DESC:Aspects of the present application relate to solid forms of Tafamidis
and preparative processes thereof. Specific aspects relate to crystalline form
T7 and T8 of Tafamidis and their processes for their preparation.
The drug compound having the adopted name “Tafamidis” has
chemical name: 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid as
below.
Tafamidis is a selective stabilizer of transthyretin developed by The
Scripps Research Institute and marketed by Pfizer as VYNDAQEL®
(Tafamidis meglumine) and VYNDAMAXTM (Tafamidis) oral capsule for the
treatment of the cardiomyopathy of wild type or hereditary transthyretinmediated
amyloidosis in adults to reduce cardiovascular mortality and
cardiovascular-related hospitalization.
US 7214695 B2 patent first disclosed Tafamidis and its use thereof for
the treatment of transthyretin amyloid disease. It further discloses a general
procedure for the preparation of benzoxazoles, particularly Tafamidis. US
9249112 B2 patent discloses the meglumine salt of Tafamidis along with its
amorphous and crystalline forms. The US 9770441 B2 patent discloses
amorphous and crystalline forms (Form 1, 2, 4 and 6) of Tafamidis.
The reported solid forms of Tafamidis are not viable at industrial scale
due to stability or other issues and there remains a need for alternate solid
forms of Tafamidis and their preparative processes.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a crystalline Form T7 of
Tafamidis, characterized by a PXRD pattern comprising the peaks at about
12.21, 13.98, 16.81 and 31.65 ± 0.2° 2?.
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In another aspect, the present application provides a process for the
preparation of crystalline Form T7 of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and THF.
In an aspect, the present application provides a crystalline Form T8 of
Tafamidis, characterized by a PXRD pattern comprising the peaks at about
14.52, 15.01, 21.02, 25.3 and 26.03 ± 0.2° 2?.
In another aspect, the present application provides a process for the
preparation of crystalline Form T8 of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and PEG-6000 in
suitable solvents.
In another aspect, the present application provides a process for the
preparation of crystalline Form TLP of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and L-Proline in
suitable solvent(s).
In another aspect, the present application provides a pharmaceutical
composition comprising crystalline Forms T7, T8 and TLP of Tafamidis and
atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline
Form T7 of Tafamidis, prepared by the method of Example 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline
Form T8 of Tafamidis, prepared by the method of Example 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline
Form TLP of Tafamidis, prepared by the method of Example 3.
Figure 4 is an illustrative DSC thermogram of crystalline Form TLP of
Tafamidis, prepared by the method of Example 3.
Figure 5 is an illustrative TGA of crystalline Form TLP of Tafamidis,
prepared by the method of Example 3.
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DETAILED DESCRIPTION
Aspects of the present application relates to solid form of Tafamidis
and the pharmaceutical compositions thereof. Specific aspects relate to
crystalline form T7 and T8 of Tafamidis and their processes for thei r
preparation.
In an aspect, the present application provides a crystalline Form T7 of
Tafamidis, characterized by a PXRD pattern comprising the peaks at about
12.21, 13.98, 16.81 and 31.65 ± 0.2° 2?. In an embodiment, the crystalline
Form T7 is characterized by one or more additional peaks at about 7.72, 15.80,
16.53, 19.57, 23.87, 24.59, 25.88, 27.15 ± 0.2° 2?. In an embodiment, the
present application provides crystalline Form T7 of Tafamidis, characterized
by a powder X-ray diffraction pattern, as illustrated by Figure 1.
In another aspect, the present application provides a process for the
preparation of crystalline Form T7 of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and THF.
In an aspect, the present application provides a crystalline Form T8 of
Tafamidis, characterized by a PXRD pattern comprising the peaks at about
14.52, 15.01, 21.02, 25.3 and 26.03 ± 0.2° 2?. In an embodiment, the
crystalline Form TLP is characterized by one or more additional peaks at about
19.05, 21.96, 22.94, 23.20, 23.46, 26.91 and 27.08° ± 0.2o 2?. In an
embodiment, the present application provides crystalline Form T8 of
Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated
by Figure 2.
In another aspect, the present application provides a process for the
preparation of crystalline Form T8 of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and PEG-6000 in
suitable solvents.
In another aspect, the present application provides a process for the
preparation of crystalline Form TLP of Tafamidis, comprising the step of
crystallizing from a mixture comprising Tafamidis free acid and L-Proline in
suitable solvent(s).
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In embodiments, Tafamidis used in this aspect may be obtained by any
methods known in the art or a reaction mixture comprising Tafamidis may be
used directly.
In embodiments, the crystalline Form T7, T8 and TLP can be isolated by
separating the solids from the solvent through suitable techniques known in the
art such as evaporation, filtration, decantation and the like.
In embodiments, the isolated solid may be dried under suitable drying
conditions such as aerial drying, drying under vacuum or inert gas at a suitable
temperature of about 25°C or above.
In embodiments, the crystalline forms of Tafamidis of the present
application are stable under thermal, humid and stress conditions. Further, the
crystalline forms of present application exhibits superior solubility in solvents
such as water, as compared to reported crystalline forms of Tafamidis.
In another aspect, the present application provides a crystalline Forms
T7, T8 and TLP Tafamidis, and its the pharmaceutical compositions thereof,
comprising Tafamidis with a chemical purity of atleast 99% by HPLC or
atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides a pharmaceutical
composition comprising crystalline Forms T7, T8 and TLP of Tafamidis and
atleast one pharmaceutically acceptable excipient.
The suitable organic solvent at any stage of the process of the present
invention may be selected from the group consisting of alcohols, such as
methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol;
ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-
dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as
ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone
and methyl isobutyl ketone; halogenated hydrocarbons, such as
dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as
acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,Ndimethylacetamide,
N-methyl 2-pyrrolidone, dimethylsulfoxide, and the like;
water; and any mixtures thereof.
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Suitable temperatures for the reaction may be less than about 150°C,
less than about 100°C, less than about 80°C, less than about 60°C, or any other
suitable temperatures.
The compounds at any stage of the process of the present invention may be
isolated using conventional techniques known in the art. For example, useful
techniques include but are not limited to, decantation, centrifugation, gravity
filtration, suction filtration, concentrating, cooling, stirring, shaking, combining
with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple
evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the
like. The isolation may be optionally carried out at atmospheric pressure or under
reduced pressure. The solid that is obtained may carry a small proportion of
occluded mother liquor containing a higher percentage of impurities and, if
desired, the solid may be washed with a solvent to wash out the mother liquor.
The compounds at any stage of the process of the present invention may be
recovered from a suspension/solution using any of techniques such as decantation,
filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or
any other suitable techniques. The reaction can be efficiently completed at room
temperature or ambient temperature or if required reaction mass can be heated to
elevated temperatures or up to about the reflux temperatures, and maintained for
about 10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be
suitably carried out using equipment such as a tray dryer, vacuum oven, air oven,
fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric
pressure or under reduced pressure. Drying may be carried out at temperatures
less than about 100°C, less than about 60°C, less than about 40°C, or any other
suitable temperatures, at atmospheric pressure or under reduced pressure, and in
the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or
helium. The drying may be carried out for any desired time periods to achieve a
desired purity of the product, such as, for example, about 1 to about 15 hours, or
longer.
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In an embodiment, Tafamidis of present invention has average particle
size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than
60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less
than 10 µm, less than 5 µm or any other suitable particle sizes. In another
embodiment, Tafamidis of present invention may have particle size distribution:
D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or
smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm,
smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm,
smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm;
D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm,
smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110
µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than
70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than
30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Tafamidis particles may be measured using
any techniques known in the art. For example, particle size distributions of
Tafamidis particles may be measured using microscopy or light scattering
equipment, such as, for example, a Malvern Master Size 2000 from Malvern
Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred
herein, the term “D10” in the context of the present invention is 10% of the
particles by volume are smaller than the D10 value and 90% particles by volume
are larger than the D10 value. “D50” in the context of the present invention is
50% of the particles by volume are smaller than the D50 value and 50% particles
by volume are larger than the D50 value. “D90” in the context of the present
invention is 90% of the particles by volume are smaller than the D90 value and
10% particles by volume are larger than the D90 value.
In an embodiment, Tafamidis of present invention can be micronized or
milled using conventional techniques to get the desired particle size to achieve
desired solubility profile to suit to pharmaceutical composition requirements.
Techniques that may be used for particle size reduction include, but not limited to
ball milling, roller milling and hammer milling. Milling or micronization may be
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performed before drying, or after the completion of drying of the product.
The compounds of this application are best characterized by the X-ray
powder diffraction pattern determined in accordance with procedures that are
known in the art. PXRD data reported herein was obtained using CuK? radiation,
having the wavelength 1.5406 Å and were obtained using a PANalytical X’Pert
PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm.
Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969
58:911-929.
Thermogravimetry-differential thermal analysis (TG-DTA) was performed
on a Rigaku Thermo plus EVO2 TG-DTA8122 instrument. The measurement was
carried out under a dry nitrogen stream (a flow rate of 320 mL/min) and a normal
pressure at a temperature rising rate of 10 °C/min.
In an embodiment, at least one pharmaceutically acceptable excipient of
this aspect may be selected from the group consisting of polyvinyl pyrrolidone,
povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone
vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®),
polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–
polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40)
stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer
188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or
Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate (HPMC-AS),
hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL),
hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L),
hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetatepolyethylene
glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl
cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose
acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins,
gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like;
water soluble sugar excipients, preferably having low hygroscopicity, which
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include, but are not limited to, mannitol, lactose, fructose, sorbitol and the like;
polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene
glycol derivatives and the like; organic amines such as alkyl amines (primary,
secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl
amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and
guanidine or its derivatives, or any other excipient at any aspect of present
application. A thorough discussion of pharmaceutically acceptable excipients is
presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing
Company) and Remington: The Science and Practice of Pharmacy (21st ed.,
Lippincott Williams & Wilkins), which are hereby incorporated by reference.
The use of mixtures of more than one of the pharmaceutical excipients to
provide desired release profiles or for the enhancement of stability is within the
scope of this invention. Also, all viscosity grades, molecular weights,
commercially available products, their copolymers, and mixtures are all within the
scope of this invention without limitation. Solid dispersions of the present
application also include the solid dispersions obtained by combining Tafamidis
with a suitable non-polymeric excipient by employing techniques known in the art
or procedures described or exemplified in any aspect of the instant invention.
Certain specific aspects and embodiments of the present application will
be explained in greater detail with reference to the following examples, which are
provided only for purposes of illustration and should not be construed as limiting
the scope of the application in any manner. Variations of the described
procedures, as will be apparent to those skilled in the art, are intended to be within
the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of
±10%, preferably within a range of ±5%, more preferably within a range of ±2%,
still more preferably within a range of ±1 % of its value. For example "about 10"
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should be construed as meaning within the range of 9 to 11 , preferably within the
range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still
more preferably within the range of 9.9 to 10.1.
Examples
Example-1: Preparation of crystalline Form T7 of Tafamidis.
A mixture of Tafamidis (1 g) was dissolved in Tetrahydrofuran (40 mL)
followed by sonication, at room temperature. The mixture was subjected to
evaporation at ~50oC followed by drying under vacuum to afford the
crystalline Form T7 of Tafamidis.
Example-2: Preparation of crystalline Form T8 of Tafamidis.
A mixture of Tafamidis (500 mg) was dissolved in Tetrahydrofuran (20mL).
To this a solution of PEG6000 (1.5g) in water (2mL) was added at room
temperature. The obtained the clear solution was evaporated on rotavapor
maintained at 60oC followed by drying under vacuum to afford the Form T8 of
Tafamidis.
Example-3: Preparation of crystalline Form TLP of Tafamidis.
A mixture of Tafamidis (20 mg) was dissolved in Tetrahydrofuran (600mL) at
~45-50oC. Then a solution of L-Proline (14.93 g) in methanol (100mL) was
prepared at room temperature. Then, these two solutions were simultaneously
charged to acetonitrile (400mL) at room temperature. The mixture was stirred
for 5-6 hours at 20-25oC. The obtained solid was filtered under vacuum and
dried in VTD at 60-65°C about 6-8 hours to afford the title compound. ,CLAIMS:We Claim,
Claim 1: A crystalline Form T7 of Tafamidis, characterized by a PXRD pattern
comprising the peaks at about 12.21, 13.98, 16.81 and 31.65 ± 0.2° 2?.
Claim 2: A process for preparing Form T7 of Tafamidis as claimed in Claim 1,
comprising the step of crystallizing from a mixture comprising Tafamidis free
acid and THF
Claim 3: A crystalline Form T8 of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 14.52, 15.01, 21.02, 25.3 and 26.03 ± 0.2° 2?.
Claim 4: A process for the preparation of crystalline Form T8 of Tafamidis asclaimed in claim 3, comprising the step of crystallizing from a mixturecomprising Tafamidis free acid and PEG-6000 in a suitable solvent.
Claim 5: A process for the preparation of crystalline Form TLP of Tafamidis,comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in a suitable solvent.