embodiment, comprising crystallizing tafamidis from a mixture comprising polyethylene glycol (PEG). In particular, the method may comprise the steps of (a) providing a mixture comprising tafamidis in a solvent comprising polyethylene glycol, (b) stirring the mixture, and (c) optionally isolating the solid. The mixture may be a slurry. The starting material is preferably tafamidis form V, most preferably anhydrous tafamidis form V. The starting material for the method according to any aspect or embodiment may be characterized by a PXRD pattern having peaks at 6.0, 19.9, 20.6, 23.9, and 29.2 degrees 2-theta ± 0.2 degrees 2-theta, or a PXRD pattern having peaks at 6.0, 19.9, 20.6, 23.9 and 29.2 degrees 2-theta ± 0.2 degrees 2-theta and also one, two, three or four additional peaks at 17.8, 25.8, 27.3 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta, or alternatively, a PXRD pattern having peaks at 6.0, 17.8, 19.9, 20.6, 23.9, 25.8, 27.3, 29.2 and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] In any aspect or embodiment of this method, the starting material may alternatively or additionally comprise a solid state chromatographic method having peaks at 171.5, 161.0, 149.1, 144.7, 131.0±0.2 ppm. 13 C NMR spectrum and / or solid state with absolute chemical shift differences of 62.1, 51.6, 39.6, 35.2, 21.5 ± 0.1 ppm from the reference peak at 109.5 ppm ± 0.2 ppm. 13 C NMR spectrum or solid state substantially as shown in FIG. 13 It may be characterized by C NMR spectrum.

[0068] According to any aspect or embodiment of the method of the present invention, the polyethylene glycol may be PEG-400 or PEG-300 or PEG-200. The solvent may further comprise water. The volume ratio of polyethylene glycol to water may be about 70:30 to about 30:70, about 80:20 to about 20:80, about 90:10 to about 99:1, about 90:10 to about 99.8:0.2, about 90:10 to about 99.5:0.5, about 92:8 to about 99:1, about 92:10 to about 98:2, about 94:6 to about 98:2, or about 95:5.

[0069] According to any aspect or embodiment of the method of the present invention, the mixture may be stirred at a temperature of about 10° C. to about 45° C., about 15° C. to about 40° C., about 18° C. to about 30° C., or about 20° C. to about 25° C. Optionally, the mixture may be stirred for about 2 hours to about 72 hours, about 5 hours to about 8 hours to about 36 hours, about 12 hours to about 30 hours, or about 14 hours to about 28 hours.

[0070] According to any aspect or embodiment of the method of the invention, tafamidis form Va may be isolated, preferably by filtration, centrifugation or decantation, preferably by filtration.

[0071] According to any aspect or embodiment, the method may further comprise combining the product with at least one pharma- ceutically acceptable excipient to provide a pharmaceutical formulation, preferably the formulation is a tablet or capsule.

[0072] The present disclosure further encompasses the use of crystalline form V of tafamidis described above as a starting material for preparing a crystalline hydrate of tafamidis.

[0073] The present disclosure further encompasses the use of tafamidis crystalline form V as defined above as a starting material for preparing tafamidis crystalline form Va. Tafamidis crystalline form Va may be defined by any aspect or embodiment of the present disclosure.

[0074] The present disclosure encompasses products obtainable by any of the processes disclosed herein.

[0075] The present disclosure further encompasses a pharmaceutical composition comprising crystalline Form Va as defined in any aspect or embodiment herein and at least one pharma- ceutically acceptable excipient, which may be selected from one or more of a solubilizer, a surfactant, and an emulsifier.

[0076] The present disclosure further encompasses a pharmaceutical composition comprising crystalline Form Va as defined in any aspect or embodiment herein and a pharmaceutical excipient, wherein the excipient comprises polyethylene glycol, preferably PEG-400 or PEG-300 or PEG-200, more preferably PEG-400.

[0077] Optionally, the pharmaceutical composition may comprise at least one non-ionic surfactant, preferably a hydrophilic non-ionic surfactant, in particular an ethoxylated sorbitan ester, more particularly a polyoxyethylene sorbitan ester, preferably a polysorbate selected from polysorbate 20, polysorbate 60 and polysorbate 80, most preferably polysorbate 20 or polysorbate 80. Optionally, the pharmaceutical composition may comprise a non-ionic emulsifier, preferably a lipophilic non-ionic emulsifier, in particular a sorbitan fatty acid ester, more preferably sorbitan monostearate or sorbitan monooleate, preferably sorbitan monooleate. Optionally, the pharmaceutical composition may comprise polyvinylpyrrolidone, preferably having a molecular weight of between about 45 kDa and about 3000 kDa, between about 60 kDa and about 2000 kDa, between about 80 kDa and about 180 kDa, or between about 100 kDa and about 150 kDa.

[0078] The present disclosure further encompasses the use of the crystalline product as described in any aspect or embodiment of the present disclosure for preparing a pharmaceutical composition and / or a pharmaceutical formulation, preferably, the pharmaceutical formulation is a tablet or capsule, more preferably a capsule.

[0079] A pharmaceutical composition of the present disclosure can be prepared by combining a crystalline product according to any aspect or embodiment of the present disclosure with at least one pharma- ceutically acceptable excipient, which may be as described in any aspect or embodiment disclosed herein.

[0080] The present disclosure encompasses a crystalline product as described in any embodiment or aspect of the disclosure, or a pharmaceutical composition as described in any aspect or embodiment of the disclosure, for use as a medicament.

[0081] The present disclosure encompasses the crystalline product as described in any embodiment or aspect of the present disclosure, or the pharmaceutical composition as described in any aspect or embodiment of the present disclosure, for use in the treatment of transthyretin-mediated amyloidosis, preferably in adult patients with familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloidosis cardiomyopathy, or stage 1 symptomatic polyneuropathy.

[0082] Also provided is a method of treating transthyretin-mediated amyloidosis, preferably for use in treating transthyretin amyloidosis in adult patients with familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloidosis cardiomyopathy, or stage 1 symptomatic polyneuropathy, comprising administering to a subject in need of said treatment a therapeutically effective amount of a crystalline product as described in any aspect or embodiment disclosed herein, or a pharmaceutical composition as described in any aspect or embodiment disclosed herein.

[0083] There is further provided a use of a crystalline product as described in any aspect or embodiment herein in the preparation of another solid state form of tafamidis, a tafamidis solvate, or a tafamidis salt.

[0084] The present disclosure further provides a method of preparing a solid state form of tafamidis, a tafamidis solvate, or a tafamidis salt, comprising preparing a crystalline product according to any aspect or embodiment of the present disclosure, and converting the crystalline product to another solid state form thereof.

[0085] In any aspect or embodiment of the disclosure, the crystalline form Va of tafamidis described herein may be polymorphically pure or may be substantially free of any other solid state forms of tafamidis. In any aspect or embodiment of the disclosure, the crystalline form Va of tafamidis may contain about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, about 0.5% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other solid state forms of tafamidis, preferably as measured by XRPD. Thus, the crystalline form Va of tafamidis disclosed herein may be substantially free of any other solid state forms of tafamidis, and may contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% tafamidis form Va.

[0086] The present disclosure also provides for the use of a crystalline form of tafamidis according to any of the disclosed embodiments or aspects to prepare other solid state forms of tafamidis, tafamidis salts and solid state forms thereof.

[0087] The present disclosure further encompasses methods of preparing other solid state forms of tafamidis, or solid state forms of tafamidis, and other tafamidis salts or solid state forms thereof. The methods include preparing a solid state form of the present disclosure and converting it to another solid state form of tafamidis. Alternatively, the methods include preparing a solid state form of the present disclosure and converting it to a tafamidis salt. The conversion can be, for example, by dissolving the resulting tafamidis in a suitable base, such as meglumine, an alkali / alkaline earth metal base, such as potassium, sodium, calcium, magnesium, etc., ammonia, or an alkylamine (in embodiments, C 1~6 The reaction may be carried out by a process comprising reacting with an alkyl amine (mono-, di- or trialkylamine), in an embodiment, the alkali / alkaline earth metal base is selected from the group consisting of potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, calcium hydroxide or magnesium hydroxide.

[0088] In another embodiment, the disclosure encompasses the solid state forms of tafamidis described above for use in the preparation of pharmaceutical compositions and / or pharmaceutical formulations in embodiments for the treatment of transthyretin-mediated amyloidosis. In embodiments, the disclosure encompasses the use of the solid state forms of tafamidis described above for the preparation of pharmaceutical compositions comprising tafamidis or a salt thereof.

[0089] In another embodiment, the disclosure encompasses the use of a solid state form of tafamidis as described above for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, in embodiments an oral formulation, such as a tablet or capsule. In an embodiment, the disclosure encompasses the use of a solid state form of tafamidis as described above for the preparation of a pharmaceutical composition or pharmaceutical formulation, in embodiments an oral formulation in the form of a dispersion comprising tafamidis or a salt thereof.

[0090] The present disclosure further provides a pharmaceutical composition comprising a solid state form of tafamidis according to the present disclosure.

[0091] In yet another embodiment, the present disclosure encompasses a pharmaceutical formulation comprising a solid state form of tafamidis described herein and at least one pharma- ceutically acceptable excipient.

[0092] In addition to the active ingredients, the pharmaceutical formulations of the present disclosure may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0093] Diluents can increase the bulk of a solid pharmaceutical composition and make a pharmaceutical dosage form containing the composition easier for patients and caregivers to handle.Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microcellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0094] Solid pharmaceutical compositions that are compacted into dosage forms such as tablets can contain excipients whose function includes helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include gum arabic, alginic acid, carbomers (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0095] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition, which includes alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0096] Glidants can be added to increase the flowability of a non-compacted solid composition and improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0097] When a dosage form such as a tablet is made by compacting a powder composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surface of the punch and die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0098] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0099] Any pharma- ceutically acceptable coloring agent may be used to dye solid and liquid compositions to improve their appearance and / or to facilitate patient identification of the product and unit dosage level.

[0100] In liquid pharmaceutical compositions of the present disclosure, the active ingredient and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0101] Liquid pharmaceutical compositions may contain emulsifiers to disperse active ingredients or other excipients that are insoluble in the liquid carrier uniformly throughout the composition. Emulsifiers that may be useful in the liquid compositions of the present disclosure include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0102] The liquid pharmaceutical compositions of the present disclosure may also contain thickening agents to improve the mouthfeel of the product and / or coat the lining of the digestive tract. Such agents include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[0103] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve taste.

[0104] Preservatives and chelating agents, such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid, may be added at levels safe for consumption to improve storage stability.

[0105] According to the present disclosure, the liquid composition may also contain a buffering agent, such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate, etc. The selection of excipients and the amounts to be used can be readily determined by the formulation scientist based on experience and consideration of standard procedures and references in the field.

[0106] The solid compositions of the present disclosure include powders, granules, aggregates and compacted compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), inhaled and ophthalmic administration. The optimal administration in any given case will depend on the nature and severity of the condition being treated, but in embodiments, the route of administration is oral. Dosages can be conveniently provided in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.

[0107] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

[0108] The dosage form of the present disclosure may be a capsule containing the composition, in embodiments a powdered or granulated solid composition of the present disclosure within either a hard or soft shell. The shell may be made from gelatin and may optionally contain plasticizers such as glycerin and sorbitol, as well as opacifying agents or colorants.

[0109] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0110] Compositions for tableting or capsule filling can be prepared by wet granulation, in which some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, in embodiments water, which causes the powders to clump together into granules. The granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules can then be compressed into tablets, or other excipients such as glidants and / or lubricants can be added prior to tableting.

[0111] Tablet compositions can be prepared conventionally by dry blending. For example, the blended composition of active ingredients and excipients can be compacted into a slug or a sheet, and then milled into compacted granules. The compacted granules can then be compressed into tablets.

[0112] As an alternative to dry granulation, blended compositions can be directly compressed into compacted dosage forms using direct compression technology. Direct compression produces more uniform tablets without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skill in working on a particular formulation of direct compression tableting.

[0113] Capsule fillings of the present disclosure can include any of the above blends and granules described with respect to tableting, but which are not subjected to a final tableting step.

[0114] Pharmaceutical formulations of tafamidis may be formulated for administration to mammals, in embodiments humans. Tafamidis may be formulated, for example, as a viscous liquid solution or suspension, in embodiments a clear solution, for injection. The formulation may contain one or more solvents. A suitable solvent may be selected taking into consideration the physicochemical stability of the solvent at various pH levels, viscosity (which will allow for syringe use), flowability, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and castor oil USP. Additional substances may be added to the formulation, including, for example, buffers, solubilizers and antioxidants, among others, as disclosed in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition. The present disclosure encompasses a method of preparing said formulations of tafamidis by combining at least one of the above solid state forms with at least one pharma- ceutically acceptable excipient.

[0115] The solid state forms and pharmaceutical compositions or formulations of tafamidis described herein can be used as medicaments in embodiments for the treatment of transthyretin-mediated amyloidosis.

[0116] The present disclosure also provides a method of treating transthyretin mediated amyloidosis by administering a therapeutically effective amount of a solid state form of tafamidis of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, to a subject suffering from transthyretin mediated amyloidosis, in embodiments, wild-type or hereditary transthyretin mediated amyloidosis cardiomyopathy, or transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy, to delay peripheral neuropathy or in other treatment needs.

[0117] The present disclosure also provides a use of a solid state form of tafamidis of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, for the manufacture of a medicament for treating transthyretin mediated amyloidosis, in embodiments, in adult patients with wild-type or hereditary transthyretin mediated amyloidosis cardiomyopathy, or stage 1 symptomatic polyneuropathy, to delay peripheral neuropathy.

[0118] Although the present invention has been described in connection with certain preferred embodiments, other embodiments will become apparent to those skilled in the art from consideration of this specification. The present invention is further illustrated by reference to the following examples which detail the methods of preparing and using the compositions. It will be apparent to those skilled in the art that numerous modifications, both to materials and methods, can be made without departing from the scope of the present disclosure.

[0119] Analysis method Powder X-ray Diffraction Pattern ("PXRD") Method: The sample after powdering with a mortar and pestle is directly applied to a silicon plate holder. X-ray powder diffraction patterns were measured on a Philips X'Pert PRO X-ray powder diffractometer equipped with a Cu source = 1.541874 Å (angstroms) and an X'Celerator (2.022° 2θ) detector. Scanning parameters: angle range: 3-40 degrees, step size 0.0167, time per step 37 seconds, continuous scan. The measurement temperature was 25°C ± 3°C.

[0120] 13 C solid-state nuclear magnetic resonance ("ss-NMR" or 13 C solid-state NMR: 13 C CP / MAS and 1 H MAS NMR spectra were recorded at 16.4 T using a Bruker Avance NEO 700 SB NMR spectrometer (Karlsruhe, Germany, 2021) with a 3.2 mm probehead. Cross polarization was used. 13 C CP / MAS NMR spectra were acquired using a standard cross-polarization pulse scheme at a spin frequency of 18 kHz. 13 The C scale is glycine ( 13 C, 176.03 ppm) was used as the reference. EXAMPLES

[0121] Tafamidis can be prepared according to the procedures described in U.S. Patent No. 7,214,695. Tafamidis Form V can be prepared according to any of the procedures described in International Publication No. WO2020 / 232325.

[0122] Example 1 Preparation of tafamidis form Va 1 gram of Tafamidis Form V (anhydrous) was placed in a glass beaker. 10 ml of PEG-400 was added. The resulting slurry was mixed at room temperature for 24 hours using a magnetic stirrer and analyzed by XRPD. The XRPD pattern is shown in Figure 1.

[0123] Example 2 Preparation of tafamidis form Va 100 mg of tafamidis form V (anhydrous) was placed in a glass beaker. 1 ml of a PEG-400 / water mixture (95:5 volume ratio) was added. The resulting slurry was mixed at room temperature using a magnetic stirrer for 16 hours and analyzed by XRPD. It corresponds to form Va.

[0124] Example 3 Preparation of tafamidis form V Tafamidis (1.0 gram, 3.25 mmol) was dissolved in a solvent mixture of toluene / N-methyl-2-pyrrolidone (NMP) (15V; 15% NMP) by heating to 70-75°C. The solution was naturally cooled to 30°C and cold methanol (30V) was added slowly at 0-5°C. Crystallization was instantaneous. The resulting suspension was stirred at 0-5°C for 2 hours. The resulting crystals were isolated by vacuum filtration. The resulting solid was washed with methanol (10V) and dried in a vacuum oven at 80°C and 20 mbar for 6 hours (0.9 grams of crystals were obtained, chromatographic purity 99%). The resulting solid was analyzed by XRPD. Tafamidis form V (anhydrous) was obtained.

[0125] Example 4 Preparation of tafamidis form V Tafamidis (498 mg) was dissolved in THF (28 ml) at room temperature. Anti-solvent (methanol) was cooled to 0° C. (ice bath) and added dropwise to the solution (92 ml). Crystallization was instantaneous. The suspension was stirred for 1 h and then isolated by vacuum filtration (427 mg). The solid obtained was washed with the solvent mixture THF:methanol (1:4). The solid obtained was analyzed by XRD. Tafamidis form V (methanol solvate) was obtained. The solid obtained was heated at 80° C. in a vacuum oven for 2 h. The solid obtained was analyzed by XRPD. Tafamidis form V (anhydrous) was obtained.

[0126] Example 5 Preparation of tafamidis form V 4-(3,5-Dichlorobenzamido)-3-hydroxybenzoic acid (25.00 grams, 76.7 mmol), toluene (281.3 ml), N-methyl-pyrrolidone (93.8 ml) and methanesulfonic acid (14.9 ml, 230.0 mmol; 3.0 eq.) were charged to a reactor at 20-25° C. The reaction mixture was heated to reflux temperature (117-119° C.) and stirred until the reaction was complete (about 15 hours). The reaction mixture was then cooled to 100-110° C. and triethylamine was added (32 ml, 230.0 mmol; 3.0 eq.) to adjust the pH to 1.4-1.8. The reaction mixture was added dropwise to cold methanol (750 ml, pre-cooled to 0-5° C.) over a period of 1 hour. Crystallization occurred. The suspension was stirred at 0-5° C. for an additional 3 hours. The crystals of tafamidis methanol solvate were filtered off on a Buchner funnel and washed with methanol (2 x 100 ml). The wet crystals were suspended in fresh methanol (375 ml) at 20-25°C for 3-6 hours. The crystals of tafamidis methanol solvate were filtered off on a Buchner funnel, washed with methanol (2 x 50 ml) and dried at 80°C and 20 mbar for 10 hours. White crystals of tafamidis form V (anhydrous) were obtained.

[0127] Example 6 Preparation of tafamidis form Va Tafamidis form V (1 gram) was slurried in PEG-400 (10 ml) at 25° C. for 24 hours and after 7 days. The resulting solids were confirmed to be tafamidis form Va by XRPD, respectively. The suspension was centrifuged and the solids were filtered under vacuum and washed with a portion of methanol / water (90 / 10 v / v ratio). The resulting solids were confirmed to be tafamidis form Va by XRPD, respectively.

[0128] Example 7 Stability of Form Va 50 mg samples of Form Va and Form 4 were placed in glass vials. 1 ml of PEG400 was added at room temperature. The slurries were mixed using a magnetic stirrer, respectively. The resulting samples were analyzed by XRPD after 2 hours and 7 days. As shown in Figure 5, Form 4 rapidly converts to Form 1 within 2 hours, while Form Va is stable for at least 7 days.

Claims

1. A crystal of tafamidis having a crystalline form designated Form Va, (i) an X-ray powder diffraction pattern having peaks at 13.3, 16.3, and 19.7 degrees 2-theta ± 0.2 degrees 2-theta; (ii) solid state with characteristic peaks at 161.8, 145.3, 132.5, 126.0, and 120.3 ± 0.2 ppm 13 C NMR spectrum, or (iii) solid-state peaks with chemical shift differences of 91.8, 75.3, 62.5, 56.0, and 50.3 ± 0.1 ppm relative to the reference peak at 70.0 ± 0.2 ppm, respectively; 13 C NMR spectrum A crystal of tafamidis characterized by at least one of the following:

2. A crystal of tafamidis described in claim 1, further characterized by an X-ray powder diffraction pattern having at least one additional peak at 5.8, 9.5, 13.7, 20.0, or 28.8 degrees 2-theta ± 0.2 degrees 2-theta.

3. 2. The tafamidis crystal of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta.

4. 4. The tafamidis crystal of claim 3, further characterized by an X-ray powder diffraction pattern having one, two, three, four or five additional peaks selected from 23.3, 23.4, 23.7, 25.1 and 26.6 degrees 2-theta ± 0.2 degrees 2-theta.

5. 5. A crystal of tafamidis according to claim 4, characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, 23.3, 23.4, 23.7, 25.1 and 26.6 degrees 2-theta ± 0.2 degrees 2-theta.

6. The tafamidis crystal of claim 1, which is a hydrate.

7. 7. The tafamidis crystal of claim 6, comprising about 1% to about 8% (w / w) water, about 2% to about 7% (w / w) water, about 2% to about 7.5% (w / w) water, about 3% to about 7% (w / w) water, about 5% to about 6.5% (w / w) water, about 5.5% to about 6% (w / w) water, about 1% to about 6% (w / w), about 2% to about 6% (w / w), about 3% to about 6% (w / w), about 4% to about 6% (w / w), about 5% to about 6% (w / w), about 5.5% to about 6% (w / w), or about 6% (w / w) water.

8. 2. The crystals of tafamidis of claim 1, which are substantially free of any other crystalline forms of tafamidis.

9. A crystal of tafamidis described in claim 8, containing less than about 20% (w / w), less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w) or less or about 0% of any other crystalline form of tafamidis.

10. The crystal of tafamidis according to claim 1, which is substantially free of any amorphous form of tafamidis and contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, about 0.5% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other amorphous form of tafamidis.

11. 11. The tafamidis crystal of claim 10, which contains less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), less than about 0.5% (w / w), less than about 0.2% (w / w), less than about 0.1% (w / w), or about 0% of any solvated organic solvent in the crystalline structure.

12. 12. A method for preparing crystals of tafamidis according to any one of claims 1 to 11, comprising the step of crystallizing tafamidis from a mixture containing polyethylene glycol (PEG).

13. (a) providing a mixture comprising tafamidis in a solvent comprising polyethylene glycol; (b) stirring the mixture; and (c) optionally isolating the solid 13. The method of claim 12, comprising:

14. The method of claim 12, wherein the mixture is a slurry.

15. 13. The method of claim 12, wherein the starting material is tafamidis form V.

16. 13. The method of claim 12, wherein the starting material is anhydrous form V of tafamidis.

17. 13. The method of claim 12, wherein the starting material is characterized by an X-ray powder diffraction pattern having peaks at 6.0, 19.9, 20.6, 23.9, and 29.2 degrees two-theta ± 0.2 degrees two-theta.

18. 18. The method of claim 17, wherein the starting material is characterized by an X-ray powder diffraction pattern having peaks at 6.0, 19.9, 20.6, 23.9, and 29.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks at 17.8, 25.8, 27.3, and 31.1 degrees 2-theta ± 0.2 degrees 2-theta.

19. wherein said tafamidis Form V has peaks at 171.5, 161.0, 149.1, 144.7, and 131.0±0.2 ppm in a solid state 13 C NMR spectrum and / or solid state NMR spectra having absolute chemical shift differences of the following peaks from the reference peak at 109.5 ppm ± 0.2 ppm: 62.1, 51.6, 39.6, 35.2, 21.5 ± 0.1 ppm 13 13. The method of claim 12 characterized by a C NMR spectrum.

20. 13. The method of claim 12, wherein the polyethylene glycol is PEG-400 or PEG-300 or PEG-200.

21. The method of claim 13 , wherein the solvent further comprises water.

22. 22. The method of claim 21, wherein the volume ratio of polyethylene glycol to water is about 70:30 to about 30:70, about 80:20 to about 20:80, about 90:10 to about 99:1, about 90:10 to about 99.8:0.2, about 90:10 to about 99.5:0.5, about 92:8 to about 99:1, about 92:10 to about 98:2, about 94:6 to about 98:2, or about 95:

5.

23. 13. The method of claim 12, wherein the mixture is stirred at a temperature of about 10°C to about 45°C, about 15°C to about 40°C, about 18°C ​​to about 30°C, or about 20°C to about 25°C.

24. 13. The method of claim 12, wherein the mixture is stirred for about 2 hours to about 72 hours, about 5 hours to about 8 hours to about 36 hours, about 12 hours to about 30 hours, or about 14 hours to about 28 hours.

25. 13. The method of claim 12, wherein tafamidis form Va is isolated using at least one of filtration, centrifugation, or decantation.

26. A pharmaceutical composition comprising the crystal of any one of claims 1 to 11 and at least one pharmaceutically acceptable excipient.

27. 27. The pharmaceutical composition of claim 26, wherein the at least one pharmaceutically acceptable excipient is one of a solubilizer, a surfactant, or an emulsifier.

28. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutical excipient comprises polyethylene glycol, including at least one of PEG-400, PEG-300, or PEG-200.

29. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable excipient comprises a hydrophilic non-ionic surfactant, an ethoxylated sorbitan ester, a polyoxyethylene sorbitan ester, or a non-ionic surfactant comprising at least one polysorbate selected from polysorbate 20, polysorbate 60, and polysorbate 80.

30. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable excipient comprises a non-ionic emulsifier comprising at least one of a lipophilic non-ionic emulsifier, a sorbitan fatty acid ester, sorbitan monostearate, or a sorbitan monooleate non-ionic emulsifier.

31. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable excipient comprises polyvinylpyrrolidone having a molecular weight between about 45 kDa and about 3000 kDa, between about 60 kDa and about 2000 kDa, between about 80 kDa and about 180 kDa, or between about 100 kDa and about 150 kDa.

32. 12. A method for preparing a pharmaceutical composition, comprising combining a crystal according to any one of claims 1 to 11 with at least one pharmaceutically acceptable excipient.

33. 27. The pharmaceutical composition of claim 26, for use in the treatment of at least one of transthyretin-mediated amyloidosis, familial amyloid polyneuropathy, wild-type or hereditary transthyretin-mediated amyloidosis cardiomyopathy, or transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy.

34. 12. A method for preparing a solid state form of tafamidis, a tafamidis solvate, or a tafamidis salt, comprising preparing a crystal according to any one of claims 1 to 11, and converting said crystal to another solid state form thereof.

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