Solid forms of tafamidis methyl ethyl ketone solvate and processes for their manufacture

Abstract

The present invention relates to crystalline solid forms of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of from about 0.6 wt% to about 7 wt% with respect to the total weight of the crystalline solid form. The invention also relates to the method of preparation of these crystalline solid forms, including intermediate compound of formula (II), to pharmaceutical compositions comprising said solid forms as well as their medical uses.

Description

[0001] SOLID FORMS OF TAFAMIDIS METHYL ETHYL KETONE SOLVATE AND PROCESSES FOR THEIR MANUFACTURE FIELD OF THE INVENTION

[0002] The invention relates to crystalline solid forms of tafamidis methyl ethyl ketone solvate, their method of preparation, including intermediate compound of formula (II), pharmaceutical compositions comprising them as well as their medical uses.

[0003] BACKGROUND OF THE INVENTION

[0004] 6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) (i.e. tafamidis) was first disclosed in European patent EP 1 587821 Bl and in WO 2004 / 056315 A2.

[0005]

[0006] Tafamidis is a specific stabilizer of transthyretin (TTR). Tafamidis binds to TTR at the thyroxine binding sites and inhibits TTR tetramer dissociation, the rate limiting step in the amyloidogenic process. By stabilising the tetrameric native state of TTR, tafamidis increases the activation barrier associated with tetramer dissociation and therefore mimics the tetrameric stabilisation effect observed with naturally occurring protective transsuppressor variants. The result disrupts the amyloid cascade and fibril formation and interrupts disease progression.

[0007] In November 2011, tafamidis was approved by the European Medicines Agency (EMA), for the treatment of transthyretin amyloidosis (ATTR) in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment. In 2016, the first European consensus on transthyretin familial amyloid polyneuropathy recommendedtafamidis as the standard of care in stage 1 ATTR-PN (polyneuropathy). In 2019, the FDA granted tafamidis priority review, fast track, and breakthrough therapy designations to treat the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM).

[0008] Tafamidis is categorized as a class IV drug substance (low solubility and low permeability) according to the Biopharmaceutics Classification System (BCS). Class IV drugs are the most challenging drugs for formulation.

[0009] Several solid forms and solvates of tafamidis have been reported (WO 2016 / 038500, WO 2019 / 175263, WO 2020 / 232325, WO 2021 / 001858, WO 2021 / 152623, IN 202041049413, WO 2022 / 009221, WO 2022 / 084790, WO 2022 / 107166, WO 2022 / 185333, WO 2022 / 229026, WO 2022 / 239020, WO 2022 / 264072, WO 2023 / 091534, and WO 2024 / 084362).

[0010] Nevertheless, there remains a need for new solid forms of tafamidis showing good stability, apparent solubility, dissolution rate, mechanical properties, bioavailability and / or that can be obtained by processes which are favorable from an industrial point of view.

[0011] SUMMARY OF THE INVENTION

[0012] The inventors have unexpectedly found new crystalline solid forms of tafamidis, in particular crystalline solid forms of tafamidis methyl ethyl ketone solvates, which have good stability, apparent solubility, dissolution rate, mechanical properties, bioavailability and / or that can be obtained by processes which are favorable from an industrial point of view. Solvates of tafamidis with methyl ethyl ketone have not been disclosed in the prior art.

[0013] Thus, the first aspect of the invention relates to a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of from about 0.6 wt% to about 7 wt% with respect to the total weight of the crystalline solid form. Advantageously, the methyl ethyl ketone content from about 7 wt% is consideredtoxicologically acceptable according to ICH guideline Q3C (R6) on impurities, support document 3 on class 3 solvents for use in the manufacture of finished products.

[0014] In second and third aspects, the present invention relates to processes for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect.

[0015] The second aspect is directed to a process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect which comprises: a) suspending tafamidis, e.g. in solid Form 1, in tetrahydrofuran in a weight / volume ratio of from 10-40 mg of tafamidis per each mL of tetrahydrofuran;

[0016] b) heating the suspension of step a) at 70 °C to 80 °C until tafamidis is dissolved, c) mixing the solution obtained in step b) with methyl ethyl ketone in a volume ratio of 2-5 mL of methyl ethyl ketone per each mL of solution of step b), and wherein the methyl ethyl ketone is at a temperature of from -5 °C to 5 °C, so that crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form is obtained;

[0017] d) isolating the solid obtained after step c);

[0018] e) optionally, slurrying the solid isolated in step d) in methyl ethyl ketone and tetrahydrofuran at a ratio of about 9:1 to obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form and isolating said solid; and

[0019] f) optionally, subjecting the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form obtained in step d) or in step e) to heating at 120 to 130 °C, preferably about 125 °C, for 40 to 80 minutes to obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form.The third aspect is directed to an alternative process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect which comprises:

[0020] i) providing a solution of tafamidis in a) THF or in b) a mixture of THF and not more than 7% w / w, preferably not more than 6% w / w, more preferably not more than 5% w / w of water with respect to the total weight of the THF / water mixture, wherein the ratio of THF to tafamidis is in the range of 7-13 liters of THF per mol of tafamidis;

[0021] ii) pouring the solution of step i) over methyl ethyl ketone (MEK) wherein the ratio of MEK to tafamidis is in the range of 22-40 liters of MEK per mol of tafamidis; iii) optionally stirring at -5 to 25 °C for at least 30 min; and

[0022] iv) separating the solid product resulting from steps ii) or iii) from the liquid media.

[0023] In a fourth aspect, the invention is directed to a pharmaceutical composition comprising the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect.

[0024] In a fifth aspect, the invention relates to the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect, or the pharmaceutical composition as defined in the fourth aspect, for use in medicine, in particular for use in the treatment and / or prevention of a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis.

[0025] In a sixth aspect, the invention is directed to the use of the crystalline solid form of tafamidis methyl ethyl ketone solvate according to the first aspect and optionally obtained according to any process described in the second or third aspects to prepare the crystalline solid form of tafamidis methyl ethyl ketone solvate wherein the methyl ethyl ketonecontent is about 0.6 wt% with respect to the total weight of the crystalline solid form by drying.

[0026] In an embodiment of the sixth aspect the drying process is carried out under vacuum and at a temperature from 90 to 130 °C, preferably the drying process is carried out under vacuum and at a temperature from 95 to 125 °C, more preferably the drying process is carried out under vacuum and at a temperature from 95 to 110 °C.

[0027] DESCRIPTION OF THE FIGURES

[0028] Figure 1 shows the XRPD (X-Ray powder diffraction) pattern of tafamidis methyl ethyl ketone solvate Form 16 as prepared in Example 1.

[0029] Figure 2 shows the DSC (differential scanning calorimetry) thermogram in the upper line and TGA (thermogravimetric analysis) weight loss curve in the lower line of tafamidis methyl ethyl ketone solvate Form 16 as prepared in Example 1.

[0030] Figure 3 shows the XRPD (X-Ray powder diffraction) pattern of tafamidis methyl ethyl ketone solvate Form 16’ as prepared in Example 7.

[0031] Figure 4 shows the DSC (differential scanning calorimetry) thermogram in the upper line and TGA (thermogravimetric analysis) weight loss curve in the lower line of tafamidis methyl ethyl ketone solvate Form 16’ as prepared in Example 7.

[0032] Figure 5 shows the XRPD (X-Ray powder diffraction) pattern of tafamidis methyl ethyl ketone solvate Form 16 as prepared in Example 3.

[0033] Figure 6 shows the XRPD (X-Ray powder diffraction) pattern of tafamidis methyl ethyl ketone solvate Form 16’ as prepared in Example 8.

[0034] DEFINITIONS

[0035] When describing the compounds and methods of the invention, the following terms have the following meanings, unless otherwise indicated.

[0036] The expressions “crystalline form” or “crystalline solid form” refer to a solid material wherein the atoms are arranged in a highly ordered microscopic structure, forming acrystal lattice that extends in all directions. In contrast, an “amorphous form” refers to a non-crystalline solid material in which the atoms are not organized in a definite lattice pattern, i.e. which possesses no long-range order.

[0037] The term “solvate” refers any form of the active compound according to the invention which has another molecule, which is a solvent, attached to it via non-covalent bonding. Solvates tend to form during the process of crystallization with the help of a solvent. The crystalline solids formed contain the molecules of solvent inside their crystal assembly (stoichiometrically or non-stoichiometrically). The solvent forming the solvate of the present invention is methyl ethyl ketone. In particular, the solvate of tafamidis with methyl ethyl ketone of the present invention is non-stoichiometric. In the present invention, the methyl ethyl ketone content in the solvate is from about 0.6 wt% to about 7 wt% with respect to the total weight of the solid solvate.

[0038] In the context of the present invention, the term “about” is to be interpreted as ±10% of the value it refers to, preferably ±5% of the value it refers to.

[0039] As used herein, “alkyl” means straight-chain or branched hydrocarbon chain radical containing no unsaturation having from 1 to 4 carbon atoms, represented as (Ci-C4)alkyl. Such alkyl groups may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0040] The onset temperature of the peaks in the DSC of the solid forms disclosed herein or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of the transition and the baseline during energy absorption (tangent to the curve).

[0041] The methyl ethyl ketone content of the solid solvate forms disclosed herein may be determined by TGA and / or 'H-NMR. By TGA, the weight loss observed at 85-200 °C is attributed to the loss of the methyl ethyl ketone content in the solvate. By 'H-NMR, the molar ratio is obtained by comparing the integral of a peak corresponding to methyl ethyl ketone divided by the number of protons corresponding to that signal, with the integral of a signal corresponding to a single proton of tafamidis, which may be converted to thecorresponding weight ratios taking into account the molecular weights of methyl ethyl ketone and tafamidis.

[0042] The terms “conventional isolation techniques” or “purification” as used herein refers to the process of rendering a product clean of foreign elements whereby a purified product can be obtained. The term industrial purification refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, distillation, centrifugation or crystallization.

[0043] The term “solvent extraction” refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component and may, therefore, separate said one component from at least a second component which is less miscible than said one component with said solvent.

[0044] The term “filtration” refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression filtrate refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression filter cake refers to residual solid material remaining on a feed side of a filtration element.

[0045] The term “evaporation” refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and / or temperature.

[0046] As used herein, the term “slurrying” refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.

[0047] The term “phase separation” refers to a solution or mixture having at least two physically distinct regions.The term “crystallization” refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound, optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as dissolving the compound in a solvent and precipitating it by addition of an “antisolvent” (i.e. a solvent in which the desired compound has low solubility or insolubility, and can be used to precipitate such compound by adding it to a solution in which the compound is dissolved).

[0048] The term “pharmaceutical composition”, as used herein, relates to a composition comprising at least a combination provided by the present invention together with a pharmaceutically acceptable excipient.

[0049] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable vehicle”, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable diluent”, used interchangeably herein, refer to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any conventional type. A pharmaceutically acceptable excipient is essentially non-toxic to recipients at the employed dosages and concentrations and is compatible with other ingredients of the formulation. The number and the nature of the pharmaceutically acceptable excipient depend on the desired administration form. The pharmaceutically acceptable excipient are known and may be prepared by methods well known in the art. Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0050] The term “prevention”, “preventing” or “prevent”, as used herein, relates to the administration of a combination according to the invention or of a medicament comprising said combination to a subject who has not been diagnosed as possibly having the disease, but who would normally be expected to develop said disease or be at increased risk for said disease. The prevention intends to avoid the appearance of said disease. The prevention may be complete (e.g. the total absence of a disease). The prevention may also be partial, such that for example the occurrence of a disease in asubject is less than that which would have occurred without the administration of the composition of the present invention. Prevention also refers to reduced susceptibility to a clinical condition.

[0051] The term “treatment”, as used herein, refers to any type of therapy, which is aimed at terminating or ameliorating a clinical condition as described herein. Thus, “treatment,” “treating,” and their equivalent terms refer to obtaining a desired pharmacologic or physiologic effect, covering any treatment of a pathological condition or disorder in a mammal, including a human. The effect may a partial or complete cure for a disorder and / or adverse effect attributable to the disorder.

[0052] DETAILED DESCRIPTION OF THE INVENTION

[0053] Solid forms

[0054] The first aspect of the present invention is directed to a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of from about 0.6 wt% to about 7 wt%, with respect to the total weight of the solid form.

[0055] An embodiment of the first aspect relates to a crystalline solid form of tafamidis methyl ethyl ketone solvate wherein the methyl ethyl ketone content is about 7 wt% and to a crystalline solid form of tafamidis methyl ethyl ketone solvate wherein the methyl ethyl ketone content is about 0.6 wt% with respect to the total weight of the crystalline solid form.

[0056] In another embodiment of the first aspect, the crystalline solid form of tafamidis methyl ethyl ketone solvate may contain methyl ethyl ketone in an amount of 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.9 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt% and 0.1 wt% with respect to the total weight of the crystalline solid form.

[0057] X-ray powder diffraction (XRPD) measurements of the solid forms disclosed herein may be performed using CuKa radiation ( = 1.541874 A), in particular, following the procedure described in the examples.Differential Scanning Calorimetry (DSC) of the solid forms disclosed herein may be carried out with a heating rate of 10 °C / min, in particular, following the procedure described in the examples.

[0058] Thermogravimetric analysis (TGA) of the solid forms disclosed herein may be carried out with a heating rate of 10 °C / min, in particular, following the procedure described in the examples.

[0059] The onset temperature of the peaks in the DSC of the solid forms disclosed herein or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of the transition and the baseline during energy absorption (tangent to the curve).

[0060] The methyl ethyl ketone content of the solid solvate forms disclosed herein may be determined by TGA and / or 'H-NMR. By TGA, the weight loss observed at 85-200 °C is attributed to the loss of the methyl ethyl ketone content in the solvate. By 'H-NMR, the molar ratio is obtained by comparing the integral of a peak corresponding to methyl ethyl ketone divided by the number of protons corresponding to that signal, with the integral of a signal corresponding to a single proton of tafamidis, which may be converted to the corresponding weight ratios taking into account the molecular weights of methyl ethyl ketone and tafamidis.

[0061] Tafamidis methyl ethyl ketone solvate Form 16

[0062] In one embodiment, the crystalline solid form of tafamidis methyl ethyl ketone solvate has a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form. This crystalline solid form is also named as Form 16.

[0063] In an embodiment, the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 19.7, and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.In an embodiment, the crystalline Form 16 is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 19.7, 23.6, 26.8 and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0064] In an embodiment, the crystalline Form 16 is further characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 9.5, 13.7, 19.7, 20.0, 23.6, 24.1, 26.8 and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0065] In an embodiment, the crystalline Form 16 is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 9.5, 13.7, 16.2, 19.7, 20.0, 23.6, 24.1, 24.3, 24.6, 24.8. 26.8 and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0066] In an embodiment, the crystalline Form 16 is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 6.7, 9.5, 13.7, 14.3, 19.7, 20.0, 23.6, 24.1, 26.8 and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0067] In an embodiment, the X-ray powder diffraction pattern of the crystalline Form 16 further comprises peaks at °29 values equal to 16.2, 24.3, 24.6, 24.8 and 25.0 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0068] In an embodiment, said crystalline Form 16 has an X-ray powder diffraction pattern comprises peaks at the °29 values provided in Table 1 below ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0069] In an embodiment, said crystalline Form 16 has an X-ray powder diffraction pattern further comprises peaks at the °29 values provided in Table 1 below ±0.2 °29 and having relative intensities (Rel. Int. [%]) as provided in Table 1 below ±10% of said values, wherein the X-ray diffraction is measured using a CuKa radiation.Table 1. X-ray powder reflections and intensities (normalized) of the crystalline Form 16 as prepared in Example 1. The value 29 [°] represents the diffraction angle in degrees, and the value Rel. Int. [%] represents the relative intensity. 29=(values) ± 0.2°; Rel. Int.=(values) ± 10%.

[0070]

[0071] In an embodiment, said crystalline Form 16 has an X-ray powder diffraction pattern substantially as depicted in Figure 1.

[0072] Table 2. X-ray powder reflections and intensities (normalized) of the crystalline Form 16 as prepared in Example 3. The value 29 [°] represents the diffraction angle in degrees, and the value Rel. Int. [%] represents the relative intensity. 29=(values) ± 0.2°; Rel. Int.=(values) ± 10%.

[0073]

[0074]

[0075] In an embodiment, said crystalline Form 16 has an X-ray powder diffraction pattern substantially as depicted in Figure 5.

[0076] In an embodiment, said crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 285 °C ±5 °C.

[0077] In a particular embodiment, said crystalline Form 16 has a differential scanning calorimetry (DSC) thermogram further comprising one or more, preferably all, of the following:

[0078] an endothermic peak with an onset at 98 °C ±5 °C;

[0079] a broad endotherm with an onset at 133 °C ±5 °C;

[0080] an endothermic peak with an onset at 168 °C ±5 °C; and

[0081] an exothermic peak with an onset at 173 °C ±5 °C.

[0082] In an embodiment, said crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight ofthe crystalline solid form (i.e. Form 16) has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2. When referring to the DSC thermogram of Figure 2, reference is made only to the part of the figure representing the DSC analysis and does not include the part of the figure representing the thermogravimetric analysis (TGA).

[0083] In a particular embodiment, said crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) has TGA weight loss curve with about a 7% weight loss between 85 °C ±5 °C and 190 °C ±5 °C.

[0084] In an embodiment, said crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) has a TGA weight loss curve substantially as depicted in Figure 2. When referring to the TGA weight loss curve of Figure 2, reference is made only to the part of the figure representing the TGA analysis and does not include the part of the figure representing the DSC analysis.

[0085] Tafamidis methyl ethyl ketone solvate Form 16’

[0086] In an embodiment, the crystalline solid form of tafamidis methyl ethyl ketone solvate has methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form. This crystalline solid form is also named Form 16’.

[0087] In an embodiment, the crystalline Form 16’ is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.9, 14.0 and 27.1±0.2 °20, wherein the X-ray diffraction is measured using a CuKa radiation.

[0088] In an embodiment, the crystalline Form 16’ is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °20 values equal to 5.9, 14.0, 16.5, 27.1 and 28.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.In an embodiment, the crystalline Form 16’ is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °20 values equal to 5.9, 14.0, 16.5, 19.9, 23.4, 24.1, 26.7, 27.1, 27.3 and 28.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0089] In an embodiment, the crystalline Form 16’ is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °20 values equal to 5.9, 14.0, 16.5, 19.9, 20.4, 23.4, 24.1, 25.6, 26.7, 27.1, 27.3 and 28.6 ±0.2 °20, wherein the X-ray diffraction is measured using a CuKa radiation.

[0090] In an embodiment, the X-ray powder diffraction pattern of the crystalline Form 16’ further comprises peaks at °29 values equal to 11.7, 17.0, 17.7, 19.3 and 24.8 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0091] In an embodiment, the X-ray powder diffraction pattern of the crystalline Form 16’ further comprises peaks at °29 values equal to 11.7, 17.0, 17.7, 19.3, 20.4, 24.8 and 25.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0092] In another embodiment, the crystalline Form 16’ is characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.9, 11.7, 14.0, 16.5, 17.0, 17.7, 19.3, 19.9, 23.4, 24.1, 24.8, 26.7, 27.1, 27.3 and 28.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0093] In particular, said crystalline Form 16’ has an X-ray powder diffraction pattern comprises peaks at the °29 values provided in Table 3 below ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

[0094] Even more preferably, said crystalline Form 16’ has an X-ray powder diffraction pattern further comprises peaks at the °29 values provided in Table 2 below ±0.2 °29 and having relative intensities (Rel. Int. [%]) as provided in Table 3 below ±10% of said values, wherein the X-ray diffraction is measured using a CuKa radiation.Table 3. X-ray powder reflections and intensities (normalized) of crystalline Form 16’ as prepared in Example 7. The value 29 [°] represents the diffraction angle in degrees, and the value Rel. Int. [%] represents the relative intensity. 29=(values) ± 0.2°; Rel. Int.=(values) ± 10%.

[0095]

[0096] In an embodiment, said crystalline Form 16’ has an X-ray powder diffraction pattern substantially as depicted in Figure 3

[0097] Table 4. X-ray powder reflections and intensities (normalized) of crystalline Form 16’ as prepared in Example 8. The value 29 [°] represents the diffraction angle in degrees, and the value Rel. Int. [%] represents the relative intensity. 29=(values) ± 0.2°; Rel. Int.=(values) ± 10%.

[0098]

[0099]

[0100] In an embodiment, said crystalline Form 16’ has an X-ray powder diffraction pattern substantially as depicted in Figure 6.

[0101] In an embodiment, said crystalline Form 16’ has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 286 °C ±5 °C.

[0102] In a particular embodiment, said crystalline Form 16’ has a differential scanning calorimetry (DSC) thermogram further comprising one or more, preferably all, of the following:

[0103] an endothermic peak with an onset at 94 °C ±5 °C;

[0104] an endothermic peak with an onset at 160 °C ±5 °C; and

[0105] an exothermic peak with an onset at 172 °C ±5 °C.

[0106] In an embodiment, said crystalline Form 16’ has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 4. When referring to the DSC thermogram of Figure 4, reference is made only to the part of the figure representing the DSC analysis and does not include the part of the figure representing the thermogravimetric analysis (TGA).In a particular embodiment, said crystalline Form 16’ has TGA weight loss curve with about a 0.6% weight loss between 115 °C ±5 °C and 200 °C ±5 °C.

[0107] In an embodiment, said crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16’) has a TGA weight loss curve substantially as depicted in Figure 4. When referring to the TGA weight loss curve of Figure 4, reference is made only to the part of the figure representing the TGA analysis and does not include the part of the figure representing the DSC analysis.

[0108] Processes for the preparation of solid forms

[0109] A process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect comprises the steps of:

[0110] a) suspending tafamidis, e.g. Form 1, in tetrahydrofuran in a weight / volume ratio of from 10-40 mg of tafamidis per each mL of tetrahydrofuran;

[0111] b) heating the suspension of step a) at 70 to 80 °C until tafamidis is dissolved, c) mixing the solution obtained in step b) with methyl ethyl ketone in a volume ratio of 2-5 mL of methyl ethyl ketone per each mL of solution of step b), and wherein the methyl ethyl ketone is at a temperature of from -5 °C to 5 °C, so that a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) is obtained;

[0112] d) isolating the solid obtained after step c);

[0113] e) optionally, slurrying the solid isolated in step d) in methyl ethyl ketone and tetrahydrofuran at a ratio of about 9:1 to obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16), and isolating said solid; and

[0114] f) optionally, subjecting the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) obtained in step d) or in step e) to heating at 120 to 130 °C, preferably about 125 °C, for 40 to 80 minutesto obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16’).

[0115] Step a) of the process is suspending tafamidis, e.g. Form 1, in tetrahydrofuran in a weight / volume ratio of from 10-40 mg of tafamidis per each mL of tetrahydrofuran, preferably in a weight / volume ratio of from 20-30 mg of tafamidis per each mL of tetrahydrofuran, more preferably about 25 mg of tafamidis per each mL of tetrahydrofuran.

[0116] Tafamidis Form 1 is characterized in patent document WO 2016 / 038500 Al and may be obtained following the procedure described in Example 1 of patent document WO 2016 / 038500 Al.

[0117] Step b) is heating the suspension of step a) at 70 to 80 °C until tafamidis is dissolved, preferably about 75 °C.

[0118] Step c) is mixing the solution obtained in step b) with methyl ethyl ketone in a volume ratio of 2-5 mL of methyl ethyl ketone per each mL of solution of step b), preferably ketone in a volume ratio of 3-4 mL of methyl ethyl ketone per each mL of solution of step b). The methyl ethyl ketone of step c) is at a temperature of from -5 °C to 5 °C, preferably about 0 °C. After said mixing is carried out crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) is obtained.

[0119] Step d) is isolating the solid obtained after step c). Said step may be performed by any conventional means in the art, such as by filtration, decantation, or solvent evaporation.

[0120] Step e) is optional and is slurrying the solid isolated in step d) in methyl ethyl ketone and tetrahydrofuran at a ratio of about 9:1 to obtain the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) and isolating thesolid thus obtained. Preferably, a volume of about 0.01 mL of said mixture of methyl ethyl ketone and tetrahydrofuran per each mg of solid is used in step e). Preferably, the slurrying of step e) is carried out for 6 to 20 hours, preferably for 10 to 15 hours. Preferably, step e) is carried out at a temperature of from 0 °C to -30 °C, preferably from -10 to -30 °C, more preferably about -20 °C. Isolation of the solid may be performed by any conventional means in the art, such as by filtration, decantation, or solvent evaporation. Preferably, step e) is carried out.

[0121] Step f) is optional and is subjecting the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16) obtained in step d) or in step e) to heating at 120 °C to 130 °C, preferably about 125 °C, for 40 to 80 minutes to obtain crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16’). If step f) is carried out in the process of the invention, the product obtained by the above process is the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16’). If step f) is not carried out in the process of the invention, the product obtained by the above process is the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form (i.e. Form 16).

[0122] A process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect comprises:

[0123] i) providing a solution of tafamidis in either a) THF or in b) a mixture of THF and not more than 7% w / w, preferably not more than 6% w / w, more preferably not more than 5% w / w of water with respect to the total weight of the THF / water mixture, wherein the ratio of THF to tafamidis is in the range of 7-13 liters of THF per mol of tafamidis;

[0124] ii) pouring the solution of step i) over methyl ethyl ketone (MEK) wherein the ratio of MEK to tafamidis is in the range of 22-40 liters of MEK per mol of tafamidis;iii) optionally stirring at -5 to 25 °C for at least 30 min; and iv) separating the solid product resulting from steps ii) or iii) from the liquid media.

[0125] In an embodiment of the third aspect, tafamidis is dissolved in a mixture of THF and water in step i) wherein the amount of water is not more than 7% w / w, 6.5% w / w, 6% w / w, 5.5% w / w, 5% w / w, 4.5% w / w, 4% w / w, 3.5% w / w, 3% w / w, 2.5% w / w, 2% w / w, 1.5% w / w, or not more than 1% w / w, as determined by Karl Fisher analysis.

[0126] In an embodiment of the process, the molar ratio of the MEK used in step ii) to the THF used in step i) of the above-described process is comprised between 2.8 and 3.4, preferably between 3.0 and 3.3, more preferably between 3.1 and 3.2.

[0127] In an embodiment of the process, the temperature of step ii) is carried out between -5 °C to 25 °C, preferably between 0 °C to 25 °C, more preferably step ii) at 0 °C.

[0128] In an embodiment of the process, the solid product of step iv) may be separated by conventional isolation techniques or purification.

[0129] In an embodiment of the process, the solution of tafamidis of step i) is obtained by hydrolysis of an alkyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate of formula (II)

[0130]

[0131] wherein R represents a C1-C4 alkyl group. In an embodiment of compound (II) wherein R is methyl, particularly the methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate, is prepared as in example 2 of WO 2020 / 207753 Al.

[0132] In an embodiment the hydrolysis of compound of formula (II) comprises the steps of:a) providing a solution of C1-C4 alkyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate of formula (II), preferably methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate, in at least 8 liters of THF per mol of (I) at a temperature sufficient to maintain the methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate in solution;

[0133] b) adding to the solution of step a) an aqueous solution of 1-2 mols of MOH per mol of (II), wherein M represents Li, Na or K, preferably Li and wherein MOH can be used in amorphous form or in the form of a hydrate;

[0134] c) optionally, maintaining the solution of step b) at a temperature of 40-66°C while stirring;

[0135] d) adding an aqueous hydrochloric acid solution to the solution of step c) at a temperature of 40-66° C to adjust the pH of the solution between 2.0 and 2.5 to provide tafamidis in solution;

[0136] e) optionally stirring the mixture of step d) for at least 5 minutes.

[0137] In a further embodiment the temperature at which step a) of the above-described process is carried out is from 40 to 66 °C.

[0138] In a further embodiment the amount of MOH added in step b) above is between 1.1 and 1.9, preferably between 1.2 and 1.8, more preferably between 1.3 and 1.7, even more preferably between 1.4 and 1.6, and most preferably about 1.5 moles.

[0139] In a further embodiment the base MOH added in step b) can be used in anhydrous form or more preferably in the form of a hydrate thereof.

[0140] In a further embodiment the base MOH added in step b) is LiOH, which can be used in anhydrous form or more preferably in the form of a hydrate such as LiOH H2O.

[0141] In a further embodiment the amount of water contained in the MOH aqueous solution of step b) of the above-described process is between 1.5 and 2.5 liters of water per mol of MOH.In a further embodiment the temperature at which the solution of step b) is maintained in step c) is from 55 to 60 °C.

[0142] In a further embodiment the aqueous hydrochloric acid solution added is step d) is added at a temperature between 55 and 60 °C.

[0143] In a further embodiment the above described process further comprises the steps of: f) adding between 6 and 10 moles of NaCl per mol of (I);

[0144] g) separating the aqueous and organic layers of the mixture obtained in step f); h) keeping the organic phase obtained in step g);

[0145] i) optionally washing the organic phase from step h) with brine.

[0146] In a further embodiment the brine used in step f) is a solution of NaCl in water wherein the concentration of NaCl is between 2 and 4 M.

[0147] In a further embodiment the above described process further comprises the steps of: j) adding THF and distilling from 80% to 110% of the added volume;

[0148] k) optionally repeating step j) 1 to 2 times;

[0149] In an embodiment the amount of THF added and the amount distilled in step j) are identical. In an embodiment step k) is repeated once. In an embodiment THF is added in step j) in an amount of between 2-4 liters per mol of compound of formula (II).

[0150] In an embodiment, the process for the preparation of the crystalline solid form of tafamidis methyl ethyl ketone solvate comprises the steps of:

[0151] a) providing a solution of C1-C4 alkyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate of formula (II), preferably methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate, in at least 8 liters of THF per mol of (I) at a temperature sufficient to maintain the methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate in solution;b) adding to the solution of step a) an aqueous solution of 1-2 mols of MOH per mol of (II), wherein M represents Li, Na or K, preferably Li and wherein MOH can be used in amorphous form or in the form of a hydrate;

[0152] c) optionally, maintaining the solution of step b) at a temperature of 40-66°C while stirring;

[0153] d) adding an aqueous hydrochloric acid solution to the solution of step c) at a temperature of 40-66° C to adjust the pH of the solution between 2.0 and 2.5 to provide tafamidis in solution;

[0154] e) optionally stirring the mixture of step d) for at least 5 minutes

[0155] f) adding between 6 and 10 moles of NaCl per mol of (I);

[0156] g) separating the aqueous and organic layers of the mixture obtained in step f); h) keeping the organic phase obtained in step g);

[0157] i) optionally washing the organic phase from step h) with brine.

[0158] j) adding THF and distilling from 80% to 110% of the added volume;

[0159] k) optionally repeating step j) 1 to 2 times;

[0160] l) pouring the solution of step a) over methyl ethyl ketone (MEK) wherein the ratio of MEK to tafamidis is in the range of 22-40 liters of MEK per mol of tafamidis; m) optionally stirring at -5 to 25 °C for at least 30 min; and

[0161] n) separating the solid product resulting from steps 1) or m) from the liquid media, o) optionally, washing the solid obtained in step n) with MEK and drying it.

[0162] In an embodiment, the process for the preparation of the crystalline solid form of tafamidis methyl ethyl ketone solvate comprises the steps of:

[0163] a) providing a solution of methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate, in at least 8 liters of THF per mol of (I) at a temperature of from 40 to 66 °C;

[0164] b) adding to the solution of step a) an aqueous solution of 1-2 mols of Li OH per mol of (II), wherein LiOH can be used in amorphous form or in the form of a hydrate; c) optionally, maintaining the solution of step b) at a temperature of 40-66°C while stirring;d) adding an aqueous hydrochloric acid solution to the solution of step c) at a temperature of 40-66° C to adjust the pH of the solution between 2.0 and 2.5 to provide tafamidis in solution;

[0165] e) optionally stirring the mixture of step d) for at least 5 minutes

[0166] f) adding between 6 and 10 moles of NaCl per mol of (I);

[0167] g) separating the aqueous and organic layers of the mixture obtained in step f); h) keeping the organic phase obtained in step g);

[0168] i) optionally washing the organic phase from step h) with brine.

[0169] j) adding THF and distilling from 80% to 110% of the added volume;

[0170] k) optionally repeating step j) 1 to 2 times;

[0171] l) pouring the solution of step a) over methyl ethyl ketone (MEK) wherein the ratio of MEK to tafamidis is in the range of 22-40 liters of MEK per mol of tafamidis; m) optionally stirring at -5 to 25 °C for at least 30 min; and

[0172] n) separating the solid product resulting from steps 1) or m) from the liquid media, o) optionally, washing the solid obtained in step n) with MEK and drying it.

[0173] Compositions

[0174] In an embodiment of the invention refers to a pharmaceutical composition comprising an effective therapeutic amount of the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in the first aspect, and a pharmaceutical acceptable carrier or pharmaceutically acceptable vehicle. Particularly, a pharmaceutical composition comprising an effective therapeutic amount of the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of from about 0.6 wt% to about 7 wt%, with respect to the total weight of the solid form, and a pharmaceutical acceptable carrier or pharmaceutically acceptable vehicle.

[0175] Some examples of materials which can serve as pharmaceutically acceptable excipients include: (a) sugars (e.g. lactose, glucose and sucrose), (b) starches (e.g. com starch and potato starch), (c) cellulose and its derivatives (e.g. sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), (d) powdered tragacanth, (e) malt, (f) gelatin, (g) talc, (h) excipients (e.g. cocoa butter and suppository waxes), (i) oils (e.g. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil), (j) glycols(e.g. propylene glycol), (k) polyols (e.g. glycerin, sorbitol, mannitol and polyethylene glycol), (1) esters (e.g. ethyl oleate and ethyl laurate), (m) agar, (n) buffering agents (e.g. magnesium hydroxide and aluminum hydroxide), (o) alginic acid, (p) pyrogen-free water, (q) isotonic saline, (r) Ringer's solution, (s) ethyl alcohol, (t) phosphate buffer solutions and (u) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants (e.g. sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically-acceptable antioxidants include: (a) water soluble antioxidants (e.g. ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite or sodium sulfite), (b) oil-soluble antioxidants (e.g. ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate or a-tocopherol), and (c) metal chelating agents (e.g. citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid or phosphoric acid).

[0176] Examples of pharmaceutical compositions include any solid (capsules, tablets, pills, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

[0177] In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be capsules, tablets, syrups or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as polyethylene glycols and sodium lauryl sulfate.

[0178] The compositions may be prepared by conventional methods in the art.

[0179] Medical usesAs previously explained, tafamidis stabilizes the protein transthyretin (TTR), dissociation of which is implicated in TTR amyloidosis and has been developed for the treatment of transthyretin amyloid diseases in particular wild-type transthyretin amyloidosis (previously kwon as senile systemic amyloidosis), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis (WO 2016 / 038500 Al).

[0180] Thus, the crystalline solid forms of tafamidis methyl ethyl ketone solvate as defined in the first aspect are suitable for the treatment and prevention of transthyretin amyloid diseases.

[0181] In another aspect, the invention relates to the crystalline solid form of tafamidis methyl ethyl ketone as defined in the first aspect or a pharmaceutical composition as previously defined, for use in the treatment and / or prevention of a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis; preferably wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC).

[0182] In another aspect, the invention relates to the use of the crystalline solid form of tafamidis methyl ethyl ketone as defined in the first aspect or a pharmaceutical composition as previously defined, in the manufacture of a medicament for the treatment and / or prevention of a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis; preferably wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC).

[0183] In a further aspect, the invention relates to a method of treatment and / or prevention of a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis; preferably wild-type transthyretin amyloidosis, familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC); comprising administering to a subject in need thereof the crystalline solid form of tafamidis methyl ethyl ketone as defined in the first aspect or a pharmaceutical composition as previously defined.

[0184] The following examples represent specific embodiments of the present invention. They do not intend to limit in any way the scope of the invention defined in the present description.

[0185] EXAMPLES

[0186] Characterization methods

[0187] X-ray powder di ffraction (XRPD)

[0188] Diffraction data was collected using a PANanalytical EMPYREAN vs. 8.2 20201404 diffractometer with a Cu-Ka radiation ( = 1.541874 A) source operating at 45 kV and 40 mA in transmission theta-theta configuration. Samples were scanned from 2 to 40 °2theta with a step size of 0.013 °2theta and a time per step of 78.795 sec. Data collection was performed with DATA COLLECTOR vs. 7.1.

[0189] Differential scanning calorimetry (DSC)

[0190] DSC analyses were performed using a Thermal Analysis (TA) Discovery instrument model DSC 25. The samples, typically weighing 1-3 mg, were heated in a sealed standardTzero aluminum pan at a heating rate of 10 °C / min under a nitrogen glass flow of 50 ml / min. A sealed empty Tzero aluminum pan was used as a reference. Data collection was performed with TRIOS software.

[0191] Thermogravimetric analysis (TGA)

[0192] TGA analyses were conducted in a Thermal Analysis (TA) Discovery instrument model TGA 550 using a nitrogen atmosphere with a gas flow of 60 mL / min and a heating rate of 10 °C / min. Approximately 1 to 5 mg of sample was used. Data collection was performed with TRIOS software.

[0193] Proton nuclear magnetic resonance d H-NMR)

[0194] 'H-NMR analyses were performed using an Agilent Mercury400 NMR Spectrometer. Approximately 5 mg of the sample was dissolved in 0.5-0.7 mL of deuterated DMSO.

[0195] Synthesis procedures

[0196] Tafamidis methyl ethyl ketone solvate Form 16

[0197] Example 1: Tafamidis methyl ethyl ketone solvate Form 16 was obtained by suspending tafamidis Form 1 (100 mg) in THF (4 mL) and heating the suspension at 75 °C for 15 min. The clear solution thus obtained was added in a vial containing pre-chilled methyl ethyl ketone (MEK) (13.4 mL) in an ice / water bath. The solid was isolated by vacuum filtration and air dried at room temperature. Then the solid was slurried in MEK:THF 9:1 v:v (10 vol) at -20 °C overnight. Form 16 was characterized by XRPD, DSC and TGA. The results are shown in Figures 1 and 2. The TGA weight loss curve is consistent with a MEK of about 7 wt% with respect to the total weight of the solid form; the product was also analyzed by 'H-NMR (data not shown), and the results are also consistent with this weight ratio.

[0198] Example 2: Tafamidis methyl ethyl ketone solvate Form 16 was obtained by suspending tafamidis Form 1 (500 mg) in THF (20 mL, 40 vol), the suspension was heated to 75 °C for 15 min. The clear solution was added into a beaker containing pre-chilled MEK (67 mL, 134 vol) in an ice / water bath. Solid was isolated by vacuum filtration and air-driedat room temperature for 5 min. Then the solid was slurried in MEK:THF 9: 1 v:v (10 vol) at -20 °C for 16 hours. Solid was filtered, washed with 1 mL of MEK and dried under nitrogen flow.

[0199] Example 3: In a 250 mL three-neck round-bottom flask, magnetic stirring, condenser, thermometer, and nitrogen, methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (5.00 g, 15.52 mmol), pale yellow-pink solid, was loaded, followed by THF (125 mL). The resulting suspension was heated to 60°C to obtain a solution. Meanwhile, a solution of lithium hydroxide hydrate (977 mg, 23.28 mmol) in water (50.0 mL) was prepared and added gently to the former solution for 2 min, keeping the temperature at 55-60°C. The resulting solution was stirred at 55-60°C for 1 hour. HC1 (922 mg, 4.22 mL, 6.0 molar, 25.29 mmol) was added to reach a pH of 2.0-2.5, while maintaining a complete dissolution and stirred for 10 minutes. Afterwards, NaCl (7.5 g, 128.34 mmol) was added and it dissolved easily. Then, layers were separated; the aqueous phase with salt was discarded, and the organic phase was washed with 25.0 mL of a warmed brine solution. THF was then added (50 mL) and the same volume distilled off at atmospheric pressure. The same amount of THF was added and the distillation repeated (KF: 6.7%). After this second distillation, the hot THF solution was poured over cold MEK (400 mL) in an ice bath with stirring, to achieve rapid precipitation. A white solid precipitated almost immediately which was left stirring at 0 °C for 1-1.5 hours. The white solid was filtered through a pore plate no. 3, washed with MEK at 0 °C. Mother liquor was discarded. The solid was dried in a vacuum oven at 40-42°C for 18 h. Yield: 3.51 g (73%). Sample was analyzed by XRPD and the diffractograms displayed crystalline pattern corresponding to tafamidis in pure polymorphic form 16. See Figure 5.

[0200] Example 4: Methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (2.00 g, 6.21 mmol) was suspended in tetrahydrofuran 50.0 mL) and heated to 55-65 °C to obtain a yellowish solution. A solution of lithium hydroxide hydrate (391 mg, 9.31 mmol) in water (20.0 mL) was added at 55-65 °C for 10 minutes. Hydrochloric acid (369 mg, 1.69 mL, 6.0 molar, 10.1 mmol) was added until reaching pH 2.0-2.5, keeping full dissolution throughout. Sodium chloride (3.00 g, 51.3 mmol) was added and aqueous phase was discarded. The organic phase was transferred to a 2 L four-neck reactor with mechanicalstirring, THF (20 mL) was added and distilled to reduce water content (as described: azeotropic distillation reduces water by 5% at atmospheric pressure), KF: 5.1%. THF (20 mL) was added and distilled, KF: 3.8%. While hot (45-55 °C), the solution was poured into MEK (160 mL) at room temperature (20 °C) and stirred for 2.5 h. The resulting solid was filtered off and dried in an oven at 40-45 °C under vacuum overnight to yield form tafamidis form 16. Yield: 0.82 g (43%). Residual solvents: MEK 1000 ppm, THF 390 ppm (as determined by1H-NMR).

[0201] Example 5: Methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (5.00 g, 15.5 mmol) was suspended in tetrahydrofuran (125 mL) and heated to 55-60 °C to obtain a yellowish solution. A solution of lithium hydroxide hydrate (977 mg, 23.3 mmol) in water (50.0 mL) was added at 55-60 °C for 10 minutes. Hydrochloric acid (922 mg, 4.22 mL, 6.0 molar, 25.3 mmol) was added until reaching pH 2.0-2.5, keeping full dissolution throughout. Sodium chloride (7.50 g, 128 mmol) was added and aqueous phase was discarded. The organic phase (KF: 7.7%) was transferred to a two-neck reactor with mechanical stirring, THF (50 mL) was added and distilled to reduce water content (KF: 5.4%). THF (50 mL) was added and distilled (KF: 4.5%). THF (25 mL) was added and distilled to reduce water content (KF: 2.6%). While hot (45-55 °C), the solution was poured into MEK (400 mL) at room temperature (20 °C) and stirred for 1 hour, cooled down to 0°C and stirred for 1 hour. The resulting solid was filtered off, washed with cold MEK and dried in an oven at 40-45 °C under vacuum for 18 hours to yield form tafamidis form 16. Yield: 3.67 g (77%)

[0202] Example 6: In a 4-necked spherical flask of 2 L, mechanical stirring, condenser, thermometer, and nitrogen, methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (35.00 g, 108.64 mmol), pale yellow-pink solid, was loaded, followed by THF (875.0 mL). The resulting suspension was heated to 55-65°C to obtain a solution. Meanwhile, a solution of lithium hydroxide hydrate (6.838 g, 163.0 mmol) in water (350.0 mL) was prepared and added gently to the former solution for 10 min, keeping the temperature at 55-60°C. The resulting solution was stirred at 55-60°C for 1 hour. HC1 (6.457 g, 29.52 mL, 6.0 molar, 177.1 mmol) was added (pH of 2.0-2.5), while maintaining a complete dissolution and stirred for 5 minutes. Afterwards, sodium chloride (52.51 g,898.53 mmol) was added and it dissolved easily. Then, layers were separated; the aqueous phase with salt was discarded, and the organic phase was analyzed by KF (7.4%). The hot organic phase was transferred to a 2 L four-neck reactor with mechanical stirring, THF was added (350 mL) and approximately the same volume was distilled to reduce the water content (KF: 5.1%). Then, the same amount of THF was added (350 mL) and the distillation process repeated (KF: 3.4%). The resulting hot solution (45-55 °C) was poured over MEK (2.800 L) in a jacketed reactor at 0 °C, with mechanical stirring, to precipitate the product over a total period of 25 minutes. The stirring is maintained at 0-5 °C for 1 hour, filtered using a plate with pore number 3, and washed with MEK at 0 °C. The resulting solid was dried in an oven at 40-45 °C overnight to provide tafamidis in pure polymorphic form 16. Yield: 25.4g (76%)

[0203] Tafamidis methyl ethyl ketone solvate Form 16’

[0204] Example 7: Tafamidis methyl ethyl ketone solvate Form 16’ was obtained by heating tafamidis methyl ethyl ketone solvate Form 16 to 125 °C (optionally in TGA). The temperature was held for 1 hour and then sample was exposed to room temperature. Form 16’ was characterized by XRPD, DSC and TGA. The results are shown in Figures 3 and 4. The TGA data is consistent with a MEK content of about 0.6 wt% with respect to the total weight of the solid form; the product was also analyzed by 'H-NMR (data not shown), and the results are also consistent with this weight ratio.

[0205] Example 8: The tafamidis form 16 obtained in example 3 (2 g) was suspended in water (20 mL) and stirred between 5-10 °C for 3 hours. After this time, filter through No. 3 filter plate, wash with water (10 mL). Then, the solid was washed with cold MEK (20 mL), filtered under vacuum, washed with cold MEK (10 mL), and dried in a vacuum oven at 100 °C for 16 hours. Sample was analyzed by XRPD and the diffractograms displayed crystalline pattern corresponding to tafamidis in polymorphic form 16’. See Figure 6. Similar result was obtained by slurring in water between 15-20 °C.

[0206] Example 9: Tafamidis in polymorphic form 16’, was obtained by drying the product of example 6 in a vacuum oven at 100 °C for 24 hours.Comparative examples

[0207] Comparative example 1: Mixture of polymorphs 6 and 10

[0208] The following example differs from the invention in that the ratio of MEK to tafamidis is 3.08 liters per mol (lower than 20 liters per mol)

[0209] A suspension of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (1.00 g, 3.25 mmol) in THF (25 mL) was heated to 65°C. The resulting hot solution was poured over cold MEK (10 mL) in an ice bath with stirring, to achieve rapid precipitation. A white solid precipitated which was left stirring at 0 °C for 1 hour. The white solid was filtered through a pore plate no. 3, washed with MEK at 0 °C. Mother liquor was discarded. The solid was dried in a vacuum oven at 40-42°C for 18 h. Yield: 691 mg (69%). Sample was analyzed by XRPD and the diffractograms displayed tafamidis in a mixture of polymorphic form 6 (anhydrous phase disclosed in WO 2016 / 038500 Al) and polymorphic form 10 (Form II as described in WO 2020 / 232325 Al).

[0210] Comparative example 2: Mixture of polymorphs 1 and 4

[0211] The following example differs from the invention in that the ratio of MEK to tafamidis is 43.17 liters per mol (higher than 43 liters per mol)

[0212] In a 250 mL three-neck round-bottom flask, magnetic stirring, condenser, thermometer, and nitrogen, methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (5.00 g, 15.52 mmol), pale yellow-pink solid, was loaded, followed by THF (200 mL). The resulting suspension was heated to 45-50°C to obtain a solution. Meanwhile, a solution of lithium hydroxide hydrate (0.98 g, 23 mmol) in water (50.0 mL) was prepared and added gently to the former solution for 2 min, keeping the temperature at 45-50°C. The resulting solution was stirred at 50-60°C for 1 hour. HC1 (0.92 g, 4.2 mL, 6.0 molar, 25 mmol) was added (pH of 2.0-2.5), while maintaining a complete dissolution and stirred for 10 minutes. Then, layers were separated; the aqueous phase with salt was discarded, and the organic phase was poured over cold MEK (670 mL) in an ice bath, with stirring, to achieve rapid precipitation. A white solid precipitated almost immediately which was left stirring at 0 °C for 2 hours. The white solid was filtered through pore plate no. 3, the solid obtained was analyzed by KF (15.0%), washed with MEK at 0 °C and dried in a vacuum oven at 40-42°C for 18 h. Yield: 1.36 g (28%). The sample analyzed by XRPDdisplayed tafamidis in a mixture of polymorphic forms 1 and 4 (disclosed in WO 2016 / 038500 Al).

[0213] Comparative example 3: Mixture of polymorphs 6 (major) and 10 (minor)

[0214] The following example differs from the invention in that the ratio of MEK to tafamidis is 4.62 liters per mol (lower than 20 liters per mol)

[0215] A suspension of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (1.00 g, 3.25 mmol) in THF (25 mL) was heated to 65°C. The resulting hot solution was poured over cold MEK (15 mL) in an ice bath with stirring, to achieve rapid precipitation. A white solid precipitated which was left stirring at 0 °C for 1 hour. The white solid was filtered through a pore plate no. 3, washed with MEK at 0 °C. Mother liquor was discarded. The solid was dried in a vacuum oven at 40-42°C for 18 h. Yield: 681 mg (68%). Sample was analyzed by XRPD and the diffractograms displayed tafamidis in a mixture of polymorphic form 6 (anhydrous phase disclosed in WO 2016 / 038500 Al) impurified with polymorphic form 10 (Form II as described in WO 2020 / 232325 Al).

[0216] Comparative example 4: Mixture of polymorphs 1 (major), 16 (minor) and 4 (minor) The following example differs from the invention in that the ratio of MEK to tafamidis is 19.32 liters per mol (lower than 20 liters per mol)

[0217] In a 250 mL three-neck round-bottom flask, magnetic stirring, condenser, thermometer, and nitrogen, methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate (5.00 g, 15.52 mmol), pale yellow-pink solid, was loaded, followed by THF (125 mL). The resulting suspension was heated to 55-60°C to obtain a solution. Meanwhile, a solution of lithium hydroxide hydrate (977 mg, 23.3 mmol) in water (50.0 mL) was prepared and added gently to the former solution for 2 min, keeping the temperature at 45-50°C. The resulting solution was stirred at 50-60°C for 1 hour. HC1 (922 mg, 4.22 mL, 6.0 molar, 25.3 mmol) was added (pH of 2.0-2.5), while maintaining a complete dissolution and stirred for 10 minutes. Then, layers were separated; the aqueous phase with salt was discarded, and the organic phase was analyzed by KF (16.3%). THF was added (50 mL) and approximately the same volume was distilled. These steps were repeated 6 times. The analysis of by KF was 2.7%. The resulting organic phase was then poured over cold MEK (300 mL) in an ice bath with stirring, to achieve rapid precipitation. A white solidprecipitated almost immediately which was left stirring at 0 °C for 2 hours. The white solid was filtered through pore plate no. 3, washed with MEK at 0 °C and dried in a vacuum oven at 40-42°C for 18 h. Yield: 3.42 g (72%). The sample analyzed by XRPD displayed tafamidis in polymorphic form 1 impurified with form 16 and form 4 (disclosed in WO 2016 / 038500 Al).

[0218] Stability analysis

[0219] A contained environment of constant relative humidity of 75% at 40°C was obtained in a desiccator containing a NaCl salt solution beneath the samples shelf, which was placed in an oven at 40°C. Samples of the different forms were placed in the desiccator and exposed for 7 days at 40°C / 75% RH followed by XRPD analysis, in order to assess their physical stability on storage at elevated temperature and relative humidity.

[0220] Tafamidis methyl ethyl ketone solvates Form 16 and Form 16’ were stable for at least 6 months at 40°C and 75% RH, as the XRPD analysis showed no changes with respect to the original corresponding XRPD of the solids.

Claims

36CLAIMS1. Crystalline solid form of tafamidis methyl ethyl ketone solvate wherein the methyl ethyl ketone content is from about 0.6 wt% to about 7 wt% with respect to the total weight of the crystalline solid form.

2. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to claim 1, wherein the methyl ethyl ketone content is about 7 wt% with respect to the total weight of the crystalline solid form.

3. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to claim 2, characterized in that it has an X-ray powder diffraction pattern comprising peaks at °29 values equal to 5.8, 19.7 and 27.2 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation; preferably wherein the X-ray powder diffraction pattern comprises peaks at °29 values equal to 5.8, 19.7, 23.6, 26.8 and 27.2 ±0.2 °29.

4. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 2 or 3, characterized in that it has an X-ray powder diffraction pattern substantially as depicted in any one of Figure 1 or Figure 5.

5. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 2 to 4, characterized in that it has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 285 °C ±5 °C.

6. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 2 to 5, characterized in that it has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.

7. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to claim 1, wherein the methyl ethyl ketone content is about 9.6 wt% with respect to the total weight of the crystalline solid form.

378. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to claim 7, characterized in that it has an X-ray powder diffraction pattern comprising peaks at °20 values equal to 5.9, 14.0 and 27.1, 27.3 and 28.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation; preferably, wherein the X-ray powder diffraction pattern comprises peaks at °20 values equal to 5.9, 14.0, 16.5, 27.1 and 28.6 ±0.2 °29, wherein the X-ray diffraction is measured using a CuKa radiation.

9. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claim 7 or 8, characterized in that it has an X-ray powder diffraction pattern substantially as depicted in Figure 3 and Figure 6.

10. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 7 to 9, characterized in that it has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with an onset at 286 °C ±5 °C.

11. Crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 7 to 10, characterized in that it has a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 4.

12. Process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in any one of the preceding claims, which comprises:a) suspending tafamidis Form 1 in tetrahydrofuran in a weight / volume ratio of from 10-40 mg of tafamidis per each mL of tetrahydrofuran;b) heating the suspension of step a) at 70 to 80 °C until tafamidis is dissolved, c) mixing the solution obtained in step b) with methyl ethyl ketone in a volume ratio of 2-5 mL of methyl ethyl ketone per each mL of solution of step b), and wherein the methyl ethyl ketone is at a temperature of from -5 °C to 5 °C, so that crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form is obtained;d) isolating the solid obtained after step c);e) optionally, slurrying the solid isolated in step d) in methyl ethyl ketone and tetrahydrofuran at a ratio of about 9:1 to obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form and isolating said solid; andf) optionally, subjecting the crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 7 wt% with respect to the total weight of the crystalline solid form obtained in step d) or in step e) to heating at 120 °C to 130 °C, preferably about 125 °C, for 40 to 80 minutes to obtain a crystalline solid form of tafamidis methyl ethyl ketone solvate having a methyl ethyl ketone content of about 0.6 wt% with respect to the total weight of the crystalline solid form.

13. A process for preparing the crystalline solid form of tafamidis methyl ethyl ketone solvate according to claims 2 to 4, which comprises:i) providing a solution of tafamidis in a) THF or in b) a mixture of THF and not more than 7% w / w, preferably not more than 6% w / w, more preferably not more than 5% w / w of water with respect to the total weight of the THF / water mixture, wherein the ratio of THF to tafamidis is in the range of 7-13 liters of THF per mol of tafamidis;ii) pouring the solution of step i) over methyl ethyl ketone (MEK) wherein the ratio of MEK to tafamidis is in the range of 22-40 liters of MEK per mol of tafamidis; iii) optionally stirring at -5 to 25 °C for at least 30 min; andiv) separating the solid product resulting from steps ii) or iii) from the liquid media.

14. The process according to claim 13, wherein the solution of tafamidis of step i) of claim 13 is obtained by hydrolysis of an alkyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate of formula (II)wherein R represents a C1-C4 alkyl group.

15. The process according to claim 14, which comprises:a) providing a solution of C1-C4 alkyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6 carboxylate of formula (I), preferably methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate, in at least 8 liters of THF per mol of (II) at a temperature sufficient to maintain the methyl 2-(3,5- dichlorophenyl)benzo[d]oxazole-6 carboxylate in solution;b) adding to the solution of step b) an aqueous solution of 1-2 mols of MOH per mol of (I), wherein M represents Li, Na or K, preferably Li and wherein MOH can be used in amorphous form or in the form of an hydrate;c) optionally, maintaining the solution of step b) at a temperature of 40-66°C while stirring;d) adding an aqueous hydrochloric acid solution to the solution of step c) at a temperature of 40-66° C to adjust the pH of the solution between 2.0 and 2.5 to provide tafamidis in solution;e) optionally stirring the mixture of step d) for at least 5 minutes.

16. The process according to claim 15, wherein the temperature at which step a) is carried out is from 40 to 66 °C.

17. The process according to any one of claims 15 to 16, wherein the amount of water contained in the MOH aqueous solution of step b) is between 1.5 and 2.5 liters of water per mol of MOH.

18. The process according to any one of claims 15 to 17, wherein the addition of the hydrochloric acid solution of step d) is carried out at a temperature of 40-66° C.

19. The process according to any one of claims 15 to 18, wherein the process further comprises the steps of:f) adding between 6 and 10 moles of NaCl per mol of (I);g) separating the aqueous and organic layers of the mixture obtained in step f);h) keeping the organic phase obtained in step g);i) optionally washing the organic phase from step h) with brine.

20. The process according to anyone of claims 15 to 19, wherein the process further comprises the steps of:j) adding THF and distilling from 80% to 110% of the added volume;k) optionally repeating step j) 1 to 2 times;21. The process according to claim 20 wherein THF is added in step j) of claim 15 in an amount of between 2-4 liters per mol of compound (I).

22. Pharmaceutical composition comprising the crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in any one of claims 1 to 11.

23. Crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in any one of claims 1 to 11, or pharmaceutical composition as defined in claim 22, for use in medicine.

24. Crystalline solid form of tafamidis methyl ethyl ketone solvate as defined in any one of claims 1 to 11, or pharmaceutical composition as defined in claim 22, for use in the treatment and / or prevention of a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, cardiac amyloidosis following liver transplantation, peripheral nerve amyloidosis following liver transplantation, leptomeningeal amyloidosis, transthyretin mutant-associated carpal tunnel syndrome, vitreous deposition and transthyretin mutant-associated skin amyloidosis; preferably a disease selected from the group consisting of wild-type transthyretin amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy (FAC).

25. Use of the crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 2 to 4 to prepare the crystalline solid form of tafamidis methyl ethyl ketone solvate according to any one of claims 7 to 9 by drying.

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