Claims:1. A Tafamidis free acid novel crystalline form-N, characterized by peaks in the powder x-ray diffraction spectrum having 2-theta angle positions at about 5.97, 13.72, 20.3 and 27.07 ~ 0.2 degrees.

2. A Tafamidis free acid novel crystalline form-N, characterized by peaks in the powder x-ray diffraction spectrum having 2-theta angle positions at about 5.97, 6.72, 8.96, 11.08, 11.89, 13.42, 13.72, 14.65, 16.30, 17.83, 19.0, 20.13, 20.34, 22.40, 23.59, 23.82, 24.54, 27.07, 31.01, 33.82, 36.17, 39.71, 41.73, 44.43 and 48.23 ~ 0.2 degrees.

3. A Tafamidis free acid novel crystalline form-N, characterized by an x-ray powder diffractogram as shown in figure 1.

4. A Tafamidis free acid novel crystalline form-N characterized by a differential scanning calorimetry (DSC) thermogram exhibiting a phase transition of about 283 °C - 290 °C.

5. A Tafamidis free acid novel crystalline form-N, characterized by a differential scanning calorimetry (DSC) as shown in figure 3.

6. A process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis free acid amorphous Form of formula I.
ii) dissolving Tafamidis free acid amorphous Form of formula I in solvent;
iii) heating the reaction mixture obtained in step (ii) to 60 °C to 80 °C;
iv) adding second solvent to the reaction mixture obtained in step (iii);
v) cool the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N of Tafamidis free acid.

7. A process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis free acid crystalline Form IV of formula I.
ii) dissolving Tafamidis free acid crystalline Form IV of formula I in solvent;
iii) heating the reaction mixture obtained in step (ii) to 60 °C to 80;
iv) adding second solvent to the reaction mixture obtained in step (iii);
v) cool the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N of Tafamidis free acid.

8. A process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) adding seed material to the mixture obtained step (iv);
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

9. A process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) adding seed material to the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.
10. A process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) stirring the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

11. The process claimed in claims 6 to 7, wherein the base used in in step i) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide.

12. The process claimed in claims 6 to 10, wherein the solvent used in step i, ii, iii, iv, v, vi and vii) is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof.

13. The process claimed in claims 6 to 10, wherein the second solvent used in step iii and iv) is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. , Description:FIELD OF THE INVENTION
The present invention relates to a novel crystalline Form-N of Tafamidis free acid of formula I.
The present invention also relates to a process for the preparation of novel crystalline form-N of Tafamidis free acid of formula-I.

BACKGROUND OF THE INVENTION
Tafamidis free acid (VYNDAMAX®) is chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecular formula is C14H7Cl2NO3 and the molecular weight is 308.11 g g/mol. and is represented by the structural formula I:

Tafamidis free acid (VYNDAMAX®) is indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

VYNDAQEL is Brand name of Tafamidis meglumine.

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. VYNDAMAX and VYNDAQEL are not substitutable on a per mg basis.

US 7,214,695 B2 discloses Tafamidis and its pharmaceutically acceptable salts. The patent also discloses the process for the preparation of Tafamidis using chromatography which is not industrially feasible.

US 9,770,441 B2 claims crystalline Form 1 of Tafamidis. This patent also discloses crystalline forms like Form 2, 4 & 6; amorphous form of Tafamidis and process for their preparation.

WO 2019/175263 A1 claims crystalline Form of Tafamidis free acid, Crystalline Tafamidis acetic acid adduct and crystalline Tafamidis formic acid adduct and process for their preparation.

The USFDA recommends that applicants for drug product registration investigate whether the drug substance can exist in polymorphic forms; this is discussed in the agency's draft guidance for industry entitled "ANDAs: Pharmaceutical Solid Polymorphism," which was published in December 2004. Therefore, it is always desirable to identify as many polymorphic forms as possible, in connection with the product development.

OBJECTS OF THE INVENTION
The primary object of the invention is to provide a novel crystalline Form-N of Tafamidis free acid.

Another object of the invention is to provide a process for the preparation of novel crystalline Form-N of Tafamidis free acid.

SUMMARY OF THE INVENTION

The present invention relates to a novel crystalline form-N of Tafamidis free acid.

In one aspect, the present invention provides novel crystalline form-N of Tafamidis free acid characterized by PXRD pattern with strong peaks at about 5.97, 13.72, 20.34 and 27.07 ± 0.2 ° 2?.

In another aspect, the present invention provides novel crystalline form-N of Tafamidis free acid further characterized by PXRD pattern with peaks at about 5.97, 6.72, 8.96, 11.08, 11.89, 13.42, 13.72, 14.65, 16.30, 17.83, 19.0, 20.13, 20.34, 22.40, 23.59, 23.82, 24.54, 27.07, 31.01, 33.82, 36.17, 39.71, 41.73, 44.43 and 48.23 ° 2? ° 2? and PXRD pattern substantially as depicted in Figure - 1.

In another aspect, the present invention provides novel crystalline form-N of Tafamidis free acid further characterized by a differential scanning calorimetry (DSC) thermogram exhibiting phase transitions at about 283 °C - 290 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline
form-N of Tafamidis free acid.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid Amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vi) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N compound of formula I.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis free acid amorphous form of formula I.
ii) dissolving Tafamidis free acid amorphous form of formula I in solvent;
iii) heating the reaction mixture obtained in step (ii) to 60 °C to 80 °C;
iv) adding second solvent to the reaction mixture obtained in step (iii);
v) cool the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N compound of formula I.

In another aspect, the present invention provides process for the preparation of novel crystalline
form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vi) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N compound of formula I.

In another aspect, the present invention provides process for the preparation of novel crystalline
form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis crystalline Form IV of formula I.
ii) dissolving Tafamidis free acid crystalline Form IV of formula I in solvent;
iii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N compound of formula I.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) adding seed material to the mixture obtained step (iv);
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) adding seed material to mixture obtained step (iv) to -10 °C to 10°C;
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

In yet another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) stirring the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure - 1: represents X-ray Powder Diffraction Pattern of Novel Crystalline Form-N of Tafamidis free acid.
Figure - 2: represents a table showing the X-ray powder diffraction peaks and calculated d-values for the Novel Crystalline Form-N of Tafamidis free acid.
Figure - 3: represents Differential Scanning calorimetry (DSC) curve Novel Crystalline Form-N Tafamidis free acid.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel crystalline form-N of Tafamidis free acid.

In one aspect, the present invention provides novel crystalline form-N of Tafamidis free acid characterized by PXRD pattern with strong peaks at about 5.97, 13.72, 20.34 and 27.07 ± 0.2 ° 2?.

In another aspect, the present invention provides novel crystalline form-N of Tafamidis free acid further characterized by PXRD pattern with peaks at about 5.97, 6.72, 8.96, 11.08, 11.89, 13.42, 13.72, 14.65, 16.30, 17.83, 19.0, 20.13, 20.34, 22.40, 23.59, 23.82, 24.54, 27.07, 31.01, 33.82, 36.17, 39.71, 41.73, 44.43 and 48.23 ± 0.2 ° 2? and PXRD pattern substantially as depicted in Figure - 1.

In another aspect, the present invention provides novel crystalline form-N of Tafamidis free acid further characterized by a differential scanning calorimetry (DSC) thermogram exhibiting phase transitions at about 283°C – 290 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline
form-N of Tafamidis free acid.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vi) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N of formula I.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step iii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iii) second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step v) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step v) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis free acid amorphous form of formula I.
ii) dissolving Tafamidis free acid amorphous form of formula I in solvent;
iii) heating the reaction mixture obtained in step (ii) to 60 °C to 80 °C;
iv) adding second solvent to the reaction mixture obtained in step (iii);
v) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure novel crystalline form-N of formula I.

In step i) base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide and the like. Preferably lithium hydroxide.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Water, Methanol and THF.

In step ii) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step iii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iv) second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step vi) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step v) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vi) dry the solid in hot air oven/vacuum oven at 55 °C to 75 °C to obtain pure novel crystalline form-N compound of formula I.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Water, Methanol and THF.

In step iii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70°C.

In step iii) second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step iii & v) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step v) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In yet another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) hydrolysis compound of formula 1

in the presence of base and solvent to give Tafamidis crystalline Form IV of formula I.
ii) dissolving Tafamidis free acid crystalline Form IV of formula I in solvent;
iii) heating the reaction mixture obtained in step (ii) to 60 °C to 80 °C;
iv) adding second solvent to the reaction mixture obtained in step (iii);
v) cool the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven/vacuum oven at 55 °C to 75 °C to obtain pure crystalline form-N compound of formula I.

In step i) base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide and the like. Preferably lithium hydroxide.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Water, Methanol and THF.

In step ii) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step iii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iv) second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step v) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vi) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step vii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) adding seed material to the mixture obtained step (iv);
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step ii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iii & iv) Second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step iii & vi) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vii) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step viii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) adding second solvent to the reaction mixture obtained in step (ii);
iv) cool the reaction mixture obtained in step (iii) to -10 °C to 10 °C;
v) adding seed material to mixture obtained step (iv) to -10 °C to 10°C;
vi) stirring the reaction mixture obtained in step (v) to -10 °C to 10 °C;
vii) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
viii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step ii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iii) Second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step iv, v & vi) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vii) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step viii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

In yet another aspect, the present invention provides process for the preparation of novel crystalline form-N of Tafamidis free acid comprising the steps of:
i) dissolving Tafamidis free acid crystalline Form IV or amorphous form of formula I in solvent;
ii) heating the reaction mixture obtained in step (i) to 60 °C to 80 °C;
iii) pre-cooled second solvent to -10 °C to 10 °C;
iv) adding second solvent to the reaction mixture obtained in step (ii);
v) stirring the reaction mixture obtained in step (iv) to -10 °C to 10 °C;
vi) isolating Tafamidis free acid crystalline form of formula I and wash with chilled solvent; and
vii) dry the solid in hot air oven at 55 °C to 75 °C to obtain pure crystalline form-N of formula I.

In step i) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF.

In step ii) the reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 65 °C to 70 °C.

In step iii & iv) Second solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step iii & v) the reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C.

In step vi) solvent used is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Methyl tert butyl ether.

In step vii) the reaction temperature may range from 55 °C to 75 °C and preferably at a temperature in the range from 60 °C to 65 °C.

The XRD and DSC are shown in the Figures 1-3. The novel crystalline form-N of Tafamidis free acid is characterized by X-ray powder diffraction spectrum having principal peaks at 5.97, 6.72, 8.96, 11.08, 11.89, 13.42, 13.72, 14.65, 16.30, 17.83, 19.0, 20.13, 20.34, 22.40, 23.59, 23.82, 24.54, 27.07, 31.01, 33.82, 36.17, 39.71, 41.73, 44.43 and 48.23 ° 2?.

PXRD:

X-ray diffractometer system:
Instrument : PANalytical X’pert PRO
Generator settings : PW3040;45Kv, 40mA
Sample stage : Pw 3064/00 sample spinner (spinning with 1°/sec).
X-ray radiation : ? (CuKa1) = 1.540598 A°
Incident beam optics
Primary soller slit : 0.02 rad
PDS : Automatic, Irradiated length 10.0mm
Anti Scatter Slit Slit 1°
Primary mask : 10 mm
Diffracted beam optics
Filter : Nickel (no monochromator should be used)
Secondary soller slit : 0.02 rad
Prog.Anti Scatter Slit : Slit 2°
Detector : X’celerator detector (Scanning mode, active length of 2.1°)
Control software : X’pert data collector
Program type : Absolute scan

Scan type : gonio
Scan mode : continuous
Range : 2°.00 to 50°.00
Step size : 0.01671°
Time per Step : 19.685 sec
Scan speed : 0.107815 °/sec

DSC:

Differential scanning calorimeter:
Instrument Make : Perkin Elmer
Model : DSC 4000
Initial Temperature* : 30 °C
End Temperature * : 300 °C
Nitrogen Flow* : 20 mL
Ramp Temperature /Heating Rate? : 10 °C/minute
Hold time* : 1 minute at Initial & End Temperatures.
Sample Preparation : Take about 2-5 mg of sample in DSC pan and place the cover over the pan then seal the pan by using crimper

EXAMPLES

Example 1: Process for the preparation of novel crystalline form-N of Tafamidis free acid from Amorphous from.
Lithium hydroxide monohydrate (4.0 eq) was added to a mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole 1 (1.0 eq), THF (20 vol), Methanol (5 vol) and Purified water (5.0 vol) at 25-35 °C and stir the mass at same temperature for 2-3 hours. After completion of the reaction, reaction mass pH adjust to 1.5-2.0 with 1N HCl solution. Cool the reaction mass to 0- 5 °C and stir for 1 hour at 0- 5 °C. Filter the resulting solid and wash with purified water. The wet solid was slurry with purified water (10 vol) for 1 hour at 25-35 °C. Filter the resulting solid and wash with purified water. Dry the solid in air oven at 80-85 °C. Above dried material taken into Tetrahydrofuran (20 vol) and heated to 65-70 °C for 30 minutes. The resulting clear solution undergo carbon treatment and filtered through Hyflo bed. Filtrate again heated to 65-70 °C and add Methyl tert butyl ether (20 vol) and stir the contents for 20 minutes. cool the contents to 0-5 °C and stir for 2-3 hours at same temperature. The resulting solid filter and washed with chilled Methyl tert butyl ether. Dry the solid in Hot air oven at 60-65 °C to give novel crystalline form-N of Tafamidis free acid.
Yield: 80%.

Example 2: Process for the preparation of novel crystalline form-N of Tafamidis free acid from crystalline Form IV.
Lithium hydroxide monohydrate (4.0 eq) was added to a mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole 1 (1.0 eq), THF (20 vol), Methanol (5 vol) and Purified water (5.0 vol) at 25-35 °C and stir the mass at same temperature for 2-3 hours. After completion of the reaction, reaction mass pH adjust to 2.0 – 3.0 with Acetic acid. Cool the reaction mass to 0- 5 °C and stir for 1 hour at same temperature. Filter the resulting solid and wash with purified water. The wet solid was slurry with purified water (10 vol) for 1hour at 25-35 °C. Filter the resulting solid and wash with purified water. Dry the solid in Air oven at 80-85 °C. Above dried material taken into Tetrahydrofuran (20 vol) and heated to 65-70 °C for 30 minutes. The resulting clear solution undergo carbon treatment and filtered through Hyflo bed. Filtrate again heated to 65-70 °C and add Methyl tert butyl ether (20 vol) and stir the contents for 20 minutes. cool the contents to 0-5 °C and stir for 2-3 hours at same temperature. The resulting solid filter and wash with chilled Methyl tert butyl ether. Dry the solid in Hot air oven at 60-65 °C to give novel crystalline form-N of Tafamidis free acid.
Yield: 80%.

Example 3: Process for the preparation of novel crystalline form-N of Tafamidis free acid from crystalline From-IV or amorphous.
Tafamidis (From-IV or amorphous) taken into Tetrahydrofuran (20 vol) and heated to 65-70 °C and stirred for 30 minutes at same temperature. The resulting clear solution undergo carbon treatment and filtered through Hyflo bed and be washed with THF (2 vol). The lower filtrate heated to 60-70 °C and stirred for 10-30 minutes at same temperature. Pre-cooled MTBE (25 v) to 0-10 oC. The reaction mass was added to MTBE at 0-10 oC and seed material was added. The resulted mass was stirred for at least 2 hours at same temperature. The resulting solid filter and wash with chilled Methyl tert butyl ether. Dry the solid in Hot air oven at 60-65 °C to give novel crystalline form-N of Tafamidis free acid.
Yield: 80%.

Example 4: Process for the preparation of novel crystalline form-N of Tafamidis free acid from crystalline From-IV or amorphous.
Tafamidis (From-IV or amorphous) taken into Tetrahydrofuran (20 vol) and heated to 65-70 °C and stirred for 30 minutes at same temperature. The resulting clear solution undergo carbon treatment and filtered through Hyflo bed and be washed with THF (2 vol). The lower filtrate heated to 60-70 °C and stirred for 10-30 minutes at same temperature. Pre-cooled MTBE (25 v) to 0-10 oC. The reaction mass was added to MTBE at 0-10 oC and stirred for at least 2 hours at same temperature. The resulting solid filter and washed with chilled Methyl tert butyl ether. Dry the solid in Hot air oven at 60-65 °C to give novel crystalline form-N of Tafamidis free acid.
Yield: 80%.

Example 5: Process for the preparation of novel crystalline form-N of Tafamidis free acid from crystalline From-IV or amorphous.
Tafamidis (From-IV or amorphous) taken into Tetrahydrofuran (20 vol) and heated to 65-70 °C and stirred for 30 minutes at same temperature. The resulting clear solution undergo carbon treatment and filtered through Hyflo bed and be washed with THF (2 vol). The lower filtrate heated to 60-70 °C and stirred for 10-30 minutes at same temperature. Add Methyl tert butyl ether (20 vol) and stir the contents for 20 minutes. Cool the contents to 0-5 °C and seed material was added and stir for 2-3 hours at same temperature. The resulting solid filter and washed with chilled Methyl tert butyl ether. Dry the solid in Hot air oven at 60-65 °C to give novel crystalline form-N of Tafamidis free acid.
Yield: 80%.