DESC:Field of invention:
The present invention relates to a process for the preparation of stable crystalline form of Tafamidis free acid and its pharmaceutically acceptable salts.

Background of the invention:
This invention relates to solid forms of 6-carboxy-2-(3.5-dichlorophenyl)-benzoxazole (Tafamidis) that are useful in the treatment of transthyretin amyloid diseases, such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC), in mammals. The compound 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole having the structure

The solid states of Tafamidis are described in U.S. patent Nos. 9770441 name as crystalline forms 1, 2, 4, 6 and methods of making carboxy-2-phenyl-benzoxazoles, as well as pharmaceutical compositions comprising the same, are also described therein.
Although significant strides have been made in the development of polymorphic form of Tafamidis still there is a need in the art to develop a stable and commercially viable polymorphic forms.
Summary of the Invention
The present invention relates to a stable crystalline form of Tafamidis and a process for its preparation. In course of our investigations on industrially feasible procedures for Tafamidis, we surprisingly found a novel crystalline form of Tafamidis. During our continuous efforts in research and development of novel polymorphic forms, we have come across a novel crystalline form of Tafamidis which is consistently reproducible and found to be more stable under standard pharmaceutical operation conditions such as drying, milling, compression, granulation and blending.
In one aspect of the present invention provides a method for preparing crystalline Form-N1 of Tafamidis said method comprising:
1) adding the acid to the compound of 4- [(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) distil the solvent to obtain the compound,
5) optionally, adding the solvent and cool to obtain the compound.

Second aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.4±0.2 and 16.3±0.2, 11.8±0.2 ?.

Another aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2 ?) essentially the same as shown in FIG. 1.
Another aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 ± 2 ° C and second onset peak temperature at about 286 to 288 ± 2 ° C (DSC, Fig. 2).

Another aspect of the present invention provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by DSC thermogram same as shown in FIG. 2.
Another aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by Infrared spectroscopy (IR) spectrum comprising wave numbers (cm-1) selected from at 3434 ± 2, 3081± 2, 2984± 2, 2631± 2, 2490± 2, 1921± 2, 1706± 2, 1571± 2, 1546± 2, 1387± 2, 1101± 2, 781± 2 (cm-1) (IR, Fig. 3).
Another aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by an Infrared spectroscopy (IR) spectrum same as shown in FIG. 3.

Yet another aspect of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by significant weight loss by thermo gravimetric analysis (TGA) same as show in FIG. 4.

In third aspect of the present invention provides a method for preparing crystalline Form-N2 of Tafamidis, wherein said method comprising:
1) adding solvent to Tafamidis Meglumine,
2) adding acid solution to step 1) at ambient temperature,
3) after completion of reaction filter to obtain crystalline Tafamidis Form-N2.

In forth aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 9.8±0.2,11.5±0.2 and 19.3±0.2 ?.
In another aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) essentially the same as shown in FIG. 5.
Yet another aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by an DSC thermogram comprising an endotherm onset peak temperature with a maximum at about 288 ± 2 0C (DSC, Fig. 6).

Yet another aspect of the present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by significant weight loss by Thermo Gravimetric Analysis (TGA) same as show in FIG. 7.

In fifth aspect of the present invention provides a method for preparing Tafamidis meglumine without isolating Tafamidis free acid comprises:
1) adding the acid to the compound of 4-[(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) stir the reaction mixture to get clear solution,
5) adding the N-methyl-glucamine and stir to obtain the compound.

Brief description of the Drawings:

Fig. 1: XRPD diffractogram of crystalline polymorph, Form-N1 of Tafamidis
Fig. 2: DSC thermogram of crystalline polymorph, Form-N1 of Tafamidis.
Fig. 3: Infrared spectrum of crystalline polymorph, Form-N1 of Tafamidis.
Fig. 4: Thermogravimetric analysis of crystalline polymorph, Form-N1 of Tafamidis.
Fig. 5: XRPD diffractogram of crystalline polymorph, Form-N2 of Tafamidis
Fig. 6: DSC thermogram of crystalline polymorph, Form-N2 of Tafamidis.
Fig. 7: Thermogravimetric analysis of crystalline polymorph, Form-N2 of Tafamidis.

Detailed description of the Invention:
In one embodiment, the present invention provides a method for preparing crystalline Form-N1 of Tafamidis said method comprising:
1) adding the acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) distil the solvent to obtain the compound,
5) optionally add the solvent and cool to obtain the compound.

The acid used in step 1) is selected from the group Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or a mixture thereof preferably Methanesulphonic acid.

The acid can be added to the compound 4-[(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid or to slurry of the compound 4-[(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid.
The slurry of the compound 4-[(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding the co-solvent or solvent selected form 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
The temperature of step 2) at which cyclization reaction proceeds in the range of 90-130 °C.
The base solution of Step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
Yet another embodiment of present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.4±0.2, 16.3±0.2 and 11.8±0.2 ±2 (2?).
In another embodiment of the present invention to provides a crystalline Form-N1 of Tafamidis, wherein said crystalline Form-N1 of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 ± 2 ° C and second onset peak temperature at between about 286 to 288 ± 2 ° C (DSC, Fig. 2).
In another embodiments of the present invention to provides crystalline polymorph, Form-N1 of Tafamidis is characterized by Infrared spectroscopy (IR) spectrum wave numbers (cm-1) comprising at 3434± 2, 3081± 2, 2984± 2, 2631± 2, 2490± 2, 1921± 2, 1706± 2, 1571± 2, 1546± 2, 1387± 2, 1101± 2, 781± 2 (IR, Fig. 3).
In another embodiments of the present invention to provides crystalline polymorph, Form-N1 of Tafamidis is characterized by significant weight loss by Thermogravimetric analysis (TGA) as shown in Fig.4.
In one embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is prepared from Tafamidis meglumine by adding solvent at ambient temperature, followed by addition of acid solution and stir to obtain the compound.
The solvent adding to Tafamidis meglumine is water at 20 to 25 0C.
The acid used in process of crystalline Form -N2 Tafamidis is hydrochloric acid.
Yet another embodiment of present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 9.8±0.2,11.5±0.2 and 19.3±0.2 (2?).
In another embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is characterized by a DSC thermogram comprising an endotherm onset peak temperature maximum at about 288 0C ± 2°C.
In another embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is characterized by weight loss by Thermo Gravimetric Analysis (TGA) same as show in FIG. 7.

Yet another embodiment of the invention to provides the process of Tafamidis meglumine without isolating the Tafamidis comprises:
1) adding acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid;
2) heating the reaction mixture;
3) after completion of reaction, adding base solution;
4) stir the reaction mixture up to get clear solution;
5) adding the N-methyl-glucamine and stir to obtain the compound.

The acid used at step 1) is selected from group of Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or mixture of acid or thereof preferably Methanesulphonic acid.
The acid can be added to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid or to the slurry of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid.
The slurry of the compound 4-[(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding co-solvent or solvent selected from group of 1,4-dioxane, Tetrahydrofuran , Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
The temperature of step 2) at which cyclization reaction proceed in the range of 90-130°C preferably 105-110°C.
The base solution of Step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
Advantages of the present invention:
1. The process of the present invention is feasible to produce novel crystalline polymorph, Form-N1 and N2 of Tafamidis on commercial scale.
2. The crystalline Tafamidis Form-N1 and N2 are stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.
3. The crystalline Tafamidis Form-N1 and N2 are stable at ambient temperature and at elevated temperatures (60°C).
4. Crystalline Tafamidis Form-N1 and N2 are non-hygroscopic and are compatible for further converting to Tafamidis meglumine pharma.

The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention.

Experimental procedure:
Example 1: Process for the preparation of crystalline Form-N1 of Tafamidis.
Into the round bottom flask containing 4-[(3,5-Dichlorobenzoyl)amino]-3-hydroxybenzoic acid (25g) was added Methanesulfonic acid (37.5 mL). The reaction mass was heated to 105-110°C and maintained under stirring up to reaction completion by monitoring HPLC. After completion of reaction, Cyclohexane (75 mL) was added to the homogeneous reaction mass at higher temperature. A mixture of Tetrahydrofuran (107 ml) and Trimethylamine (107 mL) was slowly added at the reflux temperature followed by addition of Tetrahydrofuran (143 mL). Volatile solvents were distilled from the reaction mass at atmospheric pressure keeping the vapour temperature up to 85 °C. Later 375 mL of water was added at 80-85°C allowing volatiles to collect in receiver and maintained for 2 to 3 hours at same temperature. Obtained solid was cooled, filtered, and dried to afford Tafamidis crystalline polymorph Form-N1 with 13.93 % w/w TEA content.
Yield: 25g; 92% by theory; HPLC purity: >99%
XRPD (2?): The XPRD pattern with characteristic peaks are observed at 5.4±0.2 and 16.3±0.2. (see Fig.1).
DSC: DSC thermogram with endotherm having an onset peak temperature at about 165°C, and second endotherm having an onset peak temperature at about 287°C. (see Fig:2)
IR (?, cm-1): The IR spectrum comprising IR shift peaks observed at about 3434, 3081, 2984, 2631, 2490, 1921, 1706, 1571, 1546, 1387, 1101, and 781 ± 4. (see Fig. 3)
TGA: Weight loss of 13.93% w/w was observed due to loss of Triethylamine (see Fig. 4)

Example 2: Process for the preparation of crystalline Form-N1 of Tafamidis.
Into the round bottom flask 4- [(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid (100g) was added Methanesulphonic acid (150 mL). The reaction mixture was heated to 110-115°C and maintained under stirring up to reaction completion (monitored by HPLC). After completion of reaction, reaction mass was cooled to 85-90°C. In another flask, mixture of Tetrahydrofuran (430 ml) and Triethylamine (430 mL) is taken and cooled to 0-5°C. The above reaction was slowly added to the Tetrahydrofuran and Triethylamine mixture at below 25°C followed by addition of Tetrahydrofuran (1070 mL) and Triethylamine (82 mL). After completion of the maintenance at 35-40°C for 1 hour, solvent was completely distilled under vacuum at below 40°C. After that, 1500 mL of water was added to the reaction mass at 30-35°C and maintained for 2.5-3.0 hours at 30-35°C. Obtained solid was filtered and dried to afford Tafamidis crystalline Form-N1 with 14.5 % TEA content.

Example 3: Process of Tafamidis meglumine without isolation of Tafamidis free acid (direct preparation of crystalline polymorph of Tafamidis Meglumine from 4- [(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid):
Into the round bottom flask added 4-[(3, 5-Dichlorobenzoyl) amino]-3- hydroxybenzoic acid (0.015 mole) and 1,4-dioxane (50 mL), Triflic acid (0.030 moles). The reaction mass was heated to 105-110°C and progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was cooled to 60-80°C and Triethylamine (0.046 moles) was added. To the above clear solution, N-methyl-D-glucamine (0.017 moles) was added. Obtained solid was cooled, filtered and dried to afford crystalline Tafamidis meglumine.
Yield: 4.6g; 64.7% by theory; HPLC Purity: >99%.

Example 4: Process for the preparation of crystalline Form-N2 of Tafamidis.
Tafamidis meglumine (100.0 gm) was suspended in water (4.0 L) at 20-25°C. After that, added Conc. HCl (25.0 gm 1.2 mole) drop-wise to the above suspension at 20-25°C for about 30 mins. After 1.0h maintenance, the obtained solid was filtered, and dried to yield Tafamidis Form-N2.
Yield: 56.5g; HPLC purity: 99.9%
XRPD (2?): The XPRD pattern with characteristic peaks are observed at 9.8±0.2,11.5±0.2 and 19.3±0.2 (2?). (see Fig.5)
DSC: DSC thermogram with endotherm having an onset peak temperature at 288 0C. (see Fig.6)
TGA: No significant weight loss was observed.
,CLAIMS:We claim:
1. A process for preparation of novel crystalline Form-N1 of Tafamidis characterized by powder X-ray diffraction pattern comprising two or more characteristic peaks selected from peaks at (2?) values 5.4±0.2, 16.3±0.2 and 11.8±0.2 ? comprising:
1) adding acid to the compound of 4-[(3,5-dichlorobenzoyl)amino]-3-hydroxybenzoic acid,
2) heating the reaction mass,
3) after completion of reaction, adding base solution,
4) distil of the solvent to obtain Form-N1 crystals of Tafamidis,
5) optionally adding the solvent and cooling to obtain Form-N1 crystals of Tafamidis.

2. The process as claimed in claim-1, wherein said acid used in step 1) is selected from Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid.
3. The process as claimed in claim-1, wherein said reaction temperature in step 2) is in the range of 90-130°C.
4. The process as claimed in claim-1, wherein said base solution in step 3) is prepared by adding Triethylamine to solvents selected from 1,4-Dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
5. The process as claimed in claim-1, wherein said crystalline Form-N1 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.4±0.2, 11.8±0.2 and 16.3±0.2 ?.
6. The process as claimed in claim-1, wherein said crystalline Form-N1 of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 ± 2 ° C and second onset peak temperature at about 286 to 288 ± 2 ° C.
7. The process as claimed in claim-1, wherein said crystalline Form-N1 of Tafamidis is characterized by Infrared spectroscopy (cm-1) spectrum comprising of characteristic wave numbers at 3434±2, 3081±2, 2984±2, 2631±2, 2490±2, 1921±2, 1706±2, 1571±2, 1546±2, 1387±2, 1101±2 and 781±2 cm-1.
8. A process for preparation of novel crystalline Form-N2 of Tafamidis characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 9.8±0.2,11.5±0.2 and 19.3±0.2 comprising, adding a solvent to Tafamidis meglumine at ambient temperature, followed by addition of acid solution to obtain the crystalline Form-N2.
9. The process as claimed in claim-8, wherein said solvent is water.
10. The process as claimed in claim-8, wherein said ambient temperature is at 20 to 30 0C, preferably 20-250C.
11. The process as claimed in claim-8, wherein said acid is hydrochloric acid.
12. The process as claimed in claim-8, wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2 ?) of 9.8±0.2, 11.5±0.2, and 19.3±0.2 ?.
13. The process as claimed in claim-8, wherein said crystalline form-N2 is characterized by DSC thermogram comprising an endotherm onset peak temperature maximum at 288± 2 0C.
14. A process to prepare the Tafamidis Meglumine without isolating the Tafamidis free acid comprising:
1) adding acid to the compound of 4-[(3,5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding the base solution,
4) stir the reaction mixture up to get clear solution,
5) adding N-methyl-glucamine and stir to obtain Tafamidis meglumine.

15. The process as claimed in claim-14, wherein said acid used in step 1) is selected from Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid.
16. The process as claimed in claim-14, wherein said reaction temperature of step 2) is about 90 to 130° ± 2 °C.
17. The process as claimed in claim-14, wherein said base solution at step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.