FEBUXOSTAT SOLID DISPERSION
Field of the Invention
The present invention provides an amorphous solid dispersion of febuxostat,
processes for its preparation, pharmaceutical compositions comprising it and its use for the
chronic management of hyperuricemia in patients with gout.
Background of the Invention
Febuxostat is a non-purine xanthine oxidase inhibitor known from U.S. Patent No.
5,614,520. It is chemically 2-[3-cyano-4-(2-memylpropoxy)phenyl]-4-memylthiazole-5-
carboxylic acid having the structure as represented by Formula I .
Formula I
Febuxostat is marketed in the United States under the brand name Uloric® for the
chronic management of hyperuricemia in patients with gout.
Amorphous form of febuxostat is disclosed in U.S. Patent No. 6,225,474. Besides
this, several other crystalline forms of febuxostat are known in literature. Solid
dispersions of febuxostat are not disclosed in literature.
Summary of the Invention
The present invention provides an amorphous solid dispersion of febuxostat,
processes for its preparation, pharmaceutical compositions comprising it and its use for the
treatment of gout. The solid dispersion of the present invention improves the stability of
the amorphous state of febuxostat.
A first aspect of the present invention provides an amorphous solid dispersion of
febuxostat and a carrier.
A second aspect of the present invention provides a process for preparing the
amorphous solid dispersion of febuxostat and a carrier comprising dissolving febuxostat
and carrier in a solvent and removing the solvent from the solution.
A third aspect of the present invention provides a pharmaceutical composition
comprising an amorphous solid dispersion of febuxostat and one or more pharmaceutically
acceptable carriers, diluents or excipients.
A fourth aspect of the present invention provides use of an amorphous solid
dispersion of febuxostat for chronic management of hyperuricemia in patients with gout.
Brief Description of the Figures
Figure 1: X-ray diffraction pattern of amorphous solid dispersion of febuxostat
with polyvinyl pyrrolidone.
Figure 2: X-ray diffraction pattern of amorphous solid dispersion of febuxostat
with polyvinyl pyrrolidone on keeping at stability at ambient conditions for about 1
month.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described
hereinafter.
The term "solid dispersion", as used herein, refers to systems having small solidstate
particles of one phase dispersed in another solid-state phase. More particularly,
amorphous solid dispersion of the present invention comprises febuxostat dispersed in a
carrier in solid state. Amorphous solid dispersion of the present invention may be
prepared by melting or solvent methods or by a combination of melting and solvent
methods.
The term "ambient temperature", as used herein, refers to temperature in the range
of about 20°C to about 35°C.
Febuxostat to be used for the preparation of the amorphous solid dispersion of the
present invention may be obtained by any of the methods known in the literature such as
those described in U.S. Patent Nos. 5,614,520; 7,541,475; and U.S. Publication No.
2009/0203919, which are incorporated herein by reference. Febuxostat, to be used as
starting material for the preparation of the amorphous solid dispersion of the present
invention, may be obtained as a solution directly from a reaction in which it is formed and
used as such without isolation or it may be isolated from the reaction mixture in which it is
formed and then used for the preparation of the amorphous solid dispersion.
Examples of carriers to be used for the preparation of the amorphous solid
dispersion of the present invention may include polyvinyl pyrrolidone (PVP), polyethylene
glycol (PEG), polyvinyl alcohol (PVA), crospovidone, starch, pectin, pullulan, mannan,
gelatin, gum arabic, a dextrin, a cyclodextrin, agar, a polyoxysorbitan fatty acid ester, an
alginate or cellulose derivatives. Examples of cellulose derivatives may include
hypromellose (HPMC), hydroxypropyl cellulose (HPC), hypromellose phthalate
(HPMCP), hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose acetate
succinate cellulose (HPMCAS), ethyl cellulose, hydroxyethyl cellulose, methyl cellulose,
carmellose (CMC), carmellose sodium (CMC-Na), carmellose calcium (CMC-Ca),
croscarmellose sodium and low-substituted hydroxypropyl cellulose (L-HPC).
The amorphous solid dispersion of the present invention may be prepared by
reacting about 0.5 to about 5 equivalents of polyvinyl pyrrolidone per equivalent
febuxostat in solvent at ambient temperature to reflux temperature of solvent. Isolation of
the solid dispersion may be carried out by quickly removing the solvent from the solution
and drying. Removal of the solvent may be carried out by distillation at a temperature of
about 50°C to 80°C, by spray drying or agitated thin film drying. Drying may be carried
out using any suitable method such as drying under reduced pressure, vacuum tray drying,
air drying or a combination thereof at about 40°C to 70°C for about 4 hours to 8 hours.
Solvent(s) to be used for the preparation of the amorphous solid dispersion of the
present invention may be selected from the group comprising of alcohols, carboxylic
acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, water or mixtures
thereof. Examples of alcohols may include methanol, ethanol, 1-propanol, 1-butanol or 2-
butanol. Examples of carboxylic acids may include formic acid, acetic acid or propionic
acid. Examples of chlorinated hydrocarbons may include dichloromethane or chloroform.
Examples of ketones may include acetone, dimethyl ketone, ethyl methyl ketone or methyl
iso-butyl ketone. Examples of ethers may include diethyl ether, ethyl methyl ether, diisopropyl
ether, tetrahydrofuran or 1,4-dioxane. Examples of amides may include N,Ndimethylformamide
or N,N-dimethylacetaniide. Examples of sulphoxides may include
dimethyl sulfoxide or diethyl sulphoxide. Examples of cyclic ethers may include
tetrahydrofuran.
In one embodiment of the present invention, the amorphous solid dispersion may
be prepared by dissolving febuxostat and polyvinyl pyrrolidone in an alcohol, removing
the alcohol and drying. In another embodiment of the present invention, the amorphous
solid dispersion may be prepared by dissolving febuxostat and polyvinyl pyrrolidone in
methanol, removing methanol and drying. In a preferred embodiment of the present
invention, the amorphous solid dispersion may be prepared by dissolving febuxostat and
polyvinyl pyrrolidone in methanol, distilling the solvent from the solution using a Buchi
rotavapor set at a temperature of about 65°C and about 250 revolutions per minute (rpm)
under reduced pressure, drying for about 10 minutes followed by vacuum tray drying at
about 55°C for about 6 hours. In another preferred embodiment, the amorphous solid
dispersion may be prepared by dissolving febuxostat and polyvinyl pyrrolidone in
methanol followed by spray drying using a spray dryer supplied with nitrogen gas at a feed
pump rate of about 6 mL/minute. The inlet temperature of the spray dryer may be
maintained at about 80°C to 140°C and outlet temperature may be maintained at about
35°C to 65°C.
The amorphous solid dispersion of the present invention is retained for a long
period of time under ambient conditions and is physically stable.
The amorphous solid dispersion of febuxostat and a carrier of the present invention
may be administered as part of a pharmaceutical composition for the chronic management
of hyperuricemia in patients with gout. Accordingly, in a further aspect, there is provided
a pharmaceutical composition comprising an amorphous solid dispersion of febuxostat and
a carrier and one or more diluents(s) or excipient(s). Amorphous solid dispersion of
febuxostat and a carrier of the present invention may conventionally be formulated into
tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
Any suitable route of administration may be employed, for example, peroral or parental.
In the foregoing section, embodiments are described by way of examples to
illustrate the processes of invention. However, these are not intended in any way to limit
the scope of the present invention. Several variants of the examples would be evident to
persons ordinarily skilled in the art which are within the scope of the present invention.
Method
X-ray diffraction pattern was recorded using an Panalytical Expert PRO with
Xcelerator as the detector, 0.02 as step size and 3-40° 2Qas range.
Spray drying was carried out using a Buchi Mini Spray Drier B-290; air inlet
temperature was maintained at about 80°C to about 140°C and the outlet temperature was
maintained at about 35°C to about 65°C.
Examples
Preparation of solid dispersion of febuxostat with polyvinyl pyrrolidone.
Example 1:
Febuxostat (5.01 g) and polyvinyl pyrrolidone (5.26 g) were dissolved in methanol
(250 mL) by heating at about 65°C. The clear solution was fed into a spray dryer at a feed
pump rate of about 6 mL/minute. The inlet temperature was maintained at about 120°C
and the outlet temperature was maintained at about 45°C. Solid material was dried in a
vacuum tray dryer at about 50°C for about 4 hours to obtain a solid dispersion of
febuxostat with polyvinyl pyrrolidone.
Yield: 4.89 g
Figure 1 depicts the X-ray diffraction pattern of the solid dispersion of febuxostat
with polyvinyl pyrrolidone.
Figure 2 depicts the X-ray diffraction pattern of the solid dispersion of febuxostat
with polyvinyl pyrrolidone stored at ambient conditions for about 1 month.
Example 2:
Febuxostat (1.2 g) and polyvinyl pyrrolidone (1.1 g) were dissolved in methanol
(60 mL). A clear solution was obtained. Solvent was distilled off using a Buchi rotavapor
set at about 65°C and about 250 rpm under reduced pressure. Solid material was dried
under these conditions for about 10 minutes followed by drying in a vacuum tray dryer at
about 55°C for about 6 hours to obtain a solid dispersion of febuxostat with polyvinyl
pyrrolidone.
Yield: 1.47 g
Example :
Febuxostat (0.99 g) and polyvinyl pyrrolidone (0.99 g) were dissolved in methanol
(60 mL). A clear solution was obtained. Solvent was distilled off using a Buchi rotavapor
set at about 65°C and about 250 rpm under reduced pressure. Solid material was dried
under these conditions for about 10 minutes followed by drying in a vacuum tray dryer at
about 55°C for about 6 hours to obtain a solid dispersion of febuxostat with polyvinyl
pyrrolidone.
Yield: 1.20 g
We claim:
1. An amorphous solid dispersion of febuxostat and a carrier.
2. A process for preparing an amorphous solid dispersion of febuxostat and a carrier
comprising dissolving febuxostat and carrier in solvent and removing the solvent from the
solution.
3. The solid dispersion according to claim 1 or claim 2, wherein the carrier is selected
from polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA),
crospovidone, starch, pectin, pullulan, mannan, gelatin, gum arabic, a dextrin, a
cyclodextrin, agar, a polyoxysorbitan fatty acid ester, an alginate or cellulose derivatives.
4. The process according to claim 2, wherein the solvent is selected from alcohols,
carboxylic acids, chlorinated hydrocarbons, ketones, amides, sulphoxides, ethers, water or
mixtures thereof.
5. The process according to claim 2, wherein dissolution of febuxostat and carrier in
solvent is carried out at ambient temperature to reflux temperature of the solvent.
6. The process according to claim 2, wherein removal of solvent is carried out by
spray drying.
7. The process according to claim 2, wherein removal of solvent is carried out by
distillation at about 50°C to 80°C.
8. Pharmaceutical composition comprising amorphous solid dispersion of febuxostat
and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s).
9. Use of amorphous solid dispersion of febuxostat for chronic management of
hyperuricemia in patients with gout.