The present invention relates to improved processes for the preparation of Tafamidis and a salt thereof. The present invention also relates to one-pot process for the preparation of Tafamidis and its purification. The present invention relates to amorphous solid dispersions of Tafamidis and its meglumine salt, and their processes. The present invention also relates to novel crystalline forms of Tafamidis and their processes.

BACKGROUND OF THE INVENTION

The drug compound having the adopted name “Tafamidis” has chemical name: 2-(3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid as below.

Tafamidis is a selective stabilizer of transthyretin developed by The Scripps Research Institute and marketed by Pfizer as VYNDAQEL® (Tafamidis meglumine) and VYNDAMAX™ (Tafamidis) oral capsule for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular - related hospitalization in U.S.

The US7214695B2 patent disclosed Tafamidis and its use thereof for the treatment of transthyretin amyloid disease. US7214695B2 further discloses a general procedure for the preparation of benzoxazoles, particularly Tafamidis (compound 19) with 11% yield.

Subsequently, the US9249112B2 patent discloses the preparation of meglumine salt of Tafamidis from the mixture of isopropyl alcohol and water. It further discloses the crystalline and amorphous forms of Tafamidis meglumine.

The US9770441B1 discloses amorphous and crystalline forms 1, 2, 4 and 6 of Tafamidis. The patent further patent discloses alternate procedure for the preparation of Tafamidis with enhanced yield, however the process disclosed therein involves multiple downstream operations such as isolation, solvent displacement through distillation for the purification of intermediates and Tafamidis, though the patent is silent about the resultant purity and other quality attributes.

The known processes for the preparation of Tafamidis are not viable at industrially scale due to the above mentioned draw backs with very low yields and purity. The reported solid forms of Tafamidis and its meglumine salt are not viable at industrial scale and there remains a need for alternate solid forms of Tafamidis and their preparative processes. Hence, there remains a need for the improved process to make Tafamidis or its meglumine salt and alternate solid forms and preparative processes thereof.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a one-pot process for the preparation of Tafamidis or a salt thereof, comprising the steps of:

(i) acylation of 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride;

(ii) cyclization of the amide intermediate formed in step (i), wherein the amide intermediate is not isolated;

(iii) optionally, converting Tafamidis obtained at step (ii) in to a salt thereof.

In another aspect, the present invention a provides process for the preparation of Tafamidis or its meglumine salt, comprising step of preparing Tafamidis organic base addition salt.

In another aspect, the present invention provides the organic base addition salt form of Tafamidis selected from the group consisting of benzylamine, dicyclohexylamine and diethanolamine salts of Tafamidis.

In another aspect the present invention provides use of organic base addition salt of Tafamidis, for the manufacture of Tafamidis or its meglumine salt.

In another aspect the present invention provides use of organic base addition salt form of Tafamidis selected from the group consisting of benzylamine, dicyclohexylamine and diethanolamine salts of Tafamidis, for the manufacture of Tafamidis or its meglumine salt.

In another aspect, the present invention provides an amorphous solid dispersion of Tafamidis or its meglumine salt, together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Tafamidis or its meglumine, comprising the steps of: a) combining Tafamidis or its meglumine salt with atleast one pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, b) Removing the solvent from step a).

In an aspect, the present invention provides a crystalline Form-Tl of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 5.90, 20.53 and 29.24° ± 0.2° 2Q.

In another aspect, the present invention provides a crystalline Form-T2 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 12.93, 15.07 and 19.57° ± 0.2° 2Q.

In another aspect, the present invention provides a crystalline Form-T3 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 14.43, 21.59 and 22.95 ° ± 0.2° 2Q.

In another aspect, the present invention provides a crystalline Form-T4 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 8.17, 21.09, 24.75° ± 0.2° 2Q.

In another aspect, the present invention provides a process for the preparation of crystalline Form-Tl of Tafamidis, comprising the step of combining Tafamidis with 2-methoxyethanol.

In another aspect, the present invention provides a process for the preparation of crystalline Form-T2 of Tafamidis, comprising the step of combining Tafamidis with N-methyl-2-pyrrolidone.

In another aspect, the present invention provides a process for the preparation of crystalline Form-T3 of Tafamidis, comprising the step of combining Tafamidis with dimethyl acetamide.

In another aspect, the present invention provides a process for the preparation of crystalline Form-T4 of Tafamidis, comprising the step of combining Tafamidis with dimethyl sulfoxide.

In another aspect, the present invention provides a pharmaceutical composition comprising crystalline Tafamidis, selected from the group consisting of Form-Tl, Form-T2, Form-T3, Form-T4 and mixtures thereof, and atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis meglumine salt prepared by the methods of Example No 3.

Figures 2, 4, 6, 8 and 10 are the illustrative X-ray powder diffraction pattern of crystalline Tafamidis prepared by the methods of Example No 4, 6, 7, 8 and 9, respectively.

Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis benzylamine salt prepared by the methods of Example No 6.

Figure 5 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis benzylamine salt prepared by the methods of Example No 7.

Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis dicyclohexylamine salt prepared by the methods of Example No 8.

Figure 9 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis dicyclohexylamine salt prepared by the methods of Example No 9.

Figure 11 is illustrative Thermogravimetric/Differential Thermal

Analyzer (TG/DTA) pattern of crystalline Tafamidis benzylamine salt prepared by the methods of Example No 6.

Figure 12 is illustrative Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of crystalline Tafamidis benzylamine salt prepared by the methods of Example No 7.

Figure 13 is illustrative Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of crystalline Tafamidis dicyclohexylamine salt prepared by the methods of Example No 8.

Figure 14 is illustrative Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of crystalline Tafamidis dicyclohexylamine salt prepared by the methods of Example No 9.

Figure 15 is illustrative X-ray powder diffraction pattern of crystalline Tafamidis diethanolamine salt prepared by the methods of Example No 10.

Figure 16 is illustrative Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of crystalline Tafamidis diethanolamine salt prepared by the methods of Example No 10.

Figures 17 to 20 are the illustrative X-ray powder diffraction patterns of amorphous solid dispersions of Tafamidis prepared by the methods of Example 11 to 14.

Figure 21 is an illustrative X-ray powder diffraction pattern of amorphous form of Tafamidis meglumine prepared by the methods of Example 15.

Figure 22 is an illustrative X-ray powder diffraction patterns of amorphous solid dispersions of Tafamidis meglumine salt prepared by the methods of Example 16.

Figure 23 is an illustrative X-ray powder diffraction pattern of crystalline Form-Tl of Tafamidis, prepared by the method of Example No 20.

Figure 24 is an illustrative X-ray powder diffraction pattern of crystalline Form-T2 of Tafamidis, prepared by the method of Example No 21.

Figure 25 is an illustrative X-ray powder diffraction pattern of crystalline Form-T3 of Tafamidis, prepared by the method of Example No 22.

Figure 26 is an illustrative X-ray powder diffraction pattern of crystalline Form-T4 of Tafamidis, prepared by the method of Example No 23. DETAILED DESCRIPTION OF THE INVENTION

In an aspect, the present invention provides a one-pot process for the preparation of Tafamidis or a salt thereof, comprising the steps of:

(i) acylation of 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride;

(ii) cyclization of amide intermediate formed in step (i), wherein the amide intermediate is not isolated;

In embodiments, the starting materials used in this aspect, 4-amino-3- hydroxybenzoic acid and 3,5-dichlorobenzoyl chloride, may be obtained according to any method known in the art or may be procured from the commercially available sources.

In embodiments, step (i) of this aspect may be carried out in the presence of suitable organic solvent. In a preferred embodiment, step (i) of this aspect may be carried out in the presence of organic solvent consisting of N-methyl 2- pyrrolidone in toluene. Inventors of the present invention have identified that use of N-methyl 2-pyrrolidone in toluene provides desired advantages w.r.t. thermal stability and ease of isolation.

In embodiments, step (i) may be carried at a suitable temperature of about 0 °C to reflux temperature of the solvent used.

In embodiments, step (i) may be carried out for sufficient time for the formation of amide intermediate and till the content of starting materials are not detected in the reaction mixture. In embodiments, step (i) may be carried out for at least one hour or more.

In embodiments, step (ii) of this aspect may be carried out without isolation of amide intermediate formed at step (i). In embodiments, the step (ii) of this aspect may be carried out in the presence of a suitable cyclization promoter. The cyclization promoter that can used in this step may include but not limited to sulfonic acids such as p- toluenesulfonic acid, benzenesulfonic acid, p-nitrobenzenesulfonic acid, trifluoromethanesulfonic acid and methanesulfonic acid; mineral acids such as sulfuric acid and hydrochloric acid; organic acids and their anhydrides such as acetic acid and acetic anhydride; acidic resins; boric acid; phosphorous pentoxide; polyphosphoric acid (PPA); phosphoryl chloride; molecular sieves or mixtures thereof. In a preferred embodiment, p-toluenesulfonic acid as cyclization promoter is employed.

In embodiments, step (ii) may be carried at a suitable temperature of about 0 °C to reflux temperature of the solvent used. In preferred embodiments, step (ii) may be carried out at reflux temperature of the solvent used.

In embodiments, step (ii) may be carried out for sufficient time for the complete cyclization of amide intermediate and till the content of amide intermediate is not detected in the reaction mixture. In embodiments, step (i) may be carried out for at least one hour or more.

In embodiments, Tafamidis obtained at step (ii) may be converted to a salt form.

In another aspect, the present invention provides a process for the preparation of Tafamidis or its meglumine salt, comprising step of preparing Tafamidis organic base addition salt.

In embodiments, the organic base for the organic base addition salt of Tafamidis may be selected from the group consisting of meglumine, dicyclohexylamine, benzylamine, dibenzylamine, phenylethylamine, 1-(1- naphthyl)ethylamine, tert-butylamine, N-methyl pyrrolidone, 1,4- diazabicyclo[2.2.2]octane, triethylamine, diisopropylethylamine, 1- methylpyrrolidine, tromethamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7- ene, hexylamine, 2,6-lutidine, piperidine, diethylamine, dibutylamine, morpholine, 3 -dimethylamino-1 -propylamine, diisopropylamine, N-benzyl-tert- butylamine, diethanolamine, l,5-diazabicyclo(4.3.0)non-5-ene, tribenzylamine, diisopropyl amine, N-methylmorpholine, N-ethylmorpholine, dimethylamino pyridine, 2,4,6-collidine, imidazole, 1 -methyl imidazole or 1,2,4-triazole.

In embodiments, the step of generating Tafamidis from its organic base addition salt form may be carried out by treating the salt with an acid. Suitable acid may include, but not limited to mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, perchloric acid; carboxylic acids such as formic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, fumaric acid and maleic acid; and sulfonic acids such as p-toluenesulfonic acid (PTSA), benzenesulfonic acid, p-nitrobenzenesulfonic acid, trifluoromethanesulfonic acid and methanesulfonic acid.

In embodiments, treating organic base addition salt with an acid may be carried out in the presence of a suitable solvent.

Inventors of the present invention have identified that the process of preparation of Tafamidis through the treatment of organic base addition salt form of Tafamidis surprisingly improves the chemical purity significantly as illustrated below.

Inventors of the present invention have identified that treatment of Tafamidis free form with inorganic bases does not result in solid form of Tafamidis inorganic base addition salts & thus may not be useful for purification of Tafamidis to achieve desired chemical purity. More particularly, it was observed that preparation of Tafamidis through the treatment of inorganic base addition salt leads to a chemical purity of not more than about 98.5% by HPLC, which is not acceptable as per the regulatory requirements.

In another aspect, the present invention provides salt form of Tafamidis selected from the group consisting of benzylamine, dicyclohexylamine and diethanolamine salts of Tafamidis.

In embodiments, the salt form is benzylamine salt of Tafamidis. In embodiments, the benzylamine salt of Tafamidis is amorphous salt. In embodiments, the benzylamine salt of Tafamidis is crystalline salt. In embodiments, the crystalline benzylamine salt of Tafamidis is characterized by the PXRD pattern of figures 3 or 5. In embodiments, the crystalline benzylamine salt of Tafamidis is characterized by Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of figure 11 or 12.

In embodiments, the salt form is dicyclohexylamine salt of Tafamidis. In embodiments, the dicyclohexylamine salt of Tafamidis is amorphous salt. In embodiments, the dicyclohexylamine salt of Tafamidis is crystalline salt. In embodiments, the crystalline dicyclohexylamine salt of Tafamidis is characterized by the PXRD pattern of figures 7 or 9. In embodiments, the crystalline dicyclohexylamine salt of Tafamidis is characterized by Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of figure 13 or 14.

In embodiments, the salt form is diethanolamine salt of Tafamidis. In embodiments, the diethanolamine salt of Tafamidis is amorphous salt. In embodiments, the diethanolamine salt of Tafamidis is crystalline salt. In embodiments, the crystalline diethanolamine salt of Tafamidis is characterized by the PXRD pattern of figures 15. In embodiments, the crystalline diethanolamine salt of Tafamidis is characterized by Thermogravimetric/Differential Thermal Analyzer (TG/DTA) pattern of figure 16.

In another aspect, the present invention provides a process for the preparation of organic base addition salt form of Tafamidis, comprising steps of: i) treating Tafamidis with organic base in one or more of suitable solvents and ii) isolating organic base addition salt form of Tafamidis.

In embodiments, the base used in step i) may be selected from the group captured in above embodiments. In preferred embodiment, meglumine, dicyclohexylamine, benzylamine, diethanolamine or dibenzylamine are the bases.

In another aspect, the present invention provides Tafamidis or its meglumine salt, obtained according to the processes of the present invention, having a chemical purity of at least 99% or at least 99.5 or at least 99.9%, by HPLC.

In another aspect the present invention provides use of organic base addition salt form of Tafamidis selected from the group consisting of benzylamine, dicyclohexylamine and diethanolamine salts of Tafamidis, for the manufacture of Tafamidis or its meglumine salt.

In another aspect the present invention provides use of diethanolamine salt of Tafamidis, for the manufacture of Tafamidis or its meglumine salt.

In another aspect the present invention provides use of organic base addition salts for the manufacture of Tafamidis or its meglumine salt increases the chemical purity to more than 98.5% by HPLC.

In another aspect, the present invention provides a process for the preparation of substantially pure Tafamidis or its meglumine salt, comprising step of preparing Tafamidis organic base addition salt.

When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 98.5% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. The "substantially pure" refers to the same as "pure" except that the lower limit is about 98.5% pure or more and likewise.

In another aspect the present invention provides Tafamidis or its meglumine salt, obtained according the processes of above aspects.

In another aspect the present invention provides a pharmaceutical composition comprising Tafamidis or its meglumine salt, obtained according the processes of above aspects and at least one pharmaceutically acceptable excipient.

In an aspect, the present invention provides amorphous solid dispersion of Tafamidis or its meglumine salt, together with atleast one pharmaceutically acceptable excipient, as characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 17 to 20 or 22.

In an embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington 's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.

The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Tafamidis or its meglumine salt with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant invention.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Tafamidis or its meglumine, comprising the steps of: a) combining Tafamidis or its meglumine salt with atleast one pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, b) Removing the solvent from step a).

In embodiments, Tafamidis or its meglumine salt may be combined with atleast one pharmaceutically acceptable excipient, under heating or mechanical stress to obtain molten mixture of components. In embodiments, the molten mixture may be optionally cooled to obtain solid dispersion of Tafamidis or its meglumine salt with atleast one pharmaceutically acceptable excipient. In embodiments, Tafamidis or its meglumine salt may be combined with atleast one pharmaceutically acceptable excipient in a suitable equipment such as hot melt extruder, twin screw extruder or the like.

In embodiments, Tafamidis or its meglumine salt may be combined with pharmaceutically acceptable excipient in the presence of a suitable solvent. The suitable solvent can be selected from the list of solvents disclosed in the application herein.

In embodiments, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group of excipients of the previous aspect.

In embodiments, combining Tafamidis or its meglumine salt may be carried out by dissolving Tafamidis or its meglumine salt and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.

In embodiments, a solution of Tafamidis or its meglumine salt and the excipient may be prepared at any suitable temperature, such as about 0 °C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In embodiments, a solution of Tafamidis or its meglumine salt and the excipient may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In embodiments, the solvent from the solution of Tafamidis or its meglumine salt and the excipient may be removed as per the methods described in this application. The solid obtained can be dried as per the methods disclosed in this application.

In embodiments, the isolation of the solid dispersion of Tafamidis or its meglumine salt with excipient is performed as per the methods described in this application.

In embodiments, the solid dispersions of Tafamidis or its meglumine salt of the present application are stable under thermal, humid and stress conditions. Further, the solid dispersions of Tafamidis or its meglumine salt of present application exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Tafamidis or its meglumine salt.

In another aspect, the present application provides a solid dispersion of Tafamidis or its meglumine salt, obtained according to the processes of the present application, having a chemical purity of atleast 99% or atleast 99.5% by HPLC. In one aspect, the present invention relates to solid forms of Tafamidis and the pharmaceutical compositions thereof. Specific aspect of present application relate to crystalline Form-Tl, Form-T2, Form-T3 and Form-T4 of Tafamidis and their preparative processes.

In an aspect, the present invention provides a crystalline Form-Tl of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 5.90, 20.53 and 29.24° ± 0.2° 2Q. In an embodiment, the crystalline Form-Tl is characterized by one or more additional peaks at about 9.72, 17.62, 19.91 and 24.06° ± 0.2° 2Q. In an embodiment, the present invention provides crystalline Form-Tl of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 23.

In another aspect, the present invention provides a crystalline Form-T2 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 12.93, 15.07 and 19.57° ± 0.2° 2Q. In an embodiment, the crystalline Form-T2 is characterized by one or more additional peaks at about 10.01, 24.40, 27.72 and 28.31° ± 0.2° 2Q. In an embodiment, the present application provides crystalline Form-T2 of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 24.

In another aspect, the present invention provides a crystalline Form-T3 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 14.43, 21.59 and 22.95 ⁰ ± 0.2° 2Q. In an embodiment, the crystalline Form-T3 is characterized by one or more additional peaks at about 8.14, 17.33 and 22.33° ± 0.2° 2Q. In an embodiment, the present application provides crystalline Form- T3 of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figures 25.

In another aspect, the present invention provides a crystalline Form-T4 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 8.17, 21.09, 24.75° ± 0.2° 2Q. In an embodiment, the crystalline Form-T4 is characterized by one or more additional peaks at about 15.14, 22.76 and 27.88° ± 0.2° 2Q. In an embodiment, the present application provides crystalline Form- T4 of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figures 26.

In another aspect, the present invention provides a process for the preparation of crystalline Form-Tl of Tafamidis, comprising the step of combining Tafamidis with 2-methoxyethanol.

In another aspect, the present application provides a process for the preparation of crystalline Form-T2 of Tafamidis, comprising the step of combining Tafamidis with N-methyl-2-pyrrolidone.

In another aspect, the present application provides a process for the preparation of crystalline Form-T3 of Tafamidis, comprising the step of combining Tafamidis with dimethylacetamide.

In another aspect, the present application provides a process for the preparation of crystalline Form-T4 of Tafamidis, comprising the step of combining Tafamidis with dimethylsulfoxide.

In embodiments, Tafamidis used in the preparation of crystalline form- Tl, form-T2, form-T3 or form-T4 may be obtained by any methods known in the art or a reaction mixture comprising Tafamidis may be used directly.

In embodiments, the crystalline forms of Tafamidis of the present application are stable under thermal, humid and stress conditions. Further, the crystalline forms of present application exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Tafamidis.

In another aspect, the present application provides a crystalline Tafamidis, selected from Form-Tl, Form-T2, Form-T3 and Form-T4, or the pharmaceutical compositions thereof, comprising Tafamidis with a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

The suitable organic solvent at any stage of the process of the present invention may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert -butyl ether, diethyl ether, 1,4- dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N- methyl 2-pyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures thereof.

Suitable temperatures for the reaction at any stage of the process of the present invention may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures.

Suitable times for the hydrogenation step at any stage of the process of the present invention may be from about 30 minutes to about 10 hours, or longer.

The removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.

The compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.

The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.

The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.

In an embodiment, Tafamidis or its meglumine salt of present invention has average particle size of particles between 1 to 100 pm, less than 90 pm, less than 80 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 20 pm, less than 10 pm, less than 5 pm or any other suitable particle sizes. In another embodiment, Tafamidis or its meglumine salt of present invention may have particle size distribution: D10 of particles smaller than 20 pm, smaller than 15 pm, smaller than 10 pm, or smaller than 5 pm; D50 of particles smaller than 100 pm, smaller than 90 pm, smaller than 80 pm, smaller than 70 pm, smaller than 60 pm, smaller than 50 pm, smaller than 40 pm, smaller than 30 pm, smaller than 20 pm, smaller than 10 pm; D90 of particles smaller than 200 pm, smaller than 175 pm, smaller than 150 pm, smaller than 140 pm, smaller than 130 pm, smaller than 120 pm, smaller than 110 pm, smaller than 100 pm, smaller than 90 pm, smaller than 80 pm, smaller than 70 pm, smaller than 60 pm, smaller than 50 pm, smaller than 40 pm, smaller than 30 pm, smaller than 20 pm, smaller than 10 pm.

Particle size distributions of Tafamidis or its meglumine salt particles may be measured using any techniques known in the art. For example, particle size distributions of Tafamidis or its meglumine salt particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “DIO” in the context of the present invention is 10% of the particles by volume are smaller than the DIO value and 90% particles by volume are larger than the DIO value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.

In an embodiment, Tafamidis or its meglumine salt of present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The compounds of this application are best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 A and were obtained using a PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.

Thermogravimetry-differential thermal analysis (TG-DTA) was performed on a Rigaku Thermo plus EV02 TG-DTA8122 instrument. The measurement was carried out under a dry nitrogen stream (a flow rate of 320 mL/min) and a normal pressure at a temperature rising rate of 10 °C/min.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application. Definitions

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

EXAMPLES

Example- 1: Preparation of Tafamidis

To a mixture of 4-amino 3-hydroxybenzoic acid (75 g) and 25% N-methyl 2- pyrrolidone in toluene (750 mL), 3,5-dichlorobenzoyl chloride (110.6 g) was added at 26 °C. The reaction mixture was heated to 115 °C and stirred at the same temperature for 18 hours. After the completion of reaction, p- toluenesulfonic acid monohydrate (67.5 g) was added to the reaction mixture at 114 °C and stirred for 20 hours at the same temperature. The mixture was cooled to 28 °C and added to hexane (1.5 litres). The reaction mixture was stirred at 28 °C for 30 minutes and the solid was filtered. The solid was combined with water (1.5 litres) at 28 °C and stirred for 30 minutes. The solid was filtered and washed with water (500 mL). The solid was again combined with water (1.5 litres) at 28 °C and stirred for 30 minutes. The solid was filtered and washed with water (500 mL). The wet solid was dried in hot air oven at 70 °C for 16 hours to obtain 90 g of the title compound as a solid with HPLC purity of 97.1%

Example-2: Preparation of Tafamidis

To a mixture of 4-amino 3-hydroxybenzoic acid (75 g) and 25% N-methyl 2- pyrrolidone in toluene (750 mL), 3,5-dichlorobenzoyl chloride (112.9 g) was added at 26 °C. The reaction mixture was heated to 120 °C and stirred at the same temperature for 6 hours. After the completion of reaction, p- toluenesulfonic acid monohydrate (46.6 g) was added slowly to the reaction mixture at 120 °C. The reaction mixture was heated further to 145 °C and stirred for 16 hours at the same temperature. Further, p-toluenesulfonic acid monohydrate (18.63 g) was added slowly and stirred for 5 hours at the same temperature. The mixture was cooled to 26 °C and added to water (4.5 litres). The reaction mixture was stirred at 26 °C for 16 hours. The solids were allowed to settle down and the supernatant liquid was separated out. Water (4.5 litres) was added to the solids and the suspension was stirred at 26 °C for 5 hours and filtered. The solid was dried in a hot air oven at 80 °C. The dried compound was stirred with 30% ethyl acetate in hexane (0.75 litres) for 2 hours at 26 °C and filtered. The solid was washed with 30% ethyl acetate in hexane (2 x 0.375 litres) and dried under vacuum for 2 hours to obtain a pale brown colored solid with HPLC purity of 93.38%. The dry solid (129 g) was combined with tetrahydrofuran (3.87 litres) and the reaction mixture was heated to 60 °C. Activated carbon (12.9 g) was added to the mixture at 60 °C and the suspension was stirred for 1 hour at the same temperature. The mixture was then filtered through celite bed. The filtrate was cooled to 25 °C and added slowly to water (5.16 litres), and the suspension was stirred for 2 hours at 25 °C. The solid was filtered and washed with water (1.29 litres), followed by hexanes (2 x 1.29 litres). The solid was dried under vacuum for 4 hours to obtain 113 g of the title compound as a as a pale brown colored solid with HPLC purity of 96.8% Example-3: Preparation of meglumine salt of Tafamidis A mixture of Tafamidis (80 g) in isopropyl alcohol (1.6 litres) was heated to 74 °C and water (280 ml) was added. A solution of N-Methyl-D-glucamine (Meglumine) (50.6 g) in water (160 mL) was added to the above mixture at 74 °C followed by the addition of carbon (8 g) and the resultant mixture was stirred for 1 hour at the same temperature. The mixture was filtered through a celite bed and the filtrate was concentrated to nearly half its volume (800 mL) at 50 °C under reduced pressure. The mixture was stirred at 26 °C for 18 hours and the solid was filtered. The solid was washed with isopropyl alcohol (80 mL) and dried in a hot air oven at 70 °C for 6 hours to obtain 105 g of title compound as off-white solid with HPLC purity of 99.3%

Example-4: Purification of Tafamidis A mixture of Tafamidis (84 g, HPLC purity: 98.0%) in isopropyl alcohol (1.7 litres) was heated to 74 °C and water (300 ml) was added. A solution of N- Methyl-D-glucamine (Meglumine) (53.2 g) in water (170 mL) was added to the above mixture at 72 °C and the resultant mixture was stirred for 2 hours at the same temperature. The mixture was filtered through celite bed and the filtrate was concentrated to nearly half its volume (1000 mL) at 50 °C under reduced pressure. The mixture was stirred at 26 °C for 18 hours and the solid was filtered. The solid was washed with isopropyl alcohol (84 mL) and dried in a hot air oven at 70 °C for 4 hours to obtain 115 g of Tafamidis meglumine salt as an off-white solid. The meglumine salt was combined with water (1150 mL), the pH of the resulting mixture was adjusted to 4 with 2 N HC1 (90 mL) at 26 °C and the resultant suspension was stirred at the same temperature for 2 hours. The solid was filtered and washed with water (575 mL). The wet solid was dried in a hot air oven at 80 °C for 16 hours to obtain 70.0 g of title compound as an off-white solid with HPLC purity of 99.22%.

Example-5: Purification of Tafamidis

Tafamidis (15 g, HPLC purity: 96.8%) was dissolved in 2 N sodium hydroxide solution (300 mL) at 25 °C and the mixture was washed with ethyl acetate (2 x 150 mL). The aqueous layer was separated, cooled to 0 °C and the pH was adjusted to 2 by addition of 1 N hydrochloric acid. The resulting suspension was stirred for 2 hours at 25 °C. The solid was filtered and washed with water (2 x 300 mL) and hexane (150 mL). The solid was dried under vacuum at 30 °C for 4 hours to obtain the of title compound as an off-white solid with HPLC purity of 98.06%.

Example-6: Purification of Tafamidis

Tafamidis (2 g, HPLC purity 98.0%) was dissolved in tetrahydrofuran (100 mL) at 26 °C and benzylamine (0.65 mL) was added. The reaction mixture was stirred for 17 hours at 26 °C and the solid was filtered. The wet solid was washed with tetrahydrofuran (6 mL) and dried in a hot air oven at 80 °C for 6 hours to obtain 1.1 g of the benzylamine salt of Tafamidis as an off-white crystalline solid with 99.8% purity by HPLC. The benzylamine salt (0.85 g) obtained above was combined with water (8.5 mL) at 26 °C. 2 N hydrochloric acid (1.7 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with water (4.25 mL). The wet solid was triturated in water (8.5 mL) for 30 minutes at 26 °C and the solid was filtered and washed with water (4.25 mL). The wet solid was dried in hot air oven at 80 °C for 18 hours to obtain 0.47 g of an off-white solid. The solid obtained above was combined with a mixture of 25% acetone in water (4.7 mL) at 26 °C. 2 N hydrochloric acid (0.94 mL) was added to the reaction mixture and stirred for 2 hours at the same temperature. The solid was filtered and washed with 25% acetone in water (2.34 mL). The wet solid was dried in hot air oven at 80 °C for 18 hours to obtain 0.35 g of the title compound as an off-white solid with HPLC purity of 99.9%.

Example-7: Purification of Tafamidis

Tafamidis (2 g, HPLC purity 98.0%) was dissolved in dimethyl suphoxide (80 mL) at 26 °C and benzylamine (0.65 mL) was added. The reaction mixture was stirred for 17 hours at 26 °C and the solid was filtered. The wet solid was washed with dimethyl suphoxide (10 mL) and dried in hot air oven at 80 °C for 6 hours to obtain 2.2 g of the benzylamine salt of Tafamidis as off-white crystalline solid with 99.7% purity by HPLC. The benzylamine salt (2 g) obtained above was combined with water (20 mL) at 26 °C. 2 N hydrochloric acid (4 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with water (10 mL). The wet solid was triturated in water (20 mL) for 30 minutes at 26 °C, filtered and washed with water (10 mL). The wet solid was dried in hot air oven at 80 °C for 18 hours to obtain 1.69 g of an off-white solid. The solid obtained above was combined with a mixture of 25% acetone in water (16.9 mL) at 26 °C. 2 N hydrochloric acid (3.38 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with 25% acetone in water (8.45 mL). The wet solid was dried in a hot air oven at 80 °C for 18 hours to obtain 1.16 g of the title compound as an off-white solid with traces of benzylamine present. To remove the benzylamine traces, the dried solid was combined with a mixture of 25% acetone in water (11.6 mL) at 26 °C. 2 N hydrochloric acid (2.3 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C the same temperature. The solid was filtered and washed with 25% acetone in water (5.8 mL). The wet solid was dried in a hot air oven at 80 °C for 18 hours to obtain 1.06 g of the title compound as an off-white solid with HPLC purity of 99.7%.

Example-8: Purification of Tafamidis

Tafamidis (1.5 g, HPLC purity 98.0%) was dissolved in dimethyl suphoxide (60 mL) at 26 °C and dicyclohexylamine (0.93 mL) was added. The reaction mixture was stirred for 16 hours at 26 °C and the solid was filtered. The wet solid was washed with dimethyl suphoxide (4.5 mL) and dried in a hot air oven at 80 °C for 6 hours to obtain 2.0 g of the dicyclohexylamine salt of Tafamidis as an off- white crystalline solid with 99.5% purity by HPLC. The salt (1.74 g) obtained above was combined with water (17.4 mL) at 26 °C. 2 N hydrochloric acid (3.48 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with water (8.7 mL). The wet solid was triturated in water (17.4 mL) for 30 minutes at 26 °C, and the solid was filtered and washed with water (8.7 mL). The wet solid was dried in hot air oven at 80 °C for 18 hours to obtain 0.76 g of title compound as off-white solid with 99.6% HPLC purity.

Example-9: Purification of Tafamidis

Tafamidis (1.5 g, HPLC purity 98.0%) was dissolved in tetrahydrofuran (75 mL) at 26 °C and dicyclohexylamine (0.93 mL) was added. The reaction mixture was stirred for 16 hours at 26 °C and the solid was filtered. The wet solid was washed with tetrahydrofuran (4.5 mL) and dried in hot air oven at 80 °C for 6 hours to obtain 1.86 g of the dicyclohexylamine salt of Tafamidis as off-white crystalline solid with 99.5% purity by HPLC. The dicyclohexylamine salt (1.74 g) obtained above was combined with water (17.4 mL) at 26 °C. 2 N hydrochloric acid (5.96 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with water (8.7 mL). The wet solid was triturated in water (17.4 mL) for 30 minutes at 26 °C, filtered and washed with water (8.7 mL). The wet solid was dried in a hot air oven at 80 °C for 18 hours to obtain 0.9 g of an off-white solid. The solid obtained above was combined with a mixture of 25% acetone in water (9.0 mL) at 26 °C. 2 N hydrochloric acid (1.8 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with 25% acetone in water (4.5 mL). The wet solid was dried in hot air oven at 80 °C for 18 hours to obtain 0.85 g of an off white solid with minor amount of dicyclohexylamine present. In order to remove the dicyclohexylamine impurity, the solid obtained above was combined with a mixture of 25% acetone in water (8.5 mL) at 26 °C. 2 N hydrochloric acid (1.8 mL) was added to the reaction mixture and the suspension obtained was stirred for 2 hours at 26 °C. The solid was filtered and washed with 25% acetone in water (4.25 mL). The wet solid was dried in a hot air oven at 80 °C for 18 hours to obtain 0.49 g of the title compound as off-white solid with HPLC purity of 99.5 %.

Example- 10: Purification of Tafamidis

Tafamidis (100 mg, HPLC purity 98.0%) was dissolved in tetrahydrofuran (5 mL) at 26 °C and diethanolamine (0.03 mL) was added. The reaction mixture was stirred for 16 hours at 26 °C and the solid was filtered. The wet solid was washed with tetrahydrofuran (1 mL) and dried under vacuum at 46 °C for 45 min to obtain 120 mg of the diethanolamine salt of Tafamidis as off-white crystalline solid with 99.6% purity by HPLC. The diethanolamine salt (60 mg) obtained above was combined with water (1.8 mL) at 26 °C. 2 N hydrochloric acid (0.12 mL) was added to the reaction mixture and the suspension obtained was stirred for 3 hours at 26 °C. The solid was filtered and washed with water (1.2 mL). The wet solid was dried under vacuum at 45 °C for 45 min to obtain 40 mg of the title compound as off-white solid with HPLC purity of 99.6 %.

Example-11: Preparation of amorphous solid dispersion of Tafamidis with povidone.

To a mixture of dichloro methane (10 mL) and tetrahydrofuran (10 mL), Tafamidis (250 mg) followed by povidone K-30 (250 mg) were added at 27 °C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45 °C under reduced pressure to obtain 450 mg of the title compound off- white solid. PXRD: Amorphous.

Example-12: Preparation of amorphous solid dispersion of Tafamidis with copovidone.

To a mixture of dichloro methane (10 mL) and tetrahydrofuran (10 mL), Tafamidis (250 mg) followed by copovidone (250 mg) were added at 27 °C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45 °C under reduced pressure to obtain 465 mg of the title compound off- white solid. PXRD: Amorphous.

Example-13: Preparation of solid dispersion of Tafamidis with HPMC.

To a mixture of dichloro methane (10 mL) and tetrahydrofuran (20 mL), Tafamidis (250 mg) followed by HPMC (250 mg) were added at 27 °C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45 °C under reduced pressure to obtain 440 mg of the title compound off- white solid. The compound (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of title compound. PXRD: Figure 19.

Example-14: Preparation of solid dispersion of Tafamidis with HPC.

To a mixture of dichloro methane (10 mL) and tetrahydrofuran (20 mL), Tafamidis (250 mg) followed by HPC (250 mg) were added at 27 °C. The mixture was stirred at the same temperature for 15 minutes and the resultant solution was filtered to make it particle free. The clear solution was evaporated at 45 °C under reduced pressure to obtain 450 mg of the title compound off- white solid. The compound (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of title compound. PXRD: Figure 20.

Example-15: Preparation of amorphous Tafamidis meglumine.

Tafamidis meglumine (250 mg) was dissolved in water (25 mL) at 27 °C and the solution was frozen at -78 °C. The frozen solution was lyophilized for 16 hours under reduced pressure to obtain 225 mg of the title compound as a solid. The solid (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of the title compound. PXRD: Amorphous.

Example-16: Preparation of amorphous solid dispersion of Tafamidis meglumine with copovidone.

Tafamidis meglumine (250 mg) and copovidone (250 mg) were dissolved in water (40 mL) at 27 °C and the solution was frozen at -78 °C. The frozen solution was lyophilized for 16 hours under reduced pressure to obtain 460 mg of the title compound as a solid dispersion. The solid dispersion (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of the title compound. PXRD: Amorphous.

Example-17: Preparation of amorphous solid dispersion of Tafamidis meglumine with povidone.

Tafamidis meglumine (250 mg) and povidone K-30 (250 mg) were dissolved in water (40 mL) at 27 °C and the solution was frozen at -78 °C. The frozen solution was lyophilized for 16 hours under reduced pressure to obtain 475 mg of the title compound as a solid dispersion. The solid dispersion (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of the title compound. PXRD: Amorphous.

Example-18: Preparation of amorphous solid dispersion of Tafamidis meglumine with HPMC.

Tafamidis meglumine (250 mg) and HPMC (250 mg) were dissolved in water (40 mL) at 27 °C and the solution was frozen at -78 °C. The frozen solution was lyophilized for 16 hours under reduced pressure to obtain 450 mg of the title compound as a solid dispersion. The solid dispersion (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 60 minutes to obtain the premix of the title compound. PXRD: Amorphous.

Example-19: Preparation of amorphous solid dispersion of Tafamidis meglumine with Soluplus. Tafamidis meglumine (250 mg) and Soluplus (250 mg) were dissolved in water (25 mL) at 27 °C and the solution was frozen at -78 °C. The frozen solution was lyophilized for 16 hours under reduced pressure to obtain 440 mg of the title compound as a solid dispersion. The solid dispersion (100 mg) was combined with Syloid 244 FP (100 mg) and ground in a mortar-pestle for 30 minutes to obtain the premix of the title compound. PXRD: Amorphous.

Example-20: Preparation of crystalline Form-Tl of Tafamidis.

A mixture of Tafamidis (200 mg) and 2-methoxyethanol (1 mL) was stirred for 4.5 hours at 27° C and the solid was filtered to obtain title compound. XRPD: Crystalline Form-Tl.

Example-21: Preparation of crystalline Form-T2 of Tafamidis.

A mixture of Tafamidis (200 mg) and N-methyl-2-pyrrolidone (1 mL) was stirred for 4 hours at 27° C and the solid was filtered to obtain title compound. XRPD: Crystalline Form-T2.

Example-22: Preparation of crystalline Form-T3 of Tafamidis.

A mixture of Tafamidis (250 mg) and dimethylacetamide (1 mL) was stirred for 5 hours at 27° C and the solid was filtered to obtain title compound. XRPD: Crystalline Form-T3.

Example-23: Preparation of crystalline Form-T4 of Tafamidis.

A mixture of Tafamidis (200 mg) and dimethylsulfoxide (0.5 mL) was stirred for 24 hours at 27° C and the solid was filtered and dried to obtain title compound. XRPD: Crystalline Form-T4.

Example-24: Preparation of crystalline Form-T4 of Tafamidis.

A mixture of Tafamidis (100 mg) and dimethylsulfoxide (0.3 mL) was milled in a ball-mill with 2 capsules for 0.5 hours at 27° C and the solid was dried to obtain title compound. XRPD: Crystalline Form-T4.

Example-25: Preparation of meglumine salt of Tafamidis.

A mixture of Tafamidis (5 g) in isopropyl alcohol (100 mL) was heated to 74 °C and water (17.6 ml) was added. A solution of N-Methyl-D-glucamine (Meglumine) (3.16 g) in water (10 mL) was added to the above mixture at 70 °C and the resultant mixture was stirred for 2 hours at the same temperature. The mixture was filtered through a celite bed; the filtrate was cooled to 0 °C and concentrated at 40 °C under reduced pressure. Acetonitrile (50 mL) was added and the mixture was stirred at 26 °C for 3 hours. The solid was filtered, washed with acetonitrile (25 mL) and dried in a hot air oven at 70 °C for 2 hours to obtain 4.4 g of title compound as an off-white solid with HPLC purity of 99.5%.