DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141016881 filed on April 10, 2021; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to process for the preparation Tafamidis meglumine (1). It also relates to the process for the preparation of Tafamidis solid dispersion forms with pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of amorphous Tafamidis (2).

BACKGROUND OF THE INVENTION
Tafamidis meglumine (1) is benzoxazole derivative chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono (1-deoxy-1-methylamino-D-glucitol) currently marked in the U.S. under the trade name VYNDAQEL (Tafamidis meglumine) with the structural formula of (1) as 20 mg, 16 mg capsule. VYNDAQEL indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults. Tafamidis is marketed as VYNADAMAX with the structural formula of (2)

The synthesis of Tafamidis meglumine (1) was reported in few patents, the contents of which are hereby incorporated as reference in their entirety.
US 7214695 patent describes the synthesis of Tafamidis (1) by coupling of 4-amino-3-hydroxybenzoic acid and 3,5-dichlorobenzoyl chloride in presence of tetrahydro furan and pyridine. It does not disclose the isolation and purification of intermediate or the final compound Tafamidis meglumine (1).
US9249112 patent, discloses the polymorphic forms of Tafamidis meglumine as form M, form B and amorphous form A.
US 9770441 patent discloses different polymorphic forms of Tafamidis as form 1, form 2, form 4, form 6 and amorphous form. And it’s preparation involves the reaction of 4-amino-3- hydroxybenzoic acid with 3,5-dichlorobenzoylchloride to provide crude 4-[(3,5- dichlorobenzoyl) amino]-3-hydroxybenzoic acid which is further isolated after work up using triethylamine. The obtained compound further cyclized to form Tafamidis and converted to form 1 using isopropanol. Further 1 converted to form 2, 4, 5 and 6.
WO2020232325 application discloses preparation of Tafamidis amorphous form and crystalline form I, II, III, IV and V. Tafamidis form I is obtained from tetrahydrofuran (THF), form II from 2-methyl tetrahydrofuran, form III, and form IV from acetic acid at different temperatures. Tafamidis form via obtained using tetrahydrofuran and methanol as antisolvent.
WO2021019448 application discloses different solid dispersion forms of Tafamidis (2) and the process of preparing the same. Wherein Tafamidis solid dispersions are disclosed with copovidone and hydroxypropyl methylcellulose.
Tafamidis meglumine (1) and Tafamidis (2) are biopharmaceutical classification system (BCS) class II drugs, which means that they are poorly soluble, but permeate biological membranes well. Hence, there is a need of other polymorphic forms, which are stable and suitable for pharmaceutical composition.

OBJECTIVE OF THE INEVNTION
The main objective of the present invention is to provide an improved process for the preparation of Tafamidis meglumine (1).

Another objective of the invention is to provide process for the preparation of stable amorphous form of Tafamidis (2).
Yet another objective of the present invention is to provide Tafamidis (2) solid dispersion and preparation thereof.
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is to provide an improved process for the preparation of Tafamidis meglumine (1) comprising:
a) converting 3,5-dichlorobenzoic acid (6) to 3,5-dichlorobenzoyl chloride (5) in-situ and coupling with 4-amino-3-hydroxybenzoic acid (4) to form 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3);
b) converting 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3) to Tafamidis (2); and
c) converting crude Tafamidis (2) to Tafamidis meglumine (1).
In another aspect, Tafamidis meglumine (1) so obtained is having purity greater than 99.5% (w/w).
In another aspect of the invention is to provide amorphous form of Tafamidis (2),
comprising the following steps:
1. adding Tafamidis (2) to a suitable solvent or mixture of solvents;
2. heating the reaction mass to a suitable temperature.
3. cooling the reaction mass to a suitable temperature; and
4. isolating amorphous Tafamidis (2).
Yet in another aspect of the present invention is to provide Tafamidis (2) solid dispersion and preparation thereof.
i. suspending Tafamidis (2), in a suitable solvent or mixture of solvents.
ii. adding a suitable pharmaceutically acceptable excipient to the reaction mixture;
iii. optionally, heating the reaction mixture at a suitable temperature; and
iv. isolating solid dispersion of Tafamidis (2) with a suitable pharmaceutically acceptable excipient using a suitable technique.
In further aspect, the present invention provides process for the preparation of Co-crystalline forms of Tafamidis (2). Wherein the suitable organic acid or organic amides can be used for the preparation of co-crystalline forms of Tafamidis (2).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1: X-Ray powder diffraction (XPRD) pattern of crystalline Tafamidis meglumine (1) prepared by example 3.
Figure 2: X-Ray powder diffraction (XPRD) pattern of amorphous Tafamidis (2) prepared by example 4.
Figure 3: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2 with ethylene glycol prepared by example 5.
Figure 4: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) with polyethylene glycol prepared by example 6.
Figure 5: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) (Eudragit) prepared by example 7.
Figure 6: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) (Eudragit) prepared by example 8.
Figure 7: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) (PVP) prepared by example 9.
Figure 8: X-Ray powder diffraction (XPRD) pattern of amorphous form of Tafamidis (2) prepared by example 10.
Figure 9: X-Ray powder diffraction (XPRD) pattern of Tafamidis (2) prepared by example 11.
Figure 10: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 12.
Figure 11: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 13.
Figure 12: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 14.
Figure 13: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 15
Figure 14: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 16.
Figure 15: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 29.
Figure 16: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 30.
Figure 17: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 31.
Figure 18: X-Ray powder diffraction (XPRD) pattern of solid dispersion of Tafamidis (2) prepared by example 34.
Figure 19: X-Ray powder diffraction (XPRD) pattern of amorphous form of Tafamidis (2) prepared by example 44.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of Tafamidis meglumine (1) as shown in scheme 1, comprising:
a) converting 3,5-dichlorobenzoic acid (6) to 3,5-dichlorobenzoyl chloride (5) in-situ and coupling with 4-amino-3-hydroxybenzoic acid (4) to form 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3);
b) converting 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3) to Tafamidis (2); and
c) converting crude Tafamidis (2) to Tafamidis meglumine (1).

Scheme-1
In one embodiment, step a) proceeds with the conversion of 3,5-dichlorobenzoic acid (6) to 3,5-dichlorobenzoyl chloride (5) with a suitable chlorinating agent, at a temperature of 0-40 °C, preferably 25-30 °C. The suitable chlorinating agent may be selected from a group comprising of thionyl chloride, phosphoryl chloride, oxalyl chloride, methane sulfonyl chloride, trichloromethane sulfonyl chloride, tert-Butyl hypochlorite, N-chlorosuccinimide, chloromethyl methyl ether, dichloro methyl ether or the like, preferably thionyl chloride was used in the present invention.
In some embodiment, step b) involves coupling of 3,5-dichlorobenzoyl chloride (5) with 4-amino-3-hydroxybenzoic acid (4) to 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3). 3,5-dichlorobenzoyl chloride (5) may be dissolved in a suitable solvent and reacted with 4-amino-3-hydroxybenzoic acid (4) in presence of suitable base and acid. The reaction mass was stirred at 25-30°C to form 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3) which may be directly used in the next step.
The suitable base used in step b) may be selected from a group comprising of organic or inorganic bases. Organic bases may be selected from a group comprising of triethyl amine, diisopropyl ethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane or the like. The inorganic base were used in the present invention was selected from the group comprising of alkoxides of alkali and alkaline metals such as potassium tertiary butoxide, lithium tertiary butoxide, or the like; hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide or the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate, magnesium carbonate or the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate or the like. Preferably, triethyl amine and sodium hydroxide was used in the present invention.
In some embodiment, step c) proceeds with cyclization of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3) in presence of a suitable acid. The reaction may be carried out at a temperature of 80-130°C preferably 100-110 °C. The reaction mass may be treated with carbon, filtered, and cooled the reaction mass to 20-40 °C, preferably 25-30°C. The solid formed may be filtered and washed with a suitable solvent to obtain Tafamidis (2).
Suitable acid used in step b) and c) can be selected from the group comprising of organic and inorganic acids. The organic acids may be selected from acetic acid trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-toluene sulphonic acid or the like. The inorganic acid may be selected from a group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, or the like. Preferably methane sulphonic acid, p-toluene sulphonic acid, acetic acid and hydrochloric acid were used in the present invention.
In some embodiment, step d) proceeds with reacting Tafamidis (2) with N-methyl meglumine to form Tafamidis meglumine (1). The reaction was carried out at 40-70 °C preferably 50-55 °C and cooling the reaction mass to 20-40 °C, preferably 25-30°C and washing with a suitable solvent to obtain Tafamidis meglumine (1).
In another embodiment, the present invention provides a process for the purification of Tafamidis meglumine (1), comprising the following steps:
1) adding Tafamidis meglumine (1) to a suitable first solvent ;
2) heating the reaction mass to a suitable temperature;
3) adding suitable second solvent; and
4) isolating pure Tafamidis meglumine (1).
Tafamidis meglumine (1) may be added to a suitable solvent or mixture of solvents and heated to 40-100 oC, preferably 50-70 oC. The reaction mass may be optionally treated with another solvent and cooled to 20-40 °C preferably 25-30 °C and isolated using a suitable technique to yield pure Tafamidis meglumine (1).
In another embodiment, the Tafamidis meglumine (1) so obtained is having purity greater than 99% (w/w).
Alternatively, Tafamidis meglumine can be prepared by isolating each stage and purifying all the intermediates to obtain purity greater than 95%. (w/w).
Another objective of the invention is to provide amorphous form of Tafamidis (2),
comprising the following steps:
1. adding Tafamidis (2) to a suitable solvent or mixture of solvents ;
2. heating the reaction mass to a suitable temperature;
3. cooling the reaction mass to a suitable temperature; and
4. isolating amorphous Tafamidis (2).
In some embodiment, the present invention provides process for the preparation of amorphous form of Tafamidis (1), by suspending Tafamidis (1) in a suitable solvent and heating to a suitable temperature of 25-50 °C, preferably 40-45 °C. The solvent may be removed and amorphous Tafamidis (2) may be isolated.
Yet, another objective of the present invention is to provide Tafamidis (2) solid dispersion and preparation thereof.
i. suspending Tafamidis (2), in a suitable solvent or mixture of solvents;
ii. adding a suitable pharmaceutically acceptable excipient to the reaction mixture;
iii. optionally, heating the reaction mixture at a suitable temperature; and
iv. isolating solid dispersion of Tafamidis (2) with a suitable pharmaceutically acceptable excipient using a suitable technique.
In some embodiment, the present invention provides process for the preparation of solid dispersions of Tafamidis (2), by suspending Tafamidis (2) and a suitable pharmaceutically acceptable excipient in a suitable solvent and heating to a suitable temperature of 30-50 °C, preferably 40-45 °C. The excess solvent may be removed and solid dispersions of Tafamidis (2) may be isolated using a suitable technique.
In some embodiment, the suitable pharmaceutically acceptable excipients used in the present invention may be selected from a group comprising of lactose, sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), polyethylene glycol (PEG), ethylene glycol , polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl methyl cellulose acetate succinate (HPMC -AS), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD), hydroxy propyl methyl cellulose -E3 (HPMC-E3), Soluplus , Neusilin , Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP) , croscarmellose, sodium croscarmellose, a-cyclodextrin, ß-Cyclodextrin, ?-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-ß-cyclodextrin (SBCED), Lactose, Sucrose, Mannitol or the like. Preferably, ethylene glycol, polyethylene glycol, polyethylene glycol (PEG-400), Eudragit, Soluplus, Lactose, Sucrose, Mannitol, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-K-30(PVP-K-30), Hydroxypropyl methylcellulose acetate succinate (HPMC-AS), 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD) were used in the present invention.

In another embodiment the solid forms obtained in the present invention may be isolated by a suitable technique comprising of but not limited to filtration, precipitation, cooling, re-crystallization, concentrating the mass, distillation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, air tray drying (ATD) , vacuum tray drying (VTD ), spray drying, thin-film drying, agitated thin-film drying, freeze-drying, decantation, centrifugation technics or the like, preferably distillation , spray drying, vacuum tray drying (VTD) and air tray drying (ATD) were used in the present invention. The drying can be carried out at a suitable temperature ranging from 30 °C to about 60°C, preferably from 40 °C to about 45 °C.
In some embodiment, the suitable solvents used may be selected from a group comprising of organic or inorganic solvents, preferably organic solvents comprising of protic or aprotic solvents may be used , which may be selected from a group comprising of acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide, methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran, water, methanol, ethanol, isopropyl alcohol (IPA), dioxane, N, N-dimethylformamide, toluene or the like. Preferably N,N-dimethylformamide, tetrahydrofuran, dichloromethane acetone, dichloromethane, toluene, methanol, water or mixtures thereof were used in the present invention.
In another embodiment, the present inventors tried hot melt extrusion method for the preparation of amorphous form of Tafamidis.
In another embodiment, the present invention provides process for the preparation of Co-crystalline forms of Tafamidis (2). Wherein the suitable organic acid or organic amides can be used for the preparation of co-crystalline forms of Tafamidis (2). Wherein the suitable organic acid is selected for the preparation of co-crystalline forms is selected from the group comprising of L-pyroglutamic acid, Fumaric acid, acetic acid, 4-hydroxy benzoic acid, ascorbic acid. Organic amide is selected from the group comprising of Nicotinamide or the like.
In another embodiment, the molar ratio of pure Tafamidis (2) and pharmaceutically acceptable excipients used herein was selected from 1:1 to 1:20.
In another embodiment, the Tafamidis (2) and its solid dispersions are having characterized by X-ray diffraction (XRD) pattern as illustrated in figure 1, figure 2, figure 3, figure 4, figure 5, figure 6, figure7, figure 8, figure 9, figure 10, figure 11, figure 12, figure 13, figure 14, figure15, figure16, figure17, figure18 and figure19.
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE-1: Preparation of 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylic acid (3)
100 g of 3,5-Dichlorobenzoic acid (6) and 3 mL of N, N-dimethylformamide were charged in 1L flask at 25-30 ?. To the reaction mixture 124.4 g of thionyl chloride was added and heated to 75-80 ?. The reaction temperature was cooled to 25-30 ? to yield 3,5-dichlorobenzoyl chloride (5). 80g of 4-amino-3-hydroxybenzoicacid (4) and 600 mL of tetrahydrofuran were added at 25-30 ?. To this reaction mixture 50 mL water and the reaction mixture containing 3,5-dichlorobenzoyl chloride (5) dissolved in 200 mL of tetrahydrofuran were added at 25-30 ?. The reaction mass was stirred for 30 minutes at 25-30 ?. Trimethylamine was added to the reaction mixture, followed by addition of 1N hydrochloric acid solution, stirred at 25-30 °C and filtered. To the filtrate, methylene chloride was added, and aqueous layers separated. The pH of aqueous layer was adjusted to 6-7 with aqueous hydrochloric acid at 25-30 ?. The product obtained was washed with water. To the crude product 800 mL of acetic acid was added and stirred for 3hrs. The product obtained was washed with acetic acid and dried to obtain 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylic acid (3). Yield:85% (w/w), Purity: 95% (w/w).

EXAMPLE-2: Preparation of Tafamidis (2)
100 g of 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylic acid (3), 294 g of methane sulfonic acid, 58 g p-toluene sulfonic acid were added together and heated to 100-110 °C for 24 hrs. On completion of reaction, acetic acid was added to the reaction mass, stirred, and heated to 115-120 ?. for 4hrs. 10g of carbon was added to the reaction mixture at 115-120 ?., stirred and filtered. The filtrate was washed with acetic acid followed by ethyl acetate, then dried ? to obtain pure Tafamidis
(2). Yield: 60%(w/w); Purity:95.4% (w/w).
EXAMPLE-3: Preparation of Tafamidis meglumine (1)
100 g of Tafamidis (2) was added to 1000 mL methanol and 150 mL of water at 25-30 ?. 63.3 g N-methyl-D-glucamine (Meglumine) was added to the reaction mass and heated to 50-55 ? for 1 hr. The reaction mass was cooled to 25-30 °C and stirred for 2 hrs. The solid obtained was filtered, washed with methanol, and dried at 60-65 ? to get Tafamidis meglumine (1). Yield: 70%, Purity:99.91%(w/w); XRD: Figure 1.
EXAMPLE-4: Preparation of Tafamidis (2) Amorphous form
1g of Tafamidis (2) was taken in dimethyl sulfoxide and heated to 120-130 ? and then the reaction mixture was cooled to room temperature to get the amorphous Tafamidis. Yield: 80%; XRD: Figure 2.
EXAMPLE-5: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was taken in dimethyl sulfoxide and then 1g of ethylene glycol was added, and the reaction mixture was heated to 120-130?. And then the reaction mixture cooled to 25-30? to get the Tafamidis solid dispersion with ethylene glycol. Yield: 80%, XRD: Figure -3.
EXAMPLE-6: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was taken in dimethyl sulfoxide at 25-35 ?. and then 1g of polyethylene glycol was added to the reaction mixture and heated to 120-130 ?. Then the reaction mixture was cooled to 25-30 ? to get Tafamidis solid dispersion with Polyethylene glycol. Yield: 85%; XRD: Figure -4.
EXAMPLE-7: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) and dimethyl sulfoxide were charged at 25-30 ? and then 1g of Eudragit was added to the reaction mass and heated to 120-130 ?. Then cooled to 25-30 ? and the solid formed yielded solid dispersion of the Tafamidis with Eudragit. Yield: 82%(w/w), Figure-5.
EXAMPLE-8: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 80 ml tetrahydrofuran at 25-30 ?. 1g of Eudragit was then added to the reaction mass and heated to 60-65 ?. Then charged 40 mL N-heptane to the reaction mixture. The reaction mass was then cooled to -50 to -45 ?. The obtained solid was washed with n-heptane to yield Tafamidis solid dispersion with Eudragit. Yield: 80%(w/w); XRD: Figure-6.
EXAMPLE-9: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) and 1g of dimethyl sulfoxide were charged at 25-30 ?. 1g of Polyvinylpyrrolidone was added to the reaction mass and heated to 120-130 ?. The reaction mass was then cooled to 25-30 ? and isolated to yield Tafamidis solid dispersion with Polyvinylpyrrolidone. Yield: 80%(w/w); XRD: Figure-7.
EXAMPLE-10: Preparation of amorphous Tafamidis (2)
1g of Tafamidis (2), 4ml of acetic acid were charged at 25-30 ? and stirred for 15-30 min at 25-30 ?. 20 mL of nitromethane was then added to the reaction mass and stirred for 24 hours at 25-30 ?. The reaction mass was dried using air tray dryer (ATD) to yield amorphous Tafamidis (2). Yield: 72%(w/w); XRD-Figure-8.
EXAMPLE-11: Preparation of Tafamidis (2)
1g of Tafamidis (2), 4ml of acetic acid were charged at 25-30 ? and stirred for 15-30 min 20 mL of water was then added and stirred for 24 hours at 25-30 ?. The reaction mass was dried using air tray dryer (ATD) to yield Tafamidis (2). Yield: 60%(w/w); XRD: Figure-9.
EXAMPLE-12: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 40mL of tetrahydrofuran and stirred for 15-20 mins. 2g of (Polyvinylpyrrolidone) K-30 (PVP-K-30) and 20mL of dichloromethane was then added to the reaction mass and stirred. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum below 65°C.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 85%(w/w); XRD: Figure :10
EXAMPLE-13: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 50mL of tetrahydrofuran and stirred for 15-20 mins. 1g of polyvinylpyrrolidone and 25 mL of dichloromethane was then added to the reaction mass and stirred. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum below 65°C.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 87%(w/w); XRD: Figure :11.
EXAMPLE-14: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 250 mL of tetrahydrofuran and stirred for 15-20 mins. 7.5g of polyvinylpyrrolidone (PVP-K-30) and 150 mL of dichloromethane was then added to the reaction mass and stirred. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum below 65°C.The solid so obtained was dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2). Yield: 89%(w/w); XRD: Figure :12
EXAMPLE-15: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 20 mL of tetrahydrofuran and stirred for 15-20 mins. 1g of polyvinylpyrrolidone (PVP-K-30) and 15 mL of dichloromethane was then added to the reaction mass and stirred. The total reaction mixture was stirred for 15-20 mins at 25-30°C and kept at 25-30°C for 3 to 5 days. The solid so obtained was dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2). Yield: 85%(w/w); XRD: Figure :13.

EXAMPLE-16: Preparation of Tafamidis (2) solid dispersion
1g of solid dispersion containing Tafamidis (2) with polyvinylpyrrolidone -K-30 (PVP-K-30) in the ratio of 1:1.5 and 1g of polyethylene glycol (PEG-400) were added in a beaker and stirred for 15-20 mins at 25-30°C. The wet solid so obtained was kept at 25-30°C for 3 to 5 days and dried to yield solid dispersion of Tafamidis (2). Yield: 95%(w/w); XRD: Figure: 14.

EXAMPLE-17: Preparation of Amorphous Tafamidis (2)
1g of Tafamidis (2) was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2mL of water was then added to the reaction mass and transferred into a petri plate and lyophilized at 10 to-40°C with vacuum pressure of 2 -5 mbar for 3days.The solid was further dried in air tray dryer (ATD) to yield amorphous Tafamidis (2). Yield: 83%(w/w).
EXAMPLE-18: Preparation of Tafamidis (2) solid dispersion
1g of solid dispersion containing Tafamidis (2) with polyvinylpyrrolidone -K-30 (PVP-K-30) in the ratio of 1:1 was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2mL of water was then added to the reaction mass and transferred into a petri plate and lyophilized at 10 to-40°C with vacuum pressure of 2 -5 mbar for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 85%(w/w).
EXAMPLE-19: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.1g of 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD) was added to 2mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2). Yield: 81%(w/w).
EXAMPLE-20: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.1g of polyethylene glycol (PEG-400) was added to 2mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 79%(w/w).

EXAMPLE-21: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.1g of mannitol was added to 2mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) polyethylene glycol (PEG-400). Yield: 80%(w/w).
EXAMPLE-22: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 30mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.1g of Sucrose was added to 2mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with Sucrose Yield:85%(w/w).
EXAMPLE-23: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of polyvinylpyrrolidone-K-30 (PVP-K-30) was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2) with polyvinylpyrrolidone-K-30 (PVP-K-30). Yield: 85% (w/w).
EXAMPLE-24: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD)was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2) with 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD) Yield: 75%(w/w).
EXAMPLE-25: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of mannitol was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with mannitol. Yield: 85%(w/w).
EXAMPLE-26: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of polyethylene glycol (PEG-400) was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) polyethylene glycol (PEG-400). Yield: 80%(w/w).
EXAMPLE-27: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of Sucrose was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2) with Sucrose. Yield: 80%(w/w).
EXAMPLE-28: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 60mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C.2g of Lactose was added to 4mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2) with Lactose. Yield:83%(w/w).

EXAMPLE-29: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 40mL of tetrahydrofuran (THF) and stirred for 15-20 mins at 25-30°C. 1.5g of 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD) was added to 20mL of methanol, then added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum below 65°C.The solid so obtained was dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD). Yield: 89%(w/w). Figure 15.
EXAMPLE-30: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 40mL of tetrahydrofuran (THF) and stirred for 15-20 mins at 25-30°C. 1.5g of Soluplus was added to 20mL of methanol, then added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum. The solid so obtained was dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with Soluplus (1:1.5). Yield: 88%(w/w). Figure 16.
EXAMPLE-31: Preparation of Tafamidis (2) solid dispersion
1g of Tafamidis (2) was added to 30mL of tetrahydrofuran (THF) and at 25-30°C. 1.5g of Eudragit was added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum. The solid so obtained was dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with Eudragit. Yield: 86%(w/w). Figure 17.
EXAMPLE-32: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 300mL of tetrahydrofuran (THF) and at 25-30°C. 7.5g of polyvinylpyrrolidone (PVP) dissolved in 80 mL of dichloromethane was added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:
Inlet Temperature : 70°C
Outlet Temperature : 40°C
Aspirator : 70%
Feed Rate : 20ml/min
N2 Pressure 2.0 kg/cm2
The solid so obtained was unloaded and dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2) with polyvinylpyrrolidone (PVP). Yield: 89%(w/w).
EXAMPLE-33: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 200mL of tetrahydrofuran (THF) and at 25-30°C. 7.5g of Eudragit was then added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to a beaker and spray dried. The solid so obtained was unloaded and dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 89%(w/w).
EXAMPLE-34: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 200mL of tetrahydrofuran (THF) and at 25-30°C. 7.5g of Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in 80 mL of dichloromethane was then added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to a beaker and spray dried. The solid so obtained was unloaded and dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 90% (w/w). Figure 18.
EXAMPLE-35: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 300mL of tetrahydrofuran (THF) at 25-30°C. 7.5g of Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was then added to the reaction mass and stirred for 15-20 mins. The total reaction mixture was then transferred to a beaker and spray dried. The solid so obtained was unloaded and dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 60% (w/w).
EXAMPLE-36: Preparation of Tafamidis (2) solid dispersion
5g of Tafamidis (2) was added to 300mL of tetrahydrofuran (THF) at 25-30°C. 10 g of Hydroxypropyl cellulose (HPC) in 80 mL of dichloromethane was then added to the reaction mass and stirred for 10-15 mins. The total reaction mixture was then transferred to a beaker and spray dried. The solid so obtained was unloaded and dried in air tray dryer (ATD) to yield solid dispersion of Tafamidis (2). Yield: 62% (w/w).
EXAMPLE-37: Preparation of Tafamidis (2) solid dispersion
200 mg of Tafamidis (2) was added to 20 mL of tetrahydrofuran and stirred for 10-15 mins. 400 mg of microcrystalline cellulose was then added to the reaction mass. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum at 60-65°C.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 86.6%(w/w);
EXAMPLE-38: Preparation of Tafamidis (2) solid dispersion
200 mg of Tafamidis (2) was added to 20 mL of tetrahydrofuran and stirred for 10-15 mins. 400 mg of microcrystalline cellulose was then added to the reaction mass. The total reaction mixture was then transferred to Beaker and keep a side at RT for 2-3days.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 95%(w/w);
EXAMPLE-39: Preparation of Tafamidis (2) solid dispersion
3 g of Tafamidis (2) was added to 90 mL of tetrahydrofuran and stirred for 10-15 mins. 6 g of Crospovidone was then added to the reaction mass. The total reaction mixture was then transferred to Buchi flask and the solvent distilled off under vacuum at 60-65°C.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 91%(w/w);
EXAMPLE-40: Preparation of Tafamidis (2) solid dispersion
200 mg of Tafamidis (2) was added to 20 mL of tetrahydrofuran and stirred for 10-15 mins. 400 mg of Crospovidone was then added to the reaction mass. The total reaction mixture was then transferred to Beaker and keep a side at RT for 2-3days.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 93.3%(w/w);
EXAMPLE-41: Preparation of Tafamidis (2) solid dispersion
500 mg of Tafamidis (2) was added to 30 mL of tetrahydrofuran at 25-30°C and stirred for 10-15 mins. 500 mg of Ascorbic acid was then added to the reaction mass. The total reaction mixture was then transferred to Beaker and keep a side at RT for 2-3days.The solid so obtained was dried to yield solid dispersion of Tafamidis (2). Yield: 91.1%(w/w);
EXAMPLE-42: Preparation of Tafamidis (2) solid dispersion
500mg of Tafamidis (2) was added to 15mL of dimethyl sulfoxide and stirred for 15-20 mins at 25-30°C. 500mg of polyvinylpyrrolidone (PVP) was added to 1mL of water, then added to the reaction mass and stirred for 15-20 mins and transferred to a petri dish. The petri plate was kept in freeze dryer for lyophilization for 3days.The solid was further dried in air tray dryer (ATD) below 45°C to yield solid dispersion of Tafamidis (2).
EXAMPLE-43: Crystallization process of Tafamidis meglumine (1)
2.5 g of Tafamidis (2) was dissolved in 2-Propanol at 25-35°C and heated to 75-80°C. 5 ml of water and 1.5 g of meglumine were added and stirred for 10-15 mins to get clear solution. Filtered the clear solution and cooled to 60-65°C, further cooled to 5-10°C. Filtered the solid and dried to get the title compound. Yield: 80%
EXAMPLE-44: Preparation of Amorphous Tafamidis (2)
5 g of Tafamidis (2) was dissolved in 150 ml of tetrahydrofuran (THF) at 25-35°C and heated to 60-65°C. The reaction mass stirred for 10-15 mins. 300 ml of water was added at 25-35°C and cooled to 2-5°C. Filtered the solid and washed the wet cake with water to get the title compound. Yield: 80%; Figure 19.
,CLAIMS:1. An improved process for the preparation of Tafamidis meglumine (1),

comprising the steps of;
a) chlorinating 3,5-dichlorobenzoic acid (6) with chlorinating agent in a suitable solvent to form 3,5-dichlorobenzoyl chloride (5) in-situ and coupling with 4-amino-3-hydroxybenzoic acid (4) in the presence of a suitable base and a suitable acid in a suitable solvent to form 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3);

b) cyclizing 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (3) in the presence of a suitable acid to form Tafamidis (2); and

c) reacting Tafamidis (2) with meglumine in a suitable solvent or mixture of solvents to form Tafamidis meglumine (1).
d) purifying Tafamidis meglumine (1), wherein the purification process comprises:
1) adding Tafamidis meglumine (1) to a suitable first solvent.
2) heating the reaction mass to a suitable temperature.
3) adding suitable second solvent; and
4) isolating pure Tafamidis meglumine (1).
2. The process as claimed in claim 1 wherein, the chlorinating agent is selected from the group consisting of thionyl chloride, phosphoryl chloride, oxalyl chloride, methane sulfonyl chloride, trichloromethane sulfonyl chloride, tert-Butyl hypochlorite, N-chlorosuccinimide, chloromethyl methyl ether, dichloro methyl ether and the like; suitable base is selected from the group consisting of an inorganic base or an organic base, wherein the organic base is selected from the group consisting of triethyl amine, diisopropyl ethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane or the like and the inorganic base is selected from the group consisting of alkoxides of alkali and alkaline metals such as potassium tertiary butoxide, lithium tertiary butoxide, or the like; hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, caesium hydroxide or the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate, magnesium carbonate or the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate or the like.

3. The process as claimed in claim 1 wherein, the suitable acid is selected from the group consisting of an organic acid or an inorganic acids, wherein the organic acid is selected from the group consisting of acetic acid trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-toluene sulphonic acid or the like, and the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, or the like.

4. A process for the preparation of amorphous form of Tafamidis (2), comprising the steps of:
1. dissolving Tafamidis (2) in a suitable solvent.
2. heating to a suitable temperature.
3. cooling to a suitable temperature; and
4. isolating amorphous Tafamidis (2).
5. A process for the preparation of amorphous form of Tafamidis (2), comprising the steps of:
1. dissolving Tafamidis (2) in a suitable solvent
2. adding water or nitromethane to the reaction mixture; and
3. drying the solid to get amorphous Tafamidis (2).
6. A process for the preparation of Tafamidis (2) solid dispersion, comprising the steps of:
i. suspending Tafamidis (2), in a suitable solvent or mixture of solvents;
ii. adding a suitable pharmaceutically acceptable excipient to the reaction mixture;
iii. optionally, heating the reaction mixture at a suitable temperature;
iv. cooling the reaction mass to a suitable temperature; and
v. isolating solid dispersion of Tafamidis (2) with a suitable pharmaceutically acceptable excipient using a suitable technique.

7. The process as claimed in claim 1, 4, 5 and 6, wherein the solvent is selected from the group consisting of acetone, acetonitrile, acetic acid, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), N, N-dimethylformamide (DMF), methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, tetrahydrofuran, water, methanol, ethanol, isopropyl alcohol (IPA), toluene and the like or mixture thereof.

8. The process as claimed in claim 7, wherein the pharmaceutically acceptable excipient is selected from the group consisting of lactose, sorbitol, mannitol, saccharose, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose (MCC), crospovidone, polyethylene glycol (PEG), ethylene glycol , polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl methyl cellulose acetate succinate (HPMC -AS), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD), hydroxy propyl methyl cellulose -E3 (HPMC-E3), Soluplus, Neusilin, Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP), croscarmellose, sodium croscarmellose, a-cyclodextrin, ß-Cyclodextrin, ?-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), sulfobutylether-ß-cyclodextrin (SBCED), Lactose, Sucrose, Mannitol or the like. Preferably, ethylene glycol, polyethylene glycol, polyethylene glycol (PEG-400), Eudragit, Soluplus, Lactose, Sucrose, Mannitol, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-K-30(PVP-K-30), Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and 2-Hydroxypropyl)-ß-cyclodextrin (HPBCD).

9. A process for the preparation of co-crystalline forms of Tafamidis (2), comprising the steps of:
I. adding Tafamidis (2) in a suitable organic acid or organic amide; and
II. isolating co-crystalline forms of Tafamidis (2).

10. The process as claimed in claim 9 wherein, the suitable organic acid is selected from the group consisting of L-pyroglutamic acid, Fumaric acid, acetic acid, 4-hydroxy benzoic acid, ascorbic acid; organic amide is selected from the group comprising of Nicotinamide or the like.