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