Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“PROCESSES FOR THE PREPARATION OF STABLE AND HIGHLY PURE CRYSTALLINE FORM 4 OF TAFAMIDIS”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B.N. Reddy Colony,
Road No. 14, Banjara Hills,
Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to novel, consistently reproducible and industrially advantageous processes for preparation of highly pure and stable crystalline Form 4 of Tafamidis essentially free of other polymorphic forms.
BACKGROUND OF THE INVENTION
U.S. Patent No. 7,214,695 (hereinafter referred to as the US‘695 patent) discloses a variety of benzoxazole derivatives, or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. Among them, Tafamidis, chemically named 2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid, is an orally active transthyretin stabilizer that inhibits tetramer dissociation and proteolysis that has been approved in certain jurisdictions for the treatment of transthyretin polyneuropathy (TTR-PN) and for the treatment of transthyretin cardiomyopathy (TTR-CM). Tafamidis is represented by the following structural formula:

Vyndamax® (Tafamidis) and Vyndaqel® (Tafamidis meglumine) were developed by Pfizer and approved in the United States for the treatment of the cardiomyopathy of wild type or hereditary. Vyndamax® is available in 61 mg of Tafamidis soft gelatin capsule orally once daily. Vyndaqel® is available in 20 mg soft gelatin capsules, each soft capsule contains 20 mg of micronized Tafamidis meglumine equivalent to 12.2 mg Tafamidis.
Vyndaqel® (Tafamidis meglumine) and Vyndamax® (Tafamidis) were also approved in the European Union for treating adults with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM).
The synthesis of Tafamidis was first described in the U.S. Patent No. 7,214,695. As per the process exemplified in US’695 patent, Tafamidis is prepared in an analogous manner by reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride in presence of pyridine using tetrahydrofuran solvent to produce 4-(3,5-dichloro-benzoylamino)-3-hydroxybenzoic acid, which is then reacted with p-toluenesulfonic acid monohydrate in presence of trimethylsilyl diazomethane in xylene solvent to produce 2-(3,5-dichlorophenyl)-benzoxazole-6-methyl carboxylate, which is finally reacted with a mixture of tetrahydrofuran, methanol and water and then treated with Lithium hydroxide hydrate to produce Tafamidis as a white solid with 10% yield.
Tafamidis is known to exhibit polymorphism and various crystalline forms and process for their preparation are apparently disclosed in U.S. Patent Nos. US 9,770,441B1, US 11,208,391B2; U.S. Patent Application Publication No. US2021/0363116A1; PCT Publication Nos. WO2020/232325A1, WO2021/232619A1, WO2022/084790A1; and Indian Patent Application Nos. IN 201941026908A, IN 202041038234A, IN202041028537A, IN202041051430A and IN202041049413A.
U.S. Patent No. 9,770,441 B1 (hereinafter referred to as the US’441 patent), assigned to Pfizer, discloses four crystalline forms of Tafamidis (designated as Form 1, Form 2, Form 4 and Form 6), processes for their preparation, and characterizes the crystalline forms with powder X-ray diffraction patterns (XRPD), Raman Spectra and 13C solid state NMR spectrum. According to the US’441 patent, the crystalline Form 1 of Tafamidis is characterized by an XRPD pattern having 2-theta peaks at 15.4, 16.5, 20.2, 23.5, 26.7, 28.6, and 29.0 ±0.2 degrees. The crystalline Form 1 of Tafamidis is further characterized by Raman spectrum having Raman shifts at 213, 287, 869, 994, 1273, 1292, and 1615 ±2 cm-1. The crystalline Form 1 of Tafamidis is further characterized by 13C solid state NMR spectrum having chemical shifts (ppm) at 120.8, 127.7, 139.6 ± 0.2.
According to the US’441 patent, the crystalline Form 4 of Tafamidis is characterized by an XRPD pattern having 2-theta peaks at about 15.9, 16.9, 18.0, 24.1, and 27.3±0.2 degrees. The crystalline Form 4 of Tafamidis is further characterized by Raman spectrum having Raman shifts at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1. The crystalline Form 4 of Tafamidis is further characterized by 13C solid state NMR spectrum having chemical shifts (ppm) at 122.1, 124.4, 130.7 and 140.1 ± 0.2. According to the US’441 patent, the crystalline Form 4 of Tafamidis is prepared by suspending Tafamidis Form 1 in tetrahydrofuran and heating the resulting suspension at 75°C, the clear solution was hot filtered through a pre-warmed 0.2 µm Nylon filter into a container with toluene chilled on an ice/water bath, the sample was stored in freezer (-10 to -25°C) overnight and finally collecting the crystalline Form 4 of Tafamidis while cold by vacuum filtration.
U.S. Patent No. 11,208,391B2 (hereinafter referred to as the US’391 patent), assigned to Azad Pharma, discloses a crystalline form of Tafamidis, crystalline Tafamidis acetic acid adduct (Form E) and crystalline Tafamidis formic acid adduct, processes for their preparation, and characterizes the crystalline forms by an X-ray powder diffraction (XRPD) patterns and Differential Scanning Calorimetry (DSC) thermograms. According to US’391 patent, the crystalline form of Tafamidis is characterized by an XRPD pattern and having 2-theta peaks at 5.1, 8.4, 10.2, 10.4, 12.1, 14.1, 15.3, 16.2, 18.2, 18.5, 20.4, 20.9, 23.2, 24.4, 25.0, 25.2, 25.7, 26.5, 27.1, 28.1, 28.5, 30.6, 31.5, 32.8, 33.2, 33.8, 34.4, 35.0, and 35.8±0.2 degrees; the crystalline acetic acid adduct of Tafamidis is characterized by an XRPD pattern and having 2-theta peaks at 5.3, 7.2, 10.1, 10.7, 11.2, 14.5, 15.4, 16.2, 16.8, 18.6, 19.5, 20.8, 21.6, 22.5, 24.7, 25.6, 26.3, 26.9, 27.1, 27.5, 28.3, 30.0, 31.9, 32.7, 34.1, 35.0, 35.5, 36.9, 38.3 and 39.5±0.2 degrees. The crystalline acetic acid adduct of Tafamidis is further characterized by a DSC thermogram having an endothermic peak at about 134°C and a further endothermic peak at about 292°C.
PCT Publication No. WO2020/232325A1 (Applicant: Teva, hereinafter referred to as the WO’325 publication) discloses Tafamidis crystalline Forms I to V, processes for their preparation, and characterizes the crystalline forms by X-ray powder diffraction (XRPD) patterns.
PCT Publication No. WO2022/084790A1 (Applicant: Glenmark, hereinafter referred to as WO’790 publication) describes processes for preparation of crystalline Form 4 of Tafamidis and its X-ray powder diffraction (XRPD) pattern.
However, the processes described in the aforementioned prior art have failed to consistently produce pure crystalline Form 4 of Tafamidis essentially free of other polymorphic forms. A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing highly pure crystalline Form 4 of Tafamidis free acid which is essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
Extensive research and experimentation have been carried out by the present inventors to produce highly pure crystalline Form 4 of Tafamidis free acid essentially free of other crystalline forms. As a result, the present inventors have unexpectedly found that highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms can be consistently produced by the processes disclosed herein.
Provided herein is simple, cost effective and consistently reproducible processes for the preparation of highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form 4 of Tafamidis essentially free from other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC, and specifically to a temperature of about 25ºC to about 30ºC.
As used herein, the term “ambient temperature” refers to a temperature of about 10ºC to about 40ºC, specifically refers to a temperature of about 20ºC to about 35ºC, and most specifically refers to a temperature of about 25ºC to about 30ºC.
The term “crystalline Form 4 of Tafamidis”, otherwise called “Tafamidis crystalline Form 4”, as used herein is intended to mean the crystalline form 4 of Tafamidis as originally disclosed in the US’441 patent.
In one embodiment, the crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 15.9, 16.9, 18.0, 24.1 and 27.3 ± 0.2 degrees substantially in accordance with Figure 1. In another embodiment, the crystalline Form 4 of Tafamidis obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having one or more additional 2-theta peaks at about 7.0, 9.9, 11.7, 12.4, 13.3, 14.1, 16.7, 18.0, 19.3, 19.8, 20.8, 23.5, 24.8, 25.3, 26.2, 26.9, 28.0, 28.6 ± 0.2 degrees.
In another embodiment, the crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained by the process disclosed herein is characterized by a Raman spectrum comprising Raman shift peaks at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1 substantially in accordance with Figure 2. In another embodiment, the crystalline Form 4 of Tafamidis obtained by the process disclosed herein is further characterized by a Raman spectrum comprising one or more additional Raman shift peaks at about 132, 173, 201, 217, 225, 416, 601, 668, 727, 755, 778, 945, 994, 1077, 1124, 1144, 1195, 1234, 1247, 1272, 1297, 1350, 1411, 1485, 1547, 1572, 1590, 1613 and 3076 ± 2 cm-1.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of highly pure crystalline Form 4 of Tafamidis.
Figure 2 is a characteristic Raman spectrum of highly pure crystalline Form 4 of Tafamidis.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a process for the preparation of the stable and highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms, comprising:
a) providing a suspension of Tafamidis free acid in acetic acid solvent;
b) stirring the suspension obtained in step-(a) at an ambient temperature; and
c) collecting the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained in step-(b).
The process disclosed herein advantageously produces the crystalline Form 4 of Tafamidis with high chemical and polymorphic purity.
The highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein has a chemical purity of greater than about 99.5%, specifically greater than about 99.7%, and most specifically greater than about 99.9% as measured by HPLC.
In one embodiment, the Tafamidis used as a starting material in step-(a) of the present invention is a crude or pure Tafamidis. In another embodiment, the crude or pure Tafamidis is in the form of a solid, wet solid, viscous solid, semi-solid, amorphous form, crystalline solid, organic layer, residual mass or a mixture thereof.
Unless otherwise specified, the crude or pure Tafamidis used as a starting material (for preparing crystalline Form 4) in the present invention can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 7,214,695; or by the processes exemplified hereinafter.
Step-(a) of providing a suspension of Tafamidis includes combining Tafamidis with acetic acid solvent at an ambient temperature or obtaining an existing suspension from a previous processing step.
Combining of the Tafamidis with acetic acid solvent is done in a suitable order, for example, the Tafamidis is added to the acetic acid solvent, or alternatively, acetic acid solvent is added to the Tafamidis. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at the room temperature, and most specifically at a temperature of about 25-30ºC.
Usually, the quantity of acetic acid employed in step-(a) is about 5 volumes to about 20 volumes, specifically about 7 volumes to 16 volumes, with respect to the quantity of Tafamidis used as a starting material.
In one embodiment, the suspension in step-(b) is stirred at ambient temperature for at least 5 minutes, specifically at a temperature of about 20°C to about 35°C for about 10 minutes to 8 hours, and most specifically at a temperature of about 25-30ºC for about 2 hours to about 4 hours.
The collection of the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In another embodiment, the highly pure crystalline Form 4 of Tafamidis obtained in step-(c) is washed with acetic acid solvent.
The highly pure crystalline Form 4 of Tafamidis obtained in step-(c) is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 50°C to about 140°C, specifically at a temperature of about 70°C to about 130°C, and most specifically at a temperature of about 80°C to about 120°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 30 minutes to 20 hours, more specifically for a period of about 45 minutes to 12 hours, and most specifically for a period of about 1 to 6 hours.
According to second aspect of the present invention, there is provided a process for the preparation of a stable and highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms, comprising:
a) providing a suspension of Tafamidis free acid in acetic acid solvent;
b) heating the suspension obtained in step-(a) while stirring at a temperature of above about 40ºC to produce a hot suspension;
c) cooling the hot suspension obtained in step-(b) to below about 35ºC; and
d) collecting the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained in step-(b).
In one embodiment, the Tafamidis used as a starting material in step-(a) of the present invention is a crude or pure Tafamidis. In another embodiment, the crude or pure Tafamidis is in the form of a solid, wet solid, viscous solid, semi-solid, amorphous form, crystalline solid, organic layer, residual mass or a mixture thereof.
Step-(a) of providing a suspension of Tafamidis free acid includes combining Tafamidis with acetic acid solvent at an ambient temperature or obtaining an existing suspension from a previous processing step.
Combining of the Tafamidis with acetic acid solvent is done in a suitable order, for example, the Tafamidis is added to the acetic acid solvent, or alternatively, acetic acid solvent is added to the Tafamidis. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at the room temperature, and most specifically at a temperature of about 25-30ºC.
Usually, the quantity of acetic acid employed in step-(a) is about 5 volumes to about 20 volumes, specifically about 7 volumes to 16 volumes, with respect to the quantity of Tafamidis.
In one embodiment, the suspension in step-(b) is heated while stirring at a temperature of about 40ºC to about 110 ºC for at least 5 minutes, specifically at a temperature of about 45ºC to about 100ºC for about 20 minutes to 6 hours, and most specifically at a temperature of about 50ºC to about 90ºC for about 30 minutes to 4 hours.
In one embodiment, the cooling of the hot suspension in step-(c) is carried out under stirring at a temperature of below about 35ºC for at least 5 minutes, specifically at a temperature of about 10ºC to about 30ºC for about 30 minutes to 8 hours, and most specifically at a temperature of about 25ºC to about 30ºC for about 2 hours to 4 hours.
The collection of the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof. In one embodiment, the highly pure crystalline Form 4 of Tafamidis obtained in step-(d) is washed with acetic acid solvent.
The highly pure crystalline Form 4 of Tafamidis obtained in step-(d) is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 50°C to about 140°C, specifically at a temperature of about 70°C to about 130°C, and most specifically at a temperature of about 80°C to about 120°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 30 minutes to 20 hours, more specifically for a period of about 45 minutes to 12 hours, and most specifically for a period of about 1 to 6 hours.
Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art. The drying can be carried out in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure or at atmospheric pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines. The stable and highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form 4 of Tafamidis obtained by the processes disclosed herein exhibits properties making it suitable for formulating Tafamidis.
In one embodiment, the highly pure crystalline Form 4 of Tafamidis, obtained by the process described herein, remains in the same crystalline form and is found to be stable.
In one embodiment, the crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 15.9, 16.9, 18.0, 24.1 and 27.3 ± 0.2 degrees substantially in accordance with Figure 1. In another embodiment, the crystalline Form 4 of Tafamidis obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having one or more additional 2-theta peaks at about 7.0, 9.9, 11.7, 12.4, 13.3, 14.1, 16.7, 18.0, 19.3, 19.8, 20.8, 23.5, 24.8, 25.3, 26.2, 26.9, 28.0, 28.6 ± 0.2 degrees.
In another embodiment, the crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained by the process disclosed herein is characterized by a Raman spectrum comprising Raman shift peaks at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1 substantially in accordance with Figure 2. In another embodiment, the crystalline Form 4 of Tafamidis obtained by the process disclosed herein is further characterized by a Raman spectrum comprising one or more additional Raman shift peaks at about 132, 173, 201, 217, 225, 416, 601, 668, 727, 755, 778, 945, 994, 1077, 1124, 1144, 1195, 1234, 1247, 1272, 1297, 1350, 1411, 1485, 1547, 1572, 1590, 1613 and 3076 ± 2 cm-1.
The crystalline Form 4 of Tafamidis obtained by the processes disclosed herein is essentially free from other polymorphic forms of Tafamidis detectable by the spectral methods typically used, e.g., Powder X-ray diffraction. In one embodiment, the crystalline Form 4 of Tafamidis obtained by the processes disclosed herein is essentially free of the crystalline forms (Forms 1, 2 and 6) and amorphous form of Tafamidis as disclosed in the US’441 patent. In another embodiment, the crystalline Form 4 of Tafamidis obtained by the processes disclosed herein is essentially free from crystalline forms of Tafamidis as disclosed in the US’391 patent.
The term “crystalline Form 4 of Tafamidis essentially free of other polymorphic forms” means that no other polymorphic forms of Tafamidis free acid can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Tafamidis” is intended to mean the polymorphic forms of Tafamidis other than crystalline Form 4.
Further encompassed herein is the use of the highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In another aspect, the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 150 microns, specifically about 2 microns to about 100 microns, and most specifically about 4 microns to about 80 microns.
In another aspect, the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 2 microns to about 50 microns, and most specifically about 4 microns to about 30 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “μm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form 4 of Tafamidis obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, and the like. A most preferable oral dosage forms is capsule.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Kα radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.

Raman Method:
Raman spectroscopy is carried out with a Bruker RAM-II spectrometer with LN-Ge Diode detector. A fine-ground powder from the test sample was prepared using a mortar and pestle. A clean and dry sample disk is placed on the sample holder. The upper piece is placed on top of the sample holder. A spatula tip of the fine-ground sample was added and compressed with the grinder. The top of the sample disk was flattened. The sample was analyzed using following conditions-Scan Range: 3600 to 0 Cm-1; Resolution: 2 Cm-1; Scan Numbers-256; Raman Laser Power: 500 mW.

The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of crude Tafamidis free acid
4-(3,5-Dichlorobenzamido)-3-hydroxybenzoic acid (200 g) was added to o-xylene (2000 ml) in a reaction flask at 25-30°C and the resulting mass was stirred for 15 minutes at the same temperature. To the reaction mass, triethylamine (92 g) was added at 25-30°C and the resulting mass was stirred for 15 minutes at the same temperature. To the reaction mass, methane sulphonic acid (92 g) was added at 25-30°C and the resulting mass was stirred for 15 minutes at the same temperature, followed by heating the mass to reflux temperature by azeotropic distillation and then maintaining the reaction mass at reflux temperature for 22-24 hours while collecting the water by azeotropic distillation. After completion of the reaction, the resulting mass was cooled to 25-30°C. The resulting viscous solid was filtered and washed with o-xylene (100 ml) to produce crude Tafamidis (Wet weight: 400 g; Purity by HPLC: 99.78%).

Example 2
Preparation of pure crystalline Form 4 of Tafamidis
Tetrahydrofuran (2600 ml) was added to the crude Tafamidis (400 g, wet solid obtained as per the process described in Example 1) at 25-30°C, the resulting mixture was heated to reflux temperature (63-68°C) and then stirred for 15 minutes at the same temperature to form a clear solution. Carbon powder (5 g) was added to the resulting solution at reflux temperature and then stirred for 30 minutes at the same temperature. The reaction mixture was filtered through celite bed and washed the bed with tetrahydrofuran (110 ml). The resulting filtrate was concentrated under vacuum to remove the solvent completely. The resulting mass was cooled to 25-35°C, followed by the addition of acetic acid (3000 ml) at ambient temperature and then stirring the suspension for 1 to 2 hours at the same temperature. The separated solid was filtered, washed the solid with acetic acid (200 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 75-80°C under vacuum for 15 to 18 hours to produce 170 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.85%).

Example 3
Preparation of pure Tafamidis
Isopropyl alcohol (1000 ml) was added to crude Tafamidis (400 g, wet solid obtained as per the process described in Example 1) at 25-30°C and the resulting mixture was stirred for 1 hour at reflux temperature (75-80°C). The resulting mass was cooled to room temperature (25-30°C) and the solid obtained was filtered, washed with isopropyl alcohol (100 ml) and then dried the material at 60-65°C under vacuum for 10 to 12 hours to produce 170 g of pure Tafamidis (Purity by HPLC: 99.8%).

Example 4
Preparation of pure crystalline Form 4 of Tafamidis
Acetic acid (1500 ml) was added to crude Tafamidis (200 g, wet solid obtained as per the process described in Example 1) at 25-30°C and the resulting suspension was stirred for 2 to 3 hours at ambient temperature. The separated solid was filtered, washed the solid with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 100-105°C for 4 to 5 hours to produce 88 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.80%).

Example 5
Preparation of pure crystalline Form 4 of Tafamidis
Acetic acid (1500 ml) was added to pure Tafamidis (100 g, Purity by HPLC: 99.8% obtained in Example 3) at 25-30°C and the resulting suspension was stirred for 2 to 3 hours at 25-35°C. The separated solid was filtered, washed the solid with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 110-115°C for 3 to 4 hours to produce 88 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.80%).

Example 6
Preparation of pure crystalline Form 4 of Tafamidis
Acetic acid (1500 ml) was added to pure Tafamidis (100 g, Purity by HPLC: 99.8% obtained as per the process described in Example 3) at 25-30°C and the resulting suspension was heated to 50-60°C and then stirred for 30-60 min at the same temperature. The resulting hot suspension was cooled to room temperature and stirred for 2-3 hours. The separated solid was filtered, washed with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 105-110°C for 3 to 4 hours to produce 88 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.70%).

Example 7
Preparation of pure crystalline Form 4 of Tafamidis
Acetic acid (1500 ml) was added to pure Tafamidis (100 g, Purity by HPLC: 99.8%) at 25-30°C and the resulting suspension was heated to 75-80°C and then stirred for 30-60 minutes at the same temperature. The resulting hot suspension was cooled to room temperature and stirred for 2-3 hours. The separated solid was filtered, washed with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 100-105°C for 4 to 5 hours to produce 86 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.82%).

Example 8
Preparation of pure crystalline Form 4 of Tafamidis
Acetic acid (1500 ml) was added to pure Tafamidis (100 g, Purity by HPLC: 99.8%) at 25-30°C and the resulting suspension was heated to 95-100°C and then stirred for 30-60 minutes at the same temperature. The resulting hot suspension was cooled to room temperature and stirred for 2-3 hours. The separated solid was filtered, washed with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 105-110°C for 3 to 4 hours to produce 85.5 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.91%).

Example 9
Preparation of pure crystalline Form 4 of Tafamidis
Isopropyl alcohol (1000 ml) was added to pure Tafamidis (100 g, Purity by HPLC: 99.8%) at 25-30°C and the resulting mixture was stirred for 1 hour at reflux temperature (75-80°C). The resulting mass was cooled to room temperature (25-30°C) and the solid obtained was filtered and then washed with isopropyl alcohol (100 ml). Acetic acid (1000 ml) was added to the resulting wet solid at 25-30°C and then stirred for 2 to 4 hours at ambient temperature. The separated solid was filtered, washed the solid with acetic acid (100 ml), suck dried the material thoroughly till mother liquors expelled completely and then finally dried the material at 115-120°C for 1 to 3 hours to produce 85 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.82%).

Example 10
Preparation of pure crystalline Form 4 of Tafamidis
Isopropyl alcohol (1000 ml) was added to pure Tafamidis (100 g; Purity by HPLC: 99.8%) at 25-30°C and the resulting mixture was stirred for 1 hour at reflux temperature (75-80°C). The resulting mass was cooled to room temperature (25-30°C) and the solid obtained was filtered and then washed with isopropyl alcohol (100 ml). Acetic acid (1000 ml) was added to the resulting wet solid at 25-30°C, the resulting suspension was heated to 45-50°C and then stirred for 1 hour at the same temperature. The resulting hot suspension was cooled to room temperature, the separated solid was filtered and then washed the solid with acetic acid (100 ml). The resulting wet material was suck dried thoroughly till mother liquors expelled completely and then finally dried the material at 115-120°C for 1 to 3 hours to produce 86 g of pure crystalline Form 4 of Tafamidis (Purity by HPLC: 99.85%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.
, Claims:We Claim:
1. A process for the preparation of the stable and highly pure crystalline Form 4 of Tafamidis characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 15.9, 16.9, 18.0, 24.1 and 27.3 ± 0.2 degrees substantially in accordance with Figure 1; and/or a Raman spectrum comprising Raman shift peaks at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1 substantially in accordance with Figure 2; which comprises:
a) providing a suspension of Tafamidis free acid in acetic acid solvent;
b) stirring the suspension obtained in step-(a) at an ambient temperature; and
c) collecting the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained in step-(b).

2. The process as claimed in claim 1, wherein the crystalline Form 4 of Tafamidis is further characterized by an X-ray powder diffraction pattern having one or more additional 2-theta peaks at about 7.0, 9.9, 11.7, 12.4, 13.3, 14.1, 16.7, 18.0, 19.3, 19.8, 20.8, 23.5, 24.8, 25.3, 26.2, 26.9, 28.0, 28.6 ± 0.2 degrees; and/or by a Raman spectrum comprising one or more additional Raman shift peaks at about 132, 173, 201, 217, 225, 416, 601, 668, 727, 755, 778, 945, 994, 1077, 1124, 1144, 1195, 1234, 1247, 1272, 1297, 1350, 1411, 1485, 1547, 1572, 1590, 1613 and 3076 ± 2 cm-1.

3. The process as claimed in claim 1, wherein the Tafamidis used as a starting material in step-(a) of the present invention is a crude or pure Tafamidis; wherein the step-(a) of providing a suspension of Tafamidis includes combining Tafamidis with acetic acid solvent at an ambient temperature or obtaining an existing suspension from a previous processing step; wherein the quantity of acetic acid employed in step-(a) is about 5 volumes to about 20 volumes with respect to the quantity of Tafamidis used as a starting material; wherein the suspension in step-(b) is stirred at ambient temperature for at least 5 minutes; wherein the collection of the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms in step-(c) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the highly pure crystalline Form 4 of Tafamidis obtained in step-(c) is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 50°C to about 140°C for a period of about 30 minutes to 20 hours.

4. The process as claimed in Claim 3, wherein the crude or pure Tafamidis used in step-(a) is in the form of a solid, wet solid, viscous solid, semi-solid, amorphous form, crystalline solid, organic layer, residual mass or a mixture thereof; wherein the quantity of acetic acid employed in step-(a) is about 7 volumes to 16 volumes with respect to the quantity of Tafamidis used as a starting material; wherein the suspension in step-(b) is stirred at a temperature of about 20°C to about 35°C for about 10 minutes to 8 hours; and wherein the highly pure crystalline Form 4 of Tafamidis obtained in step-(c) is further dried at a temperature of about 80°C to about 120°C for a period of about 45 minutes to 12 hours.

5. A process for the preparation of a stable and highly pure crystalline Form 4 of Tafamidis characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 15.9, 16.9, 18.0, 24.1 and 27.3 ± 0.2 degrees substantially in accordance with Figure 1; and/or a Raman spectrum comprising Raman shift peaks at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1 substantially in accordance with Figure 2; which comprises:
a) providing a suspension of Tafamidis free acid in acetic acid solvent;
b) heating the suspension obtained in step-(a) while stirring at a temperature of above about 40ºC to produce a hot suspension;
c) cooling the hot suspension obtained in step-(b) to below about 35ºC; and
d) collecting the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms obtained in step-(b).

6. The process as claimed in claim 5, wherein the Tafamidis used as a starting material in step-(a) of the present invention is a crude or pure Tafamidis; wherein the step-(a) of providing a suspension of Tafamidis includes combining Tafamidis with acetic acid solvent at an ambient temperature or obtaining an existing suspension from a previous processing step; wherein the quantity of acetic acid employed in step-(a) is about 5 volumes to about 20 volumes with respect to the quantity of Tafamidis used as a starting material; wherein the suspension in step-(b) is heated while stirring at a temperature of about 40ºC to about 110 ºC for at least 5 minutes; wherein the cooling of the hot suspension in step-(c) is carried out under stirring at a temperature of below about 35ºC for at least 5 minutes; wherein the collection of the highly pure crystalline Form 4 of Tafamidis essentially free of other crystalline forms in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the highly pure crystalline Form 4 of Tafamidis obtained in step-(d) is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 50°C to about 140°C for a period of about 30 minutes to 20 hours.

7. The process as claimed in Claim 6, wherein the crude or pure Tafamidis used in step-(a) is in the form of a solid, wet solid, viscous solid, semi-solid, amorphous form, crystalline solid, organic layer, residual mass or a mixture thereof; wherein the quantity of acetic acid employed in step-(a) is about 7 volumes to 16 volumes with respect to the quantity of Tafamidis used as a starting material; wherein the suspension in step-(b) is heated while stirring at a temperature of about 45ºC to about 100ºC for about 20 minutes to 6 hours; wherein the cooling of the hot suspension in step-(c) is carried out under stirring at a temperature of about 25ºC to about 30ºC for about 2 hours to 4 hours; and wherein the highly pure crystalline Form 4 of Tafamidis obtained in step-(d) is further dried at a temperature of about 80°C to about 120°C for a period of about 45 minutes to 12 hours.

8. Highly pure crystalline Form 4 of Tafamidis obtained by the processes as claimed in claims 1 and 7, wherein the crystalline Form 4 of Tafamidis is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 15.9, 16.9, 18.0, 24.1 and 27.3 ± 0.2 degrees substantially in accordance with Figure 1; and/or a Raman spectrum comprising Raman shift peaks at about 201, 266, 283, 994, 1273, 1297 and 1547 ± 2 cm-1 substantially in accordance with Figure 2.

9. A pharmaceutical composition comprising highly pure crystalline Form 4 of Tafamidis obtained by the process as claimed in Claims 1 and 7, wherein the crystalline Form 4 of Tafamidis has a D90 particle size of less than or equal to about 150 microns and/or a D50 particle size of less than or equal to about 100 microns.

10. The pharmaceutical composition as claimed in claim 9, wherein the crystalline Form 4 of Tafamidis has a D90 particle size of about 4 microns to about 80 microns and/or a D50 particle size of about 4 microns to about 30 microns.