DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORMS OF TAFAMIDIS AND PROCESS FOR THE PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION

The present invention relates to novel Tafamidis polyethylene glycol co-crystal and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Tafamidis is chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole -6-carboxylic acid, as shown below a Compound of Formula (1). Tafamidis is approved as free base and meglumine salt as shown below a Compound of Formula (2). Tafamidis and Tafamidis meglumine are marketed under the brand name of VYNDAMAXTM and VYNDAQEL® respectively. VYNDAQEL and VYNDAMAX are 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.

Formula 1

Formula 2

Tafamidis (1) along with pharmaceutically acceptable salts is disclosed in US 7214695, which is hereby incorporated by reference. US ‘695 patent also discloses a process for the preparation of Tafamidis. But this patent is silent about polymorphism of Tafamidis (1).

US 9249112 discloses crystalline form, liquid crystal form and amorphous form of Tafamidis meglumine. But this patent is silent about polymorphism of Tafamidis free acid.

Solid state forms of Tafamidis are known from US 9770441 and International Publication No. WO 2019175263. US 9770441 discloses crystalline Form 1, Form 2 (THF solvate), Form 4, Form 6 and amorphous forms of Tafamidis of formula (1) and its preparation.

US 11208391 discloses anhydrous Crystalline Form of Tafamidis and acetic acid solvate and formic acid solvate of Tafamidis.

WO 2020232325 discloses methanol solvate of Tafamidis and acetic acid solvate of Tafamidis.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. Tafamidis, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC)), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms and co-crystals) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates and co-crystals may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability). These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates and co-crystals of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

Considering the importance of Tafamidis (1), nevertheless, besides the known solid forms of Tafamidis, there is still the need for further polymorphs, which are able to deliver high quality crystalline Tafamidis polymorphs in a reproducible and environmentally friendly way, which involves the use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

The present inventors have found that Tafamidis solvates known in the prior art are hygroscopic and convert to other forms at moderate or high relative humidity at 25° C. Further, their isolation involves special precautions during isolation, drying and powder processing, which is onerous during the large scale manufacturing of Tafamidis.

In view of the above, the present inventors have now developed a novel Tafamidis polyethylene glycol co-crystal, which is stable and does not require laborious isolation. Further, the present inventors developed a process for the preparation of Tafamidis polyethylene glycol co-crystal.

OBJECTIVE OF THE INVENTION

The main objective of the present invention relates to Tafamidis polyethylene glycol co-crystal and process for the preparation thereof, and to pharmaceutical compositions.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides Tafamidis polyethylene glycol co-crystal of Formula (A):

Formula (A).

In another embodiment, the present invention provides a process for the preparation of Tafamidis polyethylene glycol co-crystal of Formula (A):
which comprises:
a) treating a solution or suspension of crude Tafamidis (1);

Formula 1
with polyethylene glycol;
b) isolating co-crystal of Tafamidis polyethylene glycol of Formula (A).

In another embodiment, the present invention provides a crystalline Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.8±0.2, 13.7±0.2, 19.7±0.2, 20.0±0.2, 23.4±0.2, 23.7±0.2, 25.0±0.2, 27.0±0.2.

In another embodiment, the present invention provides a Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A) having a Powder X-ray Diffraction (PXRD) pattern shown in Fig-1.

In another embodiment, the present invention provides Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A) which is characterized by DSC thermogram comprising an endotherm onset peak temperature at 195°C as shown in Fig.2.

In another embodiment, the present invention provides a crystalline Form-? of Tafamidis (1), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 13.7±0.2, 27.3±0.2.

In another embodiment, the present invention provides a crystalline Form-? of Tafamidis (1), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern shown in Fig-3.

Yet another embodiment of the present invention is to provide pharmaceutical compositions comprising Tafamidis polyethylene glycol co-crystal and use thereof in treating transthyretin-related hereditary amyloidosis.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 – PXRD of Form-? of a Compound of Formula (A)
Figure 2 – DSC of Form-? of a Compound of Formula (A)
Figure 3 – PXRD of crystalline Form-? of Tafamidis (1) obtained from Example 6

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (mention the instrument name_Bruker D8 Advance) with measured using CuKa radiation. Methodology of X-ray diffraction is as follows:
Scanning rate: 0.5 sec
Detector: Lynx Eye
Voltage: 40kV
Current: 40mA
Scan range: 3-40°
Step size: 0.02°

The Differential Scanning Calorimetry (DSC) thermograms were obtained on a DSC Q2000. Methodology of DSC is as follows:
Mass flow: 50.0 mL/min
Equilibrate: 25.00°C
Ramp: 10.00°C/min to 300.00°C.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides Tafamidis polyethylene glycol co-crystal of Formula (A):

Formula (A).

In another embodiment the present invention provides a process for the preparation of Tafamidis polyethylene glycol co-crystal of Formula (A):
comprising:
(a) treating a solution or suspension of Tafamidis (1);

Formula 1
with polyethylene glycol;
(b) isolating Tafamidis polyethylene glycol co-crystal of Formula (A).

In still another embodiment, the process comprises: treating Tafamidis with polyethylene glycol at elevated temperature and further cooling to room temperature followed by addition of a solvent and stirring followed by filtration and drying to obtain Tafamidis polyethylene glycol co-crystal of Formula (A).

Furthermore, the molar ratio of polyethylene glycol and Tafamidis is 1:1 to 3:1.

In still another embodiment, solvent comprises water, dimethyl formamide (DMF), acetone, acetonitrile, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol, petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether and/or mixtures thereof.

In another embodiment, the step (a) reaction is carried out at a temperature of about 10°C to about 150° C.

In another embodiment, the step (a) reaction of is carried out in about 2 hours to about 10 hours. In an embodiment of the present invention, the reaction is carried out in about 2 hours to about 4 hours.

In another embodiment, the present invention provides Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A), wherein said Form-? is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.8±0.2, 13.7±0.2, 16.2±0.2, 19.7±0.2, 20.0±0.2, 23.4±0.2, 23.7±0.2, 25.0±0.2, 27.0±0.2.

In still another embodiment, the present invention provides a crystalline Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A), wherein said crystalline Form by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) as shown in FIG. 1.

In still another embodiment, the present invention provides a crystalline Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A), wherein said crystalline Form-? is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 195°C and second onset peak temperature at about 268 to 274°C (DSC, Fig. 2).

Advantages of the present invention:
1. The process of the present invention is feasible to produce novel polymorph i.e, Form-? of Tafamidis polyethylene glycol co-crystal of Formula (A), on commercial scale.

2. The Tafamidis polyethylene glycol co-crystal of Formula (A) is stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.

In another embodiment, the present invention provides a crystalline Form-? of Tafamidis (1), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 13.7±0.2, 27.3±0.2.

In another embodiment, the present invention provides a crystalline Form-? of Tafamidis (1), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern shown in Fig-3.

Yet another embodiment of the present invention provides a method for preparing crystalline Form-? of Tafamidis (1), wherein said method comprises, adding a solvent to Tafamidis Meglumine (2), further adding acid solution to this at ambient temperature to pH adjustment, and after completion of reaction filter to obtain crystalline Form-? of Tafamidis (1).

Yet another embodiment of the present invention is to provide pharmaceutical compositions comprising Tafamidis polyethylene glycol co-crystal and use thereof in treating transthyretin-related hereditary amyloidosis.

In yet another embodiment of the invention provides a soft gelatin capsule comprising Tafamidis polyethylene glycol co-crystal or pharmaceutical compositions described herein. For example, in one embodiment the soft gelatin capsule comprises from about 1 to about 100 mg of Tafamidis polyethylene glycol co-crystal.

In yet another embodiment, for oral administration, a solid form of Tafamidis polyethylene glycol co-crystal can be formulated by combining the active agent with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active agent, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
The starting compound crude Tafamidis (1) and Tafamidis Meglumine (2) are prepared by any process known in the art.

As used herein, the term "reduced pressure" refers to a pressure below 50 mm Hg.

Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying may be carried out at temperature of less than 100°C, or less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of Tafamidis Polyethylene glycol.

Tafamidis (5 g) was added to Polyethylene glycol (PEG, 100 ml) and heated to 140-150°C for 30 min. The clear solution was cooled to 20-30°C and stirred for 4 h. Thereafter, isopropyl alcohol (220 ml) was added and stirred for 1 hr. The product was filtered and dried at 80-85°C under reduced pressure to obtain 3.5 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.1.
1H NMR (300 MHz, DMSO-d6) 7.91 (m, 2H), 7.94-7.96 (m. 1H), 8.15-8.20, (m, 2H), 8.28 (s, 1H), 13.25 (s, 1H). 3.3-3.67 (m 6H).

Example 2: Preparation of Tafamidis Polyethylene glycol.

Tafamidis (5 g) was added to Polyethylene glycol (100 ml) and heated to 140-150°C for 30 min. The clear solution was cooled to 80-85°C and stirred for 2 h. Thereafter, the slurry was cooled to 20-30°C and stirred for 4 h. Further, isopropyl alcohol (220 ml) was added and stirred for 1 hr. The product was filtered and dried at 80-85°C under reduced pressure to obtain 3.3 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.1.

Example 3: Preparation of Tafamidis Polyethylene glycol.

Tafamidis (5 g) was added to a mixture of Polyethylene glycol (PEG, 100 ml) and Purified water (5 ml) and heated to 140-150°C for 30 min. The clear solution was cooled to 80-90°C and continued stirring for 1 h. Thereafter, the slurry was cooled to 20-30°C. Further, isopropyl alcohol (400 ml) was added and stirred for 1 hr. The product was filtered and dried at 80-85°C under reduced pressure to obtain 3.8 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.1.

Example 4: Preparation of Tafamidis Polyethylene glycol.

Tafamidis (5 g) was added to Polyethylene glycol (PEG, 350 ml) heated to 90-95°C for 30 min. The clear solution was cooled to 20-30°C. Thereafter isopropyl alcohol (700 ml) was added and stirred for 1 hr. The product was filtered and dried at 80-85°C under reduced pressure to obtain 2.5 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.1.

Example 5: Preparation of Tafamidis Polyethylene glycol Form- a.

Tafamidis Form-a (1 g) was added to Purified water (20 ml). The slurry was heated to 100°C for 1h. The slurry was cooled to 20-30°C for 30 min. The product was filtered and dried at 80-85°C under reduced pressure to obtain 0.8 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.1.

Example 6: Preparation of Form ß of Tafamidis.

Tafamidis meglumine (190 g) was added to Purified water (1900 ml) at 20-30°C. Thereafter, pH was adjusted to 3.0-4.0 with 2 N hydrochloric acid and stirred for 2 h. The product was filtered. The wet product was slurried in water, filtered and dried at 75-80°C under reduced pressure to obtain 124 g of title compound. The XPRD pattern with characteristic peaks are observed in Fig.3.

Example 7: Preparation of Tafamidis softgel capsule.

Transfer the calculated quantity of Polyethylene Glycol into medicament preparation and dispersed weighed quantity of Tafamidis slowly into the content under stirring. Added calculated quantity of Polysorbate 20 under stirring to the contents and continued stirring for 20 minutes. Added calculated quantity of Povidone K 90 and BHT under stirring to the contents and continued stirring for 30 minutes get uniform mixing. Thereafter, Encapsulation has been done using gelatin mass. ,CLAIMS:WE CLAIM:

1. Tafamidis polyethylene glycol co-crystal of a Compound of Formula (A):

Formula (A).

2. A process for the preparation of Tafamidis polyethylene glycol co-crystal of Formula (A):

Formula (A)
which comprises:
a) treating a solution or a suspension of Tafamidis (1);

Formula 1
with polyethylene glycol;
b) isolating Tafamidis polyethylene glycol co-crystal of Formula (A).

3. The process as claimed in claim 1, wherein step (a) is carried out in the presence of a solvent comprises water, dimethyl formamide (DMF), acetone, acetonitrile, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol, petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether and/or mixtures thereof.

4. A crystalline Form-??of Tafamidis polyethylene glycol co-crystal of Formula (A)? which is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 5.8±0.2, 13.7±0.2, 19.7±0.2, 20.0±0.2, 23.4±0.2, 23.7±0.2, 25.0±0.2, 27.0±0.2.

5. A crystalline Form-??of Tafamidis polyethylene glycol co-crystal of Formula (A)? which is characterized by an x-ray powder diffraction pattern substantially in accordance with that shown in FIG. 1.

6. The compound of claim 5 and claim 6, which is characterized by differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 2.

7. A crystalline Form-? of Tafamidis (1), wherein said crystalline Form-? is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2?) of 13.7±0.2, 27.3±0.2.

8. A crystalline Form-? of Tafamidis (1), which is characterized by an x-ray powder diffraction pattern substantially in accordance with that shown in FIG. 3.

9. A pharmaceutical compositions comprising Tafamidis polyethylene glycol co-crystal of Tafamidis of Formula (A)? and use thereof in treating transthyretin-related hereditary amyloidosis.