Polymorphs Of 2 (3,5 Dichlorophenyl) L,3 Benzoxazole 6 Carboxylic Acid

Honour Lab Limited
Application Awaiting Examination App No 202347085680 Chemical

Patent information

IP India · live record
Application number
202347085680
Filing date
15 December 2023
Status
Application Awaiting Examination
Publication number
25/2025
Publication type
INA
Invention field
Chemical

Abstract

The present invention relates to polymorphic forms of Tafamidis of Formula I, process for their preparation and pharmaceutical composition comprising it.

Applicants

1
India
HONOUR LAB LIMITED H.NO:8-3-166/7/1, ERRAGADDA, HYDERABAD-500018, TELANGANA, INDIA

Inventors

3
India
RATHNAKAR REDDY, KuraH.NO:8-3-166/7/1, ERRAGADDA, HYDERABAD-500018, TELANGANA, INDIA
India
SUBHASH CHANDER REDDY, KesireddyH.NO:8-3-166/7/1, ERRAGADDA, HYDERABAD-500018, TELANGANA, INDIA
India
SIVA NAGI REDDY, MuleH.NO:8-3-166/7/1, ERRAGADDA, HYDERABAD-500018, TELANGANA, INDIA

Claims

7
2 A process for the preparation of Tafamidis crystalline Form HNl according to claim 1 having Powder X-Ray Diffraction pattern as shown in Figure l, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH ofthe mass with an acid to 3 - 4.5 to precipitate the solid; and c. filtering the solid and drying the solid at 80-85°C till the moisture content is <1.0% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid.
3 Tafamidis crystalline Form designated as Form HNZ having Powder X-Ray Diffraction pattern as shown in Figure 2.
4 A process for the preparation of Tafamidis crystalline Form HNZ according to claim 3 having Powder X-Ray Diffraction pattern as shown in Figure 2, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 4.5 to precipitate the solid; and c. filtering the solid and drying the solid below 50°C till the moisture content is 4- 6% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid
5 Tafamidis crystalline Form designated as Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3.
6 A process for the preparation of Tafamidis crystalline Form HN3 according to claim 5 having Powder X-Ray Diffraction pattern as shown in Figure 3, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 5 to precipitate the solid; and c. filtering the solid and drying the solid at below 40°C, wherein acid is selected fi'om group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid;
7 A pharmaceutical composition comprising an oral dosage form of Tafamidis crystalline Form HNl, Form HN2, Form HN3, wherein oral dosage form is a tablet, pill, capsule,
8 Tafamidis crystalline Form HNI, Form HN2, Form HN3 claimed in claims I, 3 and 5 and its process claimed in claims 2, 4 and 6 have yields greater than 98% WM and purity greater than 99% by HPLC

Specification

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FIELD OF THE INVENTION The present invention relates to poly morphs of 2-(3,S-Dichlorophenyl)—1,3-benzoxazole-6-carboxylic acid, process for their preparation and pharmaceutical composition comprising it BACKGROUND OF THE INVENTION Tafamidis and Tafamidis Meglumine represented by the following structures Formula I and Formula [A that contains Tafamidis as active moiety chemically known as 2-(3,5-dichloropheny|)-|,3—benzoxazole-6-carboxylic acid. In USA, Tafamidis is approved as both , Tafamidis and Tafamidis Meglumine salt, whereas in Europe it’s approved as Tafamidis Meglumine salt and are marketed under trade name VYNDAMAXTM 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 9,249,112 82 of Pfizer Inc, discloses Tafamidis meglumine different polymorphic forms, Form M, Form B and amorphous Form A. US 9,770,441 Bl of Pfizer Inc discloses different polymorphic forms of Tafamidis designated as Form 1, Form 2, Form 4, Form 6, amorphous form; wherein Tafamidis Form 1 has been prepared from lsopropanol; 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. WO 2019175263 Alof Azad Pharma Ag discloses Tafamidis crystalline form, Tafamidis acetic acid adduct, Tafamidis formic acid adduct; wherein Tafamidis crystalline form is prepared by heating dispersion of Tafamidis acetic acid adduct in solvent capable of removing acetic acid and thereafter drying the precipitate obtained. WO 2020232325 A1 of Teva discloses different polymorphic forms designated as Tafamidis Form I, II, III, IV, V, amorphous form; wherein Form 1, a hydrate form has been prepared from amorphous form and also from tetrahydrofuran and water; Form 1], a 2-methyl tetrahydrofuran solvate has been prepared by evaporating a solution of Tafamidis in 2-methyl tetrahydrofuran; Form 111, Form IV are acetic acid solvates, prepared from acetic acid; Form V is a methanol solvate obtained from solvent antisolvenl crystallization, wherein antisolvent taken is methanol and methanol solvate is dried to give Form V in anhydrous form. acid; Form N has been prepared by treating Tafamidis Form S with water and then isolated; Form R has been prepared by using polar aprotic solvent and water as anti-solvent and further treated with acetic acid and isolated. Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations ofthe 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 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 ofa drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms ofa compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR). Tafamidis exits in different polymorphic forms which differ in the physicochemica| 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 with higher solubility. The present inventors have developed the ecofriendly process for preparation of Tafamidis crystalline forms from Tafamidis meglumine by avoiding use of environmentally hazardous solvents, In view of this the present inventors have found crystalline forms of Tafamidis which are 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 OBJECTIVE OF THE INVENTION The objective of the present invention is to provide crystalline forms of Tafamidis, processes for their preparation and pharmaceutical composition comprising it. Another objective ofthe present invention is to provide crystalline forms of Tafamidis with high yields and high purity. Another objective of the present invention is to provide process for crystalline forms of Tafamidis from Tafamidis meglumine without using organic solvents. SUMMARY OF THE INVENTION The present invention relates to Tafamidis crystalline form designated as Form HNl having Powder X-Ray Diffraction pattern as shown in Figure 1. In other embodiment, the present invention relates to a process for the preparation of Tafamidis crystalline Form HNl having Powder X-Ray Diffraction pattern as shown in Figure l, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 4.5 to precipitate the solid; and c, filtering the solid and drying the solid at 80-85°C till the moisture content is <1.0% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid. In other embodiment, the present invention relates to Tafamidis crystalline form designated as Form HNZ having Powder X-Ray Diffraction pattern as shown in Figure 2. In other embodiment, the present invention relates to a process for the preparation of Tafamidis crystalline Form HN2 having Powder X-Ray Diffraction panem as shown in Figure 2, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 4.5 to precipitate the solid; and c. filtering the solid and drying the solid below 50°C till the moisture content is 4- 6% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid. In other embodiment, the present invention relates to Tafamidis crystalline form designated as Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3, In other embodiment, the present invention relates to a process for the preparation of Tafamidis crystalline Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 5 to precipitate the solid; and c. filtering the solid and drying the solid at below 40°C, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to different crystalline forms of Tafamidis designated as Form HNI, Form HN2 and Form HN3. In one aspect, the present invention relates to Tafamidis crystalline form designated as Form HN 1 having Powder X-Ray Diffraction pattern as shown in Figure 1. In another aspect, the present invention relates to Tafamidis crystalline Form HNI having Powder X-Ray Diffraction pattern as shown in Figure 1 , which comprises treating tafamidis Meglumine with water and adjusting the pH ofthe mass with an acid to 3 - 4.5 wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid to precipitate the solid, filtering the solid and drying the solid at 80-85°C for 12 - 14 hours till the moisture content is <1 .0% w/w. In another aspect, the present invention relates to Tafamidis crystalline form designated as Form HNZ having Powder X-Ray Diffraction pattern as shown in Figure 2. In another aspect, the present invention relates to Tafamidis crystalline Form HNZ having Powder X-Ray Diffraction pattern as shown in Figure 2, which comprises treating tafamidis Meglumine with water and adjusting the pH ofthe mass with an acid to 3 - 4.5 wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid to precipitate the solid, filtering the solid and drying the solid below 50°C for 18 - 24 hours till the moisture content is 4-6% w/w. In another aspect, the present invention relates to Tafamidis crystalline form designated as Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3. In another aspect, the present invention relates to Tafamidis crystalline Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3, which comprises treating tafamidis Meglumine with water and adjusting the pH ofthe mass with an acid to 3 - 5 wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid to precipitate the solid, filtering the solid and drying the solid below 40°C for [4 - 15 hours till the moisture content is less than 10%. In another aspect, the present invention provides drying the solid is carried out by using hot air or under vacuum. In another aspect, the present invention provides a pharmaceutical composition comprising an oral dosage form of Tafamidis crystalline Form HNI, Form HNZ or Form HN3 wherein oral dosage form is a tablet, pill or capsule preferably sofi gel capsule. In another aspect, the crystalline forms of the present invention are preserved in air tight containers and stored room temperature and preferably at 2-8°C temperature under nitrogen atmosphere In another aspect, the room temperature is considered at 25—30°C. In another aspect, the crystalline forms of the present invention are packed in laminated polybags filled with nitrogen. In another aspect, the crystalline forms of the present invention are protected from heat, light and moisture. In another aspect, the present invention, Tafamidis crystalline polymorphs of the present invention can be prepared from Tafamidis salts selected from Tafamidis sodium, Tafamidis potassium, Tafamidis triethanolamine. EMEA scientific discussion provides the solubility studies with Tafamidis (Form 1) showed that the active substance has water solubility < 2 pg/mL at pH 5 and below. However the crystalline Forms of the present invention has water solubility greater than or equal to 3 pg/mL at pH 5 and below We claim: I. Tafamidis crystalline Form designated as Form HNI having Powder X-Ray Diffraction pattern as shown in Figure I. 2. A process for the preparation of Tafamidis crystalline Form HNl according to claim 1 having Powder X-Ray Diffraction pattern as shown in Figure l, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH ofthe mass with an acid to 3 - 4.5 to precipitate the solid; and c. filtering the solid and drying the solid at 80-85°C till the moisture content is <1.0% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid. 3. Tafamidis crystalline Form designated as Form HNZ having Powder X-Ray Diffraction pattern as shown in Figure 2. 4. A process for the preparation of Tafamidis crystalline Form HNZ according to claim 3 having Powder X-Ray Diffraction pattern as shown in Figure 2, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 4.5 to precipitate the solid; and c. filtering the solid and drying the solid below 50°C till the moisture content is 4- 6% w/w, wherein acid is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid 5. Tafamidis crystalline Form designated as Form HN3 having Powder X-Ray Diffraction pattern as shown in Figure 3. 6. A process for the preparation of Tafamidis crystalline Form HN3 according to claim 5 having Powder X-Ray Diffraction pattern as shown in Figure 3, which comprises: a. treating Tafamidis Meglumine with water; b. adjusting the pH of the mass with an acid to 3 - 5 to precipitate the solid; and c. filtering the solid and drying the solid at below 40°C, wherein acid is selected fi'om group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid and citric acid; 7. A pharmaceutical composition comprising an oral dosage form of Tafamidis crystalline Form HNl, Form HN2, Form HN3, wherein oral dosage form is a tablet, pill, capsule, 8. Tafamidis crystalline Form HNI, Form HN2, Form HN3 claimed in claims I, 3 and 5 and its process claimed in claims 2, 4 and 6 have yields greater than 98% WM and purity greater than 99% by HPLC

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Application documents
1 202347085680-Other Patent Document-151223.pdf 29 Dec 2023
2 202347085680-Form 5-151223.pdf 29 Dec 2023
3 202347085680-Form 26-151223.pdf 29 Dec 2023
4 202347085680-Form 2(Title Page)-151223.pdf 29 Dec 2023
5 202347085680-Form 1-151223.pdf 29 Dec 2023
6 202347085680-Form 3-090524.pdf 13 May 2024
7 202347085680-Correspondence-090524.pdf 13 May 2024
8 202347085680-FORM 18 [09-06-2025(online)].pdf 09 Jun 2025