FIELD OF THE INVENTION

The present invention relates to process for the preparation of Tafamidis Meglumine as well polymorphic form of Tafamidis.

BACKGROUND OF THE INVENTION

Tafamidis and Tafamidis Meglumine represented by the following structures Formula I and Formula IA that contains Tafamidis as active moiety chemically known as 2-(3,5- dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid. In USA Tafamidis has been approved in different compositions using Tafamidis and Tafamidis Meglumine salt, whereas in Europe it’s approved using Tafamidis Meglumine salt and are marketed under the trade name VYNDAMAX™ and VYNDAQEL ^® . Tafamidis and its salts are approved and indicated for Transthyretin stabilizers for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. The recommended dosage is either VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) orally once daily, or VYNDAMAX 61 mg (one 61 -mg tafamidis capsule) orally once daily.

US 7,214,695 discloses 6-Carboxy-2-(3,5-dihalophenyl)-benzoxazole compounds or pharmaceutically acceptable salts thereof. US’ 695 disclose the process for the preparation of Tafamidis as follows:

US’ 695 is silent about the preparation of Tafamidis meglumine and Tafamidis polymorphic forms. Polymorphism is defined as“the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).

US 9,249,112 B2 of Pfizer Inc, discloses Tafamidis meglumine different polymorphic forms designated as Form M, Form B and amorphous Form A. Further Form M has been prepared by cooling the solution of Tafamidis meglumine in water and isopropanol; Form B has been prepared by freeze drying of Tafamidis meglumine Form M in water and amorphous Form A has been prepared by melting Tafamidis meglumine Form M on aluminium pan and immediately placing the hot plate in liquid nitrogen. US 2019/0119226 A1 of Crystal Pharmatech discloses Tafamidis meglumine Form E, wherein Form E has been prepared using solvents selected from ketones, ethers or esters.

US 9,770,441 B1 of Pfizer Inc discloses different polymorphic forms designated as Tafamidis polymorphs Form 1, Form 2, Form 4, Form 6, amorphous form; wherein Tafamidis Form 1 has been prepared from Isopropanol; Form 2 has been prepared by evaporating tetrahydrofuran solution of Form 1; Form 4 has been prepared by heating suspension of Form 1 in tetrahydrofuran and filtering the hot solution in to toluene and then storing in freezer overnight; Form 6 has been prepared by heating suspension of Form 1 in tetrahydrofuran, adding dimethylacetamide and the solution resulted was transferred in to dichloromethane in chilled ice/water bath and then by vacuum filtration and drying.

Tafamidis and Tafamidis meglumine exits in different polymorphic forms which differ in the physicochemical properties like dissolution and solubility, chemical and physical stability, flowability and hygroscopicity as well as preparation thereof. However, there is still a need of other polymorphs and salts, which are stable and suitable for pharmaceutical composition.

The prior art process involves the isolation of Tafamidis free base, which is time consuming and also not suitable for large scale production of Tafamidis meglumine.

The present inventors have found that in addition to the meglumine salt disclosed there are other salts which can be more easily isolated as crystalline forms and also has enhanced the purity of final active pharmaceutical ingredient.

The present inventors have now found a process for the preparation of Tafamidis meglumine which is convenient, cheap, industrially feasible and economical.

In view of this the present inventors have now found solid dispersion of Tafamidis, which is stable, reproducible, free of other polymorphic forms and suitable for pharmaceutical composition as well as a process suitable industrially for preparing Tafamidis and its pharmaceutically acceptable salt thereof. OBJECTIVES OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of Tafamidis meglumine by not isolating Tafamidis free acid which is commercially and industrially feasible.

Another objective of the present invention is to provide Tafamidis solid dispersion and process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Tafamidis meglumine compound of Formula IA,

wherein the process comprises:

a. cyclizing the compound of Formula IV

with acid or acid anhydrides;

b. adding meglumine;

c. isolating Tafamidis meglumine compound of Formula IA,

wherein the process is carried out by not isolating Tafamidis free acid of Formula I. In other embodiment, the present invention relates to Tafamidis solid dispersion, in combination with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus.

In other embodiment, the present invention relates to process for the preparation of Tafamidis solid dispersion which comprises:

a. treating Tafamidis free acid of Formula I

with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus in a solvent at a suitable temperature;

b. removing the solvent to obtain solid dispersion of Tafamidis in combination with a pharmaceutically acceptable carrier.

In other embodiment, the present invention relates to process for the preparation of Tafamidis solid dispersion which comprises:

a. desaltification of Tafamidis salt of Formula IB by adjusting the pH to 6.0-6.5 with an acid;

b. extracting into a solvent;

c. adding one or more pharmaceutically acceptable carriers selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus in a solvent at a suitable temperature; and d. removing the solvent to obtain solid dispersion of Tafamidis in combination with a pharmaceutically acceptable carrier;

wherein the process is carried out by not isolating Tafamidis free acid of Formula I.

In other embodiment, the present invention relates to process for the preparation of Tafamidis salt of Formula IB which comprises: a. cyclizing the compound of Formula IV

Formula IV with acid or acid anhydrides;

b. adding organic or inorganic base selected from group comprising of alkaline bases, amines in the presence of a solvent;

c. isolating Tafamidis salt of Formula IB;

wherein the process is carried out by not isolating Tafamidis free acid of Formula I.

In other embodiment, the present invention relates to process for the preparation of Tafamidis salt which comprises:

a. treating Tafamidis free acid of Formula I

with organic or inorganic base in a solvent at a suitable temperature; and

b. isolating solid form of Tafamidis salt of Formula IB;

wherein organic or inorganic base is selected from group comprising of alkaline bases, amines.

In other embodiment, the present invention relates to crystalline form of compound of Formula IV which is characterized peaks by Powder X-Ray Diffraction, having the °20 characteristic peaks at 13.5, 15.5, 24.3+ 0.2 degrees. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows powder X-ray diffractogram pattern of compound of Formula IV.

Figure 2 shows powder X-ray diffractogram pattern of Tafamidis solid dispersion with Copovidone.

Figure 3 shows powder X-ray diffractogram pattern of Tafamidis solid dispersion with HPMC.

X-ray powder diffraction spectrum was measured on a Bruker AXS D8 advance X-ray powder diffractometer having a copper radiation. Adequate sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 increment and scan speed of 0.2 Sec/Step. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Tafamidis meglumine compound of Formula IA, wherein the process comprises: cyclizing the compound of Formula IV with acid selected from the group comprising of Methane sulfonic acid, Ethane sulfonic acid, p-Toluene sulfonic acid, Benzene sulfonic acid, Camphor sulfonic acid, D- Camphor sulfonic acid, L- Camphor sulfonic acid, pyridine sulfonic acid, polyphosphoric acid or acid anhydride selected from the group comprising of acetic anhydride, triflic anhydride; adding meglumine; isolating Tafamidis meglumine compound of Formula IA, wherein the process is carried out by not isolating Tafamidis free acid of Formula I.

In another aspect, the present invention relates to a Tafamidis solid dispersion in combination with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus which is obtained in the form of crystalline, amorphous or mixture of crystalline and amorphous form.

In another aspect, the present invention relates to process for the preparation of Tafamidis solid dispersion in combination with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus which comprises: treating Tafamidis free acid of Formula I with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus in a solvent at suitable temperature; removing the solvent to obtain solid dispersion of Tafamidis in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to process for the preparation of Tafamidis solid dispersion in combination with a pharmaceutically acceptable carrier selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus which comprises: desaltification of Tafamidis salt of Formula IB by adjusting the pH to 6.0-6.5 with an acid selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid; extracting into a solvent; adding one or more pharmaceutically acceptable carriers selected from group comprising of copovidone, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, povidone or soluplus in a solvent at suitable temperature; and removing the solvent to obtain solid dispersion of Tafamidis in combination with a pharmaceutically acceptable carrier; wherein the process is carried out by not isolating Tafamidis free acid of Formula I.

In another aspect, the present invention relates to Tafamidis salt of Formula IB which is organic or inorganic salt selected from group comprising of alkali, alkaline earth metal salts or amine salts; wherein alkali metal salts are selected from group comprising of Sodium and Potassium salts; alkaline earth metal salts selected from group comprising of Calcium and Magnesium salts; amines salts selected from group comprising of Triethanol amine, Triethyl amine, Meglumine, racemic (R)- and (S)- isomers of Phenyl ethyl amine, racemic, (R)- and (S)- isomers of Naphthyl ethyl amine, Cyclohexyl amine, Dicyclohexyl amine salts.

In another aspect, the present invention relates to process for the preparation of Tafamidis salt of Formula IB which comprises: cyclizing the compound of Formula IV with acid selected from the group comprising of Methane sulfonic acid, Ethane sulfonic acid, p- Toluene sulfonic acid, Benzene sulfonic acid, Camphor sulfonic acid, D- Camphor sulfonic acid, L- Camphor sulfonic acid, pyridine sulfonic acid, polyphosphoric acid or acid anhydride selected from the group comprising of acetic anhydride, triflic anhydride; adding organic or inorganic base selected from group comprising of alkali bases selected from group comprising of Sodium and Potassium salts; alkaline earth metal bases selected from group comprising Calcium and Magnesium salts; amines selected from group comprising of Triethanol amine, Triethyl amine, Meglumine, racemic (R)- and (S)- isomers of Phenyl ethyl amine, racemic, (R)- and (S)- isomers of Naphthyl ethyl amine, Cyclohexyl amine, Dicyclohexyl amine amines in the presence of a solvent; isolating Tafamidis salt of Formula IB; wherein the process is carried out by not isolating Tafamidis free acid of Formula I.

In another aspect, the present invention relates to process for the preparation of Tafamidis salt which comprises: treating Tafamidis free acid of Formula I with organic or inorganic base selected from group comprising of alkali bases selected from group comprising of Sodium and Potassium salts; alkaline earth metal bases selected from group comprising Calcium and Magnesium salts; amines selected from group comprising of Triethanol amine, Triethyl amine, Meglumine, racemic (R)- and (S)- isomers of Phenyl ethyl amine, racemic, (R)- and (S)- isomers of Naphthyl ethyl amine, Cyclohexyl amine, Dicyclohexyl amine in a solvent at suitable temperature; and isolating solid form of Tafamidis salt of Formula IB.

In other aspect, the present invention relates to crystalline form of compound of Formula IV which is characterized peaks by Powder X-Ray Diffraction, having the °20 characteristic peaks at 13.5, 15.5, 24.3+ 0.2 degrees and as depicted in Figure 1.

In another aspect of the present invention, cyclizing of the compound of Formula IV is carried out in the presence of base selected from group comprising of triethylamine, tri n- butylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, pyridine, picolines, lutidines, quinolone, isoquinolone, imidazole, benzimadazole, 1,2,4-triazole, 1,3,4-triazole, pyrazine, pyrimidine.

In another aspect of the present invention, wherein pharmaceutically acceptable carrier is added to Tafamidis in the proportion of 1:1 to 1:10 and/or 1:1 to 10:1.

In another aspect of the present invention, suitable temperature is the temperature at which the reaction proceeds and is in the range of room temperatures to reflux temperatures.

In another aspect of the present invention, solvent used throughout the invention are selected from polar aprotic solvents, non-polar solvents, protic solvents selected from the group comprising of ketones, esters, nitriles, dimethyl sulfoxide, dimethyl formamide, halogenated hydrocarbons, water, alcohols, ethers, hydrocarbons.

In another aspect of the present invention, ketones are aliphatic ketones selected from the group comprising acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or mixtures thereof; esters are aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof; nitriles are selected from the group comprising of aliphatic nitriles such as C2-C8 nitrile; halogenated hydrocarbons are selected from methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof; alcohols used throughout the invention are selected from aliphatic alcohols selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol, tertiary butanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or mixtures thereof, aromatic alcohols used throughout the invention are selected from the group comprising of phenols, benzylalcohol or mixtures thereof; hydrocarbons are selected from toluene, hexane, pentane, cyclohexane or mixtures thereof; ethers used throughout the invention are selected from the group comprising of symmetrical or asymmetrical ethers or cyclic ethers selected from diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Dimethoxyethane, Anisole, diglyme or mixtures thereof;

In another aspect of the present invention removal of solvent is carried out by techniques well-known in the art, for example, by evaporation, filtration, distillation, or drying.

In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.

EXAMPLES

Reference example

Preparation of Tafamidis

4-amino-3-hydroxybenzoicacid (1.0 eq, LR) was dissolved at 20° C. in a mixture of tetrahydrofuran (19 L/kg) and water (1.9 L/Kg). 3,5-dichlorobenzoylchloride (1.3 equiv) was added as a tetrahydrofuran solution (1.9 L/kg) and the mixture stirred for at least 30 minutes at 20° C. Once the reaction was deemed complete by HPLC (<5% remaining 4- amino-3-hydroxybenzoicacid), triethylamine (1.2 equiv) was added and the mixture was heated to 35° C. and stirred for at least 90 minutes. The solvent was partially displaced with ethanol by constant level distillation until 5-15% THF remained. The slurry was cooled to 20° C. and stirred for at least 60 minutes then the slurry was filtered. The solids were washed with ethanol (3x4 L/kg) then dried under vacuum at 65° C. for at least 16 hours to give pure 4-[(3,5-dichlorobenzoyl)amino]-3-hydroxybenzoic acid in 88-92% yield.

To a slurry of 4-[(3,5-dichlorobenzoyl)amino]-3-hydroxybenzoic acid (1.0 equiv) in tetrahydrofuran (10 L/kg) was added triethylamine (1.1 equiv), followed by water (4 equiv). The mixture was held at 20-25° C. for 1 hour, then the mixture was filtered to remove any remaining insoluble material. Methane sulfonic acid (1.6 equiv) was added and a slurry formed. A constant level displacement of THF/water with toluene was carried out until the reaction temperature was at least 107° C., at which point the displacement was stopped and the reaction then refluxed for at least 15 hours. Once the reaction was deemed complete by UPLC, i.e. >95% pure, it was cooled to 20° C. and 2-propanol (5 L/kg) was added. The slurry was granulated for at least 60 minutes, then filtered and washed twice with 2- propanol (4 L/kg each wash) and dried under vacuum at 60-70° C. for a minimum of 18 hours to give Form 1 in 82-89% yield.

Preparation of Tafamidis Meglumine

6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole free acid (2.5 g, 8.1 mmol) and 2-propanol (49 mL) were charged to a 100 mL jacketed, 2-neck round bottom flask with magnetic stirrer. The resulting slurry was warmed to 70° C. with stirring. Water (8.8 mL) was then charged. In a separate 15 mL round bottom flask a solution of N-methyl-D-glucamine (1.58 g, 8.1 mmol) in 5 mL water was prepared and dissolved with stirring. The aqueous N- methyl-D-glucamine solution was then transferred to the reaction flask over 2 min. Most (but not all) of the solids dissolved by the end of this addition. After 5 min stirring and warming to 79° C., a clear, pale yellow solution resulted. The solution was filtered through a bed of Celite™, cooled to 60° C., then cooled to 10° C. over 2 h. The resulting solids were collected by filtration, washing with 10 mL of 2-propanol. 3.35 g product was obtained (82% yield).

Example 1

Preparation of Tafamidis Meglumine Charged 4-[(3,5-Dichlorobenzoyl)amino]-3-hydroxybenzoic acid (100 gm), water (2 ml), triethylamine (36.4 gm) and tetrahydrofuran (1000 ml) and stirred for 45 - 50 minutes at 25

- 30°C. The mixture was filtered and cooled the filtrate to 10 - 15 °C. Added Methanesulfonic acid (47 gm) below 20° C over a period of 30-45 min. Co-distilled with toluene (1000 ml) at 106°C and removed water azeotropically for at least 12 - 14 hours. Cooled the reaction mixture to 25 - 30°C and added water (200 ml). Added Tetrahydrofuran (1000 ml), stirred for 10 - 15 minutes, separated the layers and extracted the aqueous layer with Tetrahydrofuran (500 ml). Added Meglumine (77.8 gm) to the combined organic layer at 25 - 30°C and stirred for 7 - 8 hours. The solid thus separated was filtered.

Charged the wet solid, Water (50 ml) and Isopropanol (950 ml) at 25 - 30°C. The reaction mixture was heated to 65-70°C and stirred for 2 - 3 hours. Cooled the reaction mixture for 5 - 10° C and stirred for 30 - 40 minutes. The solid separated was filtered and washed with isopropanol and dried to yield 70 gm of Tafamidis meglumine.

Example 2

Preparation of Tafamidis Meglumine

Charged 4-[(3,5-Dichlorobenzoyl)amino]-3-hydroxybenzoic acid (100 gm), water (2 ml), triethylamine (36.4 gm) and tetrahydrofuran (1000 ml) and stirred for 45 - 50 minutes at 25

- 30°C. The mixture was filtered to remove any remaining insoluble material. Cooled the filtrate tolO - 15 °C and added Methanesulfonic acid (47 gm) below 20°C over a period of 30-45 min. Co-distilled with toluene (1000 ml) at 106°C and removed water azeotropically for a period of 12 - 14 hours. Cooled the reaction mixture to 25 - 30°C and added water (200 ml) and separated the layers. Added Meglumine (77.8 gm) to the organic layer at 25 - 30°C and stirred for 7 - 8 hours. Filtered the solid thus separated.

Charged the wet solid, Water (50 ml) and Isopropanol (950 ml) at 25 - 30°C. The reaction mixture was heated to 65-70°C and stirred for 2 - 3 hours. Cooled the reaction mixture for 5 - 10° C and stirred for 30 - 40 minutes. The solid separated was filtered and washed with isopropanol and dried to yield 70 gm of Tafamidis meglumine.

Example 3

Preparation of Tafamidis potassium

Charged Isopropanol (100 ml), Potassium tertiary butoxide (4.37 gm) and stirred for 10 -15 minutes. To the solution was added Tafamidis (10 gm) at 25 - 30°C and stirred for about 45 minutes to 1 hour. Filtered the solid, washed with Isopropanol (10 ml) and dried to give 9.5 gm of Tafamidis potassium salt.

Example 4

Preparation of Tafamidis solid dispersion

Charged 4-[(3,5-Dichlorobenzoyl)amino]-3-hydroxybenzoic acid (100 gm), water (2 ml), triethylamine (36.4 gm) and tetrahydrofuran (1000 ml) and stirred for 45 - 50 minutes at 25 - 30°C. The mixture was filtered and cooled the filtrate for 10 - 15 °C. Added Methanesulfonic acid (47 gm) at below 20° over a period of 30-45 min. Co-distilled with toluene (1000 ml) at 106°C and removed water azeotropically for at least 12 - 14 hours. Cooled the reaction mixture to 25 - 30°C and added water (200 ml), separated the layers. Added Meglumine (77.8 g) to the organic layer at 25 - 30°C and stirred for 7 - 8 hours. Filtered the solid thus separated.

Charged the wet solid, Water (50 ml) and Isopropanol (950 ml) at 25 - 30°C. The reaction mixture was heated to 65-70°C and stirred for 2 - 3 hours. Cooled the reaction mixture for 5 - 10° C and stirred for 30 - 40 minutes. The solid separated was filtered and washed with isopropanol and dried to yield 70 gm of Tafamidis meglumine.

Tafamidis meglumine (100 gm) was suspended in DM water (1000 ml) and adjusted the pH of the reaction mixture to 6.0 -6.5 with cone hydrochloric acid. Added Tetrahydrofuran (1500 ml) and heated the reaction mixture to 50-55°C, stirred for 10 - 15 minutes, separated the layers and filtered through micron filter. Added Copovidone (60 gm) to the filtrate and distilled off the solvent completely under vacuum to yield 115 gm Tafamidis solid dispersion with Copovidone.

Example 5

Preparation of Tafamidis solid dispersion

Charged Tafamidis (10 gm), Copovidone (10 gm) and tetrahydrofuran (200 ml) and heated the reaction mixture to 50 -55°C to obtain clear solution. Distilled off the reaction mixture completely under vacuum and dried to yield 20 gm of Tafamidis solid dispersion with Copovidone.

Example 6

Preparation of Tafamidis solid dispersion Charged Tafamidis (10 gm), Hydroxypropyl methylcellulose (6 gm) and tetrahydrofuran (200 ml) and heated the reaction mixture to 50 -55° C to obtain clear solution. Distilled off the reaction mixture completely under vacuum and dried to yield 16 gm of Tafamidis solid dispersion with Hydroxypropyl methylcellulose.