DESC:FIELD OF THE INVENTION
The present invention relates to novel crystalline polymorphic forms of tafamidis and processes for their preparation.

BACKGROUD OF INVENTION:
Tafamidis (2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid) is having the following chemical structure (Formula I)

Formula – I
Tafamidis and its meglumine salts are both approved under the brand names Vyndamax and Vyndaquel respectively by the USFDA to Foldrx Pharmaceuticals Inc.
Vyndaquel and Vyndamax both indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.
Tafamidis and its pharmaceutically acceptable salts thereof have been disclosed first time in US 7,214,695B2. This patent discloses process for the preparation of tafamidis which involves reaction of 4-amino-3-hydroxybenzoic acid with 3,5- dichlorobenzoyl chloride in presence of tetrahydrofuran and pyridine to provide 4-(3,5- dichlorobenzamido)-3-hydroxybenzoic acid followed by the reaction with p-toluenesulfonic acid monohydrate in presence of xylene and reflux to provide crude tafamidis. The obtained compound is dissolved in methanol-benzene and reacted with trimethylsilyl diazomethane to provide methyl ester, which is further hydrolyzed to provide tafamidis, but the patent is silent about any polymorphic form of tafamidis.
US 9,770,441 discloses crystalline form 1, form 2, form 3 and form 4 of tafamidis, wherein form 2 is a tetrahydrofuran solvate. Above all these forms, forms 4/6 are unstable, thus unacceptable for drug development. As, form 1 is more stable than other forms it is broadly used in the pharmaceutical formulations.
Another patent US 11,208,391 unveils another crystalline form of tafamidis which is prepared by dissolving tafamidis acetic adduct in a mixture of solvent ethyl acetate and water. The medium is heated to reflux until the slurry is disappeared and allowed to cool to room temperature. Further, the solution was filtered by vacuum and dried to get crystalline form of tafamidis.
However, the crystalline form obtained in above said application is unstable as said form changes while stirring at room temperature.
PCT publication WO 2021/152623 teaches different processes for the preparation of form-T1, T2, T3 and T4 of tafamidis, by mixing tafamidis with solvents selected from 2-methoxyethanol, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO) followed by stirring for 5-24 hours then finally filtering to obtain desired polymorph of tafamidis.
In above process, crystallization is performed in single solvent wherein isolation from single solvent does not provide final crystals of desired quality as impurities intact with the crystal lattice due to incomplete crystallization.
IN 201941026908 discloses crystalline form R and teaches the processes to prepare form S and N of tafamidis. Form R is prepared by dissolving tafamidis in DMSO (dimethyl sulfoxide) at 70- 75? followed by addition of water. The reaction mixture is cooled, then filtered and the obtained compound is isolated in the mixture of acetic acid and water. In addition, form S is prepared by adding tafamidis to acetic acid at 25- 30? with constant stirring for 3 hours followed by filtration and drying wherein form N is prepared by adding water to crystalline form S at 25- 30?. The obtained solid is filtered and then dried to get form N of tafamidis.
IN 202041051430 teaches the processes to prepare form N1 and N2 of tafamidis. The form N1 is prepared by adding 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid in methane sulfonic acid and heating the resulting mixture at 105- 110 ?. The obtained compound is further dissolved in cyclohexane followed by addition of triethylamine and tetrahydrofuran at reflux temperature to obtain a reaction mixture. THF is again added to the reaction mixture with subsequent distillation of solvents. Further, water is added at 80-85? to obtain crystalline form N1 of tafamidis with 13.93% w/w TEA content. The form N2 is prepared from meglumine salt of tafamidis.
Several other patent applications IN 202041028537, IN 202041038234 disclose different crystalline forms of tafamidis.
However, the crystalline forms obtained in above said applications are generally a mixture of different polymorphs. The quality of drug substance is particularly important to meet the regulatory requirements for pharmaceutical products. Indeed, the mixture of polymorphs exhibit different dissolution rates and may be converted to some other form while change in physiological factors like temperature, humidity and others which critically effects the solubility and bioavailability of pharmaceutical preparations.
In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/ or conformation of molecules in their crystal lattice. Different polymorphs may have different physical properties such as melting points, solubilities, X- ray diffraction patterns etc. The variation in solid forms may appreciably influence the pharmaceutical properties such as bioavailability, handling properties, dissolution rate, and stability and in turn such properties influence the processing, shelf life and commercial acceptance of a polymorphic form. For these reasons regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersion with a pharmaceutically acceptable carriers etc., of new drug substances. The existence and possible numbers of polymorphic forms for a given compound cannot be predicted and there are no standard procedures that can be used to prepare polymorphic forms of a substance.
Nevertheless, besides the existing routes of synthesis and the known polymorphic forms of tafamidis there is a continuing need for developing novel polymorphic forms of tafamidis which provides an opportunity to improve the performance characteristics of tafamidis.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide novel crystalline polymorphic forms of tafamidis which are suitable for pharmaceutical formulations.
Another object of the present invention is to provide efficient and industrial advantageous processes for the preparation of those polymorphic forms.
One another object of the present invention is to provide crystalline polymorphic forms of tafamidis with high purity and good stability.
SUMMARY OF INVENTION:
The present invention provides novel crystalline polymorphic forms of tafamidis and improved industrially advantageous processes for preparation of those crystalline forms.
According to one embodiment, the present invention provides novel crystalline forms of tafamidis and method of preparation thereof,

Formula – I
which comprises steps of:
i. dissolving tafamidis in a first solvent,
ii. heating the solution at reflux temperature to obtain a clear solution,
iii. adding second solvent to the clear solution,
iv. cooling the reaction mass to an ambient temperature,
v. isolating crystalline form of tafamidis.
According to yet another embodiment, the present invention provides novel crystalline forms of tafamidis and method of preparation thereof, which comprises:
i. dissolving tafamidis in a first solvent,
ii. heating the solution at reflux temperature to obtain a clear solution,
iii. adding second solvent to the clear solution,
iv. performing partially (30-50%) recovery of solution or mass,
v. cooling the reaction mass to an ambient temperature,
vi. isolating crystalline form of tafamidis.
According to yet another embodiment the novel crystalline polymorphic forms of tafamidis can be converted into form 1 or form 4 of the tafamidis with high purity and good stability.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 1.
Figure 2 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 2.
Figure 3 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 3.
Figure 4 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 4.
Figure 5 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 5.
Figure 6 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 6.
Figure 7 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 7.
Figure 8 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 8.
Figure 9 – represents PXRD pattern of crystalline form of tafamidis prepared as per example 9.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides novel crystalline polymorphic forms of tafamidis and their preparation. The novel crystalline polymorphic forms eradicate the problems of the prior art and is convenient to operate for commercial production.
As used herein, the term ‘ambient temperature’ represents a temperature 25?+ 5?.
As used herein, the term ‘partially’ represents a percentage of removal of solvent in the range of 30 to 50% from the solution.
The present invention relates to an efficient process for the preparation of novel crystalline forms of tafamidis by using specific solvent systems. The basic idea of the invention is to specifically develop novel crystalline forms of tafamidis and method of preparation thereof.
The process comprises of the step of dissolving tafamidis in a first solvent. The dissolution of tafamidis in the first solvent can be achieved by heating the reaction mixture at reflux temperature. The first solvent mentioned herein is selected from a group of an organic solvents which includes but not limited to C2-C5 ethers such as dioxane, tetrahydrofuran (THF) and the like, aliphatic nitriles such as acetonitrile or propionitrile and others. Thereafter, a second solvent is added to the above clear solution.
The second solvent as mentioned above in the reaction can be selected from any suitable organic solvent which is selected form the group consisting of hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, pentane, methylcyclohexane, ethyl benzene, m-, o-, or p-xylene, or naphthalene and like; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and like; C1-C8 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; C1-C4 amides such as dimethylformamide (DMF), dimethylacetamide (DMAc), and the like; C2-C3 sulfoxides such as dimethyl sulfoxide (DMSO) and the like; C2-C5 ethers such as dioxane, tetrahydrofuran (THF) and the like; C5-C6 pyrrolidones such as N-methyl-2-pyrrolidone and the like; C3-C10 ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; water and mixtures thereof.
In general, the second solvent used herein includes but not limited to acetone, cyclohexane, ethyl acetate, isopropyl alcohol (IPA) and water.
According to the invention it was also unexpectedly found that a good reproducibility of the crystalline polymorphic forms of tafamidis can be obtained by using a preferable first and second solvent ratio in the process. Preferably the first and second solvent ratio may be 1 to 15: 1 to 3, preferably 1 to 15 :1 to 2.
After the addition of second solvent, the resulting solution can be cooled to an ambient temperature of 25?± 5? with stirring for complete crystallization.
And optionally, the solvent can be removed partially from the solution by any method known in the literature then recovered solution can be subjected for cooling at ambient temperature with stirring for complete crystallization. Thereafter the solid obtained as a wet cake by filtration can be dried at a temperature range of 40-65? under vacuum to obtain crystalline forms of tafamidis. It is also unexpectedly found that partially recovery followed by cooling for complete crystallization of the crystalline polymorphic forms of tafamidis giving comparatively better yields. The methods may include but not limited, recovery under vacuum.
The crude tafamidis can be prepared by the methods reported in literature or by the process as given in the present specification. The process includes reacting 4-amino-3-hydroxybenzoic acid of with 3,5-dichlorobenzoyl chloride in presence of pyridine in tetrahydrofuran (THF) to produce amide intermediate which is in-situ treatment with p-toluenesulfonic acid monohydrate in xylene and quenched with sodium hydroxide (NaOH) then acidified with HCl and then dried. The resulting residue was dissolved in a mixture of MeOH:Benzene and treated with trimethylsilyl diazomethane (TMS-CHN2) in hexanes at 25° C and the residue was chromatographed to afford the desired tafamidis methyl ester. The tafamidis methyl ester was dissolved in a mixture of tetrahydrofuran: methanol: water (THF:MeOH:H2O) and treated with lithium hydroxide monohydrate LiOH.H2O. Upon completion, the mixture was acidified to pH 2 with 1 N hydrochloric acid (HCl) and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate (MgSO4), filtered and concentrated. The residue was purified by preparative thin layer chromatography to give the crude tafamidis.
X-ray powder diffraction analyses were carried out on a PANalytical X'Pert Pro diffractometer using Cu K alpha radiation. The instrument was equipped with a line focus X-ray tube, and the voltage and amperage were set to 45kV and 40mA respectively. The scanning rate was set as 10 second per step and step size is set as 0.01º. The diffractometer was equipped with X’celerator detector and rotating sample stage. X-ray diffractometer was used to record diffractogram from 4º to 50º (2-theta).
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL cyclohexane was added at 65-75?. The solution was cooled to an ambient temperature with stirring. After completion of crystallization, the reaction mass was further cooled at 0-10? and filtered to obtain product as wet cake. The wet cake was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (7.2g).
The X-ray diffraction of resulting product is shown in Figure 1.

Example 2: Process for the preparation of crystalline form of tafamidis
Tafamidis(10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL ethyl acetate was added at 65-75?. The solution was cooled to an ambient temperature with stirring till complete crystallization. The reaction mass was further cooled at 0-10? and filtered to obtain the desired product. The resulting product was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (5.6g).
The X-ray diffraction of resulting product is shown in Figure 2.

Example 3: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL acetone was added at 65-75?. The solution was cooled to an ambient temperature with stirring. After completion of crystallization, the reaction mass was further cooled at 0-10? and filtered to obtain product as wet cake. The wet cake was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (5.8g).
The X-ray diffraction of the product is shown in Figure 3.
Example 4: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL acetone was added to the reaction mass at 65-75°C and performed 50% recovery of reaction mass. Then reaction mass was allowed to cool at temperature 20-30°C and continued stirring till complete crystallization. After completion of crystallization, the reaction mass was further cooled at 0-10? and filtered to obtain product as wet cake. The wet cake was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (7.5g).
The X-ray diffraction of the product is shown in Figure 4.

Example 5: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL isopropyl alcohol was added at 65-75?. The solution was cooled to an ambient temperature with stirring till complete crystallization. The reaction mass was further cooled at 0-10? and filtered to obtain the desired product. The resulting product was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (5.0g).
The X-ray diffraction of resulting product is shown in Figure 5.

Example 6: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 220 mL of tetrahydrofuran (THF) and heated at reflux temperature 65-75?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL isopropyl alcohol was added to the reaction mass at 65-75°C and performed 50% recovery of reaction mass. Then reaction mass was allowed to cool at temperature 20-30°C and continued stirring till complete crystallization. The reaction mass was further cooled at 0-10? and filtered to obtain the desired product. The resulting product was dried at 50-60°C under vacuum to obtain crystalline form of tafamidis (7.0g).
The X-ray diffraction of resulting product is shown in Figure 6.

Example 7: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in tetrahydrofuran (220 ml) at reflux temperature (65-75°C). The reaction mass was stirred until a clear solution was obtained. After getting clear solution, cyclohexane (20 ml) was added to the reaction mass at 65-75°C and performed 50% recovery of reaction mass. Then reaction mass was allowed to cool at temperature 20-30°C and continued stirring till complete crystallization. Further the reaction mass again cooled to temperature 0-10°C & filtered the product as wet cake by filtration and dried at 50-60°C under vacuum, to obtain tafamidis (6.5g).
The X-ray diffraction of resulting product is shown in Figure 7.

Example 8: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in tetrahydrofuran (220 ml) at reflux temperature (65-75°C). The reaction mass was stirred until a clear solution was obtained. After getting clear solution, ethylacetate (20 ml) was added to the reaction mass at 65-75°C and performed 50% recovery of reaction mass. Then reaction mass was allowed to cool at temperature 20-30°C and continued stirring till complete crystallization. Further the reaction mass again cooled to temperature 0-10°C & filtered the product as wet cake by filtration and dried at 50-60°C under vacuum, to obtain crystalline form tafamidis (6.5g).
The X-ray diffraction of resulting product is shown in Figure 8.
Example 9: Process for the preparation of crystalline form of tafamidis
Tafamidis (10g) was dissolved in 200 mL of acetonitrile and refluxed at 75-85?. The reaction mass was stirred until a clear solution was obtained. To the solution, 20 mL water was added at 75-85?. The solution was cooled to an ambient temperature with stirring till complete crystallization. Thereafter, the reaction mass was filtered to obtain the desired product. The resulting product was dried at 50-60°C under vacuum to obtain crystalline tafamidis (9.6g).
The X-ray diffraction of resulting product is shown in Figure 9.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:1. Novel crystalline polymorphic forms of tafamidis of Formula-I characterized by XRPD pattern as shown in any of figure 1-9.

Formula-I
2. A process for the preparation of novel crystalline form of tafamidis of Formula-I characterized by XRPD pattern as shown in any of figure 1-9,

Formula-I
which comprises steps of:
i. dissolving tafamidis in a first solvent,
ii. heating the solution at reflux temperature to obtain a clear solution,
iii. adding second solvent to the clear solution,
iv. cooling the reaction mass to an ambient temperature,
v. isolating crystalline form of tafamidis.
3. A process for the preparation of novel crystalline form of tafamidis of Formula-I characterized by an XRPD pattern as shown in any of figure 1-9,

Formula-I
which comprises steps of:
i. dissolving tafamidis in a first solvent,
ii. heating the solution at reflux temperature to obtain a clear solution,
iii. adding second solvent to the clear solution,
iv. performing partially recovery of solvent,
v. cooling the reaction mass to an ambient temperature,
vi. isolating crystalline form of tafamidis.

4. The process as claimed in claim 2 or claim 3, wherein in step i), the first solvent is selected from the group consisting of C2-C5 ethers such as dioxane, tetrahydrofuran (THF) and the like, aliphatic nitriles such as acetonitrile or propionitrile.
5. The process as claimed in claim 2 or 3, wherein in step iii), second solvent is selected form the group consisting of hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, pentane, methylcyclohexane, ethyl benzene, m-, o-, or p-xylene, or naphthalene and like; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and like; C1-C8 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; C1-C4 amides such as dimethylformamide (DMF), dimethylacetamide (DMAc), and the like; C2-C3 sulfoxides such as dimethyl sulfoxide (DMSO) and the like; C2-C5 ethers such as dioxane, tetrahydrofuran (THF) and the like; C5-C6 pyrrolidones such as N-methyl-2-pyrrolidone and the like; C3-C10 ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; water and mixtures thereof.
6. The process as claimed in claim 2 or 3, wherein first solvent and second solvent ratio in the process is in the range to 1 to 15: 1 to 3.
7. The process as claimed in claim 2 or 3, wherein solvent and antisolvent ratio in the process is in the range to 1 to 15: 1 to 2.
8. The process as claimed in claim 3, wherein in step iv), partially recovery of solution or reaction mass is carried out at a temperature of about 65°C to 75°C.
9. The process as claimed in claim 2 or 3, wherein the novel crystalline form of tafamidis characterized by an XRPD pattern as shown in any of figure 1-9 is converted into form 1 of the tafamidis.
10. The process as claimed in claim 2 or 3, wherein the novel crystalline form of tafamidis characterized by an XRPD pattern as shown in any of figure 1-9 is converted into form 4 of the tafamidis.