BAZEDOXIFENE ACETATE FORMULATIONS
FIELD OF THE INVENTION
The present invention relates to formulations and compositions thereof of the
selective estrogen receptor modulator 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-
phenyl)-3-methyl-1H-indol-5-ol acetic acid (bazedoxifene acetate).
BACKGROUND OF THE INVENTION
Bazedoxifene acetate (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydrqxy-phenyl)-3-
methyl-1 H-indol-5-ol acetic acid), having.the chemical formula shown below:

belongs to the class of drugs typically referred to as selective estrogen receptor modulators
(SERMs). Consistent with its classification, bazedoxifene demonstrates affinity for estrogen
receptors (ER) but shows tissue selective estrogenic effects. For example, bazedoxifene
acetate demonstrates little or no stimulation of uterine response in preclinical models of
uterine stimulation. Conversely, bazedoxifene acetate demonstrates an estrogen agonist-
like effect in preventing bone loss and reducing cholesterol in an ovariectomized rat model of'
osteopenia. In an MCF-7 cell line (human breast cancer cell line), bazedoxifene acetate
behaves as an estrogen antagonist. These data demonstrate that bazedoxifene acetate is estrogenic on bone and cardiovascular lipid parameters and antiestrogenic on uterine and
mammary tissue and thus has the potential for treating a number of different diseases or
disease-like states wherein the estrogen receptor is involved.
U.S. Patent Nos. 5,998,402 and 6,479,535 report the preparation of bazedoxifene
acetate and characterize the salt as having a melting point of 174-178 °C. The synthetic
preparation of bazedoxifene acetate has also appeared in the general iiterature. See, for

example, Miller et al.,;- J. .Med..:Cben1,, 2001, 44, 1654-1657, which reports the salt as "a
crystalline solid having a rrieltiffg point of 170.5-172.5 °C. Further description of the drug's
biological activity has appeared in the general literature as well (e.g. Miller, et al. Drugs of
the Future] 2002, 27(2), 117-121).
. . It is well known that, the crystalline polymorph form of a particular drug is often an .
important determinant of the drug's ease of preparation, stability, solubility, storage stability,
ease of formulation and in vivo pharmacology. Polymorphic forms occur where the same
composition of matter crystallizes in a different lattice arrangement resulting in different- •
thermodynamic properties and stabilities specific to the particular polymorph form. In cases
where two or more polymorph substances can be produced, it is desirable to have a method
to make both polymorphs in pure form. In deciding which polymorph is preferable, the
numerous properties of the polymorphs must be compared and the preferred polymorph
chosen based on the many physical property variables. It is entirely possible that one
polymorph form can be preferable in some circumstances where" certain aspects such as
ease of preparation, stability, etc are deemed to be. critical. In other situations, a different
polymorph maybe preferred for greater solubility and/or superior pharmacokinetics.
Because of the potential advantages.associated with one pure polymorphic form, it-is- .-;
desirable to prevent or minimize polymorphic conversion (i.e., conversion of one form to
another) when two or more polymorphic forms of one substance can exist. Such polymorph
conversion can occur during-both the preparation of formulations containing the polymorph,
and during storage of a pharmaceutical dosage form containing the polymorph.
Two different crystalline polymorphs of anhydrous bazedoxifene acetate, form A and form B,
have been disclosed in U.S. Patent Application Nos. 11/100,983 and 11,100,998, both filed
April 6, 2005 and each of which is incorporated by reference herein in its entirety. Form A is
distinguished from Form B by numerous physical properties which are tabulated below. As
can be seen from the data in the Table, Form B appears to be thermodynamically more
stable than form A, contributing to numerous advantages. For example, the increased
stability of form B would facilitate manufacturing and purification processes. Form B would
also be expected to have better resistance to degradation brought on by, for example,
exposure to high temperatures and/or humidity, and have a longer shelf-life than Form A or
amorphous material.' In contrast, Form A appears to have higher solubility in aqueous and
organic solvent systems than does form B, which is advantageous in particular formulations
or doses where the solubility of the particular composition is of concern. For example,
higher solubility can contribute to better biological absorption and distribution of the drug, as
well as facilitate formulation in liquid carriers.


Given the potential advantages of a single polymorphic form, it can be seen that
formulations having reduced polymorphic conversion can provides significant benefits. The
bazedoxifene acetate formulations and compositions described herein helps meet these and
other needs.
SUMMARY OF THE INVENTION
In some embodiments, the present invention provides pharmaceutical compositions,
for example tablets, comprising bazedoxifene acetate and a pharmaceutically acceptable
carrier or excipient system. In some embodiments, the carrier or excipient system includes:
a)' a first filler/diluent component comprising from about 5% to about 85% by
weight of the pharmaceutical formulation;
b) an optional second filler/diluent component comprising from about 5% to
about 85% by weight of the pharmaceutical formulation;
c) an optional antioxidant component comprising up to about 15% by weight of
the pharmaceutical formulation;
d) a glidant/disintegrant component comprising from about 0.01% to about 10%
by weight of the pharmaceutical formulation; and
e); a lubricant component comprising from about 0.01% to about 10% by weight of the pharmaceutical formulation.

In some embodiments, the compositions are prepared by a non-aqueous process; for
example dry granulation, roller compaction, or direct blend processes.
In some embodiments, the compositions of the invention are tablets, prepared by a
direct blending procedure.
In some embodiments, the bazedoxifene acetate comprises from about 0.1% to
about 30% by weight of the pharmaceutical formulation; or from about 10% to about 30% by
weight of the pharmaceutical formulation.
In some embodiments, the bazedoxifene acetate is present substantially in a
crystalline polymorphic form; preferably substantially in the A polymorph form. In further
embodiments, at least about 90% of the bazedoxifene acetate is present in the A polymorph
form. In some further embodiments, at least about 80% of said bazedoxifene acetate is
present in the A polymorph form.
In further embodiments, the invention provides processes for making the
compositions of the invention, and products of the processes.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Figure 1 depicts a powder X-ray diffraction pattern of bazedoxifene acetate Form A
polymorph.
Figure 2 depicts an lR spectrum of bazedoxifene acetate Form A polymorph in KBr
pellet.
Figure 3 depicts a differential scanning calorimetric (DSC) trace of bazedoxifene
acetate Form A polymorph.
Figure 4 depicts a powder X-ray diffraction pattern of the bazedoxifene acetate Form
B polymorph.
Figure 5 depicts an IR spectrum of the bazedoxifene acetate Form B polymorph in
KBr pellet.
Figure 6 depicts a. differential scanning calorimetry (DSC) trace of bazedoxifene
acetate Form B polymorph.
Figure 7 shows the mean (SD) plasma bazedoxifene levels in female dogs following
single oral dose administration of 10 mg bazedoxifene as direct blend tablet, and a wet
granulation tablet, as described in Example 7.
Figure 8 shows individual dog plasma bazedoxifene levels following single oral dose
administration of 10 mg bazedoxifene direct blend tablets.
Figure 9 shows individual dog plasma bazedoxifene levels following single oral dose
administration of 10 mg bazedoxifene wet granulated tablets.

DETAILED DESCRIPTION
the present invention provides, inter alia, bazedoxifene acetate formulations and
compositions thereof having improved properties relating to reduction elimination or-
prevention of polymorphic conversion of bazedoxifene acetate. In some embodiments, the compositions are prepared by a non-aqueous process, for example dry granulation, roller
compaction or direct blend processes. In some embodiments, the present invention
provides a direct blend formulation of bazedoxifene acetate that, can reduce the potential for polymorphic conversion of bazedoxifene acetate, such as from form A to form B, compared
to other more complex formulations.
The use of a direct blend formulation is simple and cost-efficient compared to other
more time consuming processes such as wet granulation or roller-compaction, although
roller compaction processes can be utilized in some embodiments of the invention. Many of
the complex formulations such as roller compaction require large power inputs during
mixing, milling and compaction. In addition, a process with power input for an extended
period of time can also increase potential polymorphic conversions. Thus, another
advantage associated with a direct blend formulation is to use lower power in the process.
While not wishing to be-bound by any particular theory, it is believed the use of water in a wet granulation has the potential of increasing polymorphic conversion during
processing and storage because of the potential for solubilization of the bazedoxifene
acetate., Upon drying, recrystallization of the bazedoxifene acetate-can result in polymorphic
conversion, such as from form A to form B. Accordingly, in one aspect, the present invention
provides non-aqueous processes (i.e. processes that do not utilize water) for producing the
pharmaceutical compositions described herein. Examples of such non-aqueous processes
include dry granulation and roller compaction processes, as are known in the art. In one
particular embodiment, the non-aqueous process is a direct blend process, which is used to
prepare direct blend formulations of bazedoxifene acetate, and which does not require
contacting the bazedoxifene acetate with water. Such non-aqueous processes can be
advantageous wherer it is desired to minimize conversion from one polymorphic form of
bazedoxifene acetate to another, for example to minimize the conversion of the form A polymorph to the form B polymorph.
A further advantage of the present compositions is that there is no need to employ a
surfactant, such as sodium lauryl sulfate. While not wishing to be bound by any particular
theory, it is believed the use of a surfactant can increase wetting, solubility and dissolution,
and the increased solubility can facilitate potential polymorphic conversion between the
different polymorphic forms.

. In some embodiments, the present invention provides pharmaceutical compositions'"-
comprising a pharmaceutically effective amount of bazedoxifene acetate, and a carrier of
excipient system, the carrier or excipien't system comprising:
, A pharmaceutical composition comprising a pharmaceutically effective amount of
• bazedoxifene acetate and a carrier or excipient 'system, the' carrier or excipient system
comprising:
a) a first filler/diluent component comprising from about 5% to about 85% by .
weight of the pharmaceutical formulation;
b) ' an optional second filler/diluent component comprising from about 5%. to
about' 85% by weight of the pharmaceutical formulation;
c) an optional antioxidant component comprising up to about-15% by weight of
the pharmaceutical formulation;
d) a glidant/disintegrant component comprising from about 0.01% to about 10% .
by weight of the pharmaceutical formulation; and
e) a lubricant component comprising from about 0.01% to about 10% by weight
of the pharmaceutical formulation. In some embodiments, the compositions are prepared by
:,,a non-aqueous process; for example a dry granulation, ./oiler compaction-or direct blend
process.
In some embodiments, the compositions of the invention contain bazedoxifene
acetate-.substantially in one pure crystalline polymorph; preferably substantially-in the A ,:
polymorph form. In further embodiments, at least about 90% of the bazedoxifene acetate is
present in the A polymorph form. In some further embodiments, at least about 80% of said
bazedoxifene acetate is present in the A polymorph form. The direct blend formulations of
the present, invention have improved properties relating to reduction, elimination or
prevention of polymorphic conversion of bazedoxifene acetate, such as from form A to form
B, during preparation of the compositions, and during storage thereafter. Therefore, the
■ formulations of the present invention more effectively maintain advantages associated with a
single polymorph form.
. Those of skill in the art will be able to readily ascertain pharmaceutically effective
amounts" of bazedoxifene acetate. Generally, on a percentage basis, the bazedoxifene
acetate.is present in an amount of from abouf0.1% to about 30% by weight of the
pharmaceutical compositions of the present invention. In some embodiments, the
. bazedoxifene acetate is present in an amount of from about 10% to about 30% by weight of
the composition, .In some embodiments, the bazedoxifene acetate is present in an amount
of from about 10% to about 25% by weight of the composition.
As will be appreciated, ttf€'c"orripositions of the invention can be prepared as, or.'
incorporated into, a variety of dosage forms, for example tablets and capsules. In some

"embodiments, -the invention provides tablets thai contain, or are composed of a composition
of the invention. Generally, tablet dosage forms of the invention can contain bazedoxifene
• acetate in an amount of from about O.J mg to about 300 mg. In further embodiments, the
dosage forms can include bazedoxifene acetate in an amount of from about 0.5 to about 230
mg, from about 1 to about 170 mg, from about 5 to about 115 mg, or from about 1 to about-
30 mg. In some embodiments, the invention provides dosage forms, for example tablets,
containing a composition of the invention that.includes bazedoxifene acetate in an amount of
from about 15 mg to about 25 mg.
Generally, the first filler/diluent component, and the optional second filler/diluent
component, when present, can be present in an amount of from about 5% to about 85% by
weight of the- pharmaceutical formulation, or from about 25% to about 50% by weight of the
pharmaceutical formulation. In one embodiment the first filler/diluent component, and the
optional second filler/diluent component are present in an amount of from about 25% to
about 40% or more, e.g. to about 42%, by weight of the pharmaceutical formulation.
Both the first filler/diluent component.and the optional second filler/diluent component
can be selected from fillers and diluents known to be useful in the art, including for example
one or more of sugars, for example sucrose, mannitol, lactose, and the like, and/or other ■
fillers such as powdered cellulose, malodextrin, sorbitol, xylitol, carboxymethyl cellulose,
carboxyethyl cellulose, hydroxyethyl celluloses, microcrystalline celluloses, starches, calcium
phosphates, for-example anhydrous dicalcium phosphate, sodium starch glycolates, metal
. aluminosilicates, for example magnesium aluminometasilicate (Neusilin), and a mixture
thereof. In some embodiments, the first filler/diluent component includes or consists of
microcrystalline.cellulose, for example Avicel PH101, and the second filler/diluent includes or'
consists of lactose, for example lactose NF.
As used herein, the term "sugar" refers to any type of simple carbohydrate, such as a
mono or disaccharide^ either naturally obtained, refined from a natural source, or artificially
produced, and includes, without limitation, sucrose, dextrose, maltose, glucose, fructose,
galactose, marrnose, lactose, trehalose, lactulose, levulose, raffinose, ribose, and xylose.
. The term "sugar," as used herein, also includes various "sugar substitutes" widely known to
those ofbrdinary skill in the art of preparing solid dosage forms, such as the polyhydric
alcohols (sometimes referred to as "sugar alcohols" or hydrogenated saccharides), for
example sorbitol, mannitol, xylitol, and erythritol, and the sugar derivatives of polyhydric .
alcohols, such as-maltitol,' lactitol, isomalt, and polyalditol. Accprdingly, the recitation of the
' term "sugar" generically should be interpreted to include such specifiGcompounds, as well
as others not expressly recited. In certain embodiments, the sugar is a mono-or
disaccharide, for example, sucrose; dextrose, maltose, glucose, fructose, galactose, '

mannose, or lactose. In some embodiments, (he second filler/diluent component of the
compositions of the invention include or consist of lactose.
Generally, the glidant/disintegrant component is present'in an amount of from about
0.01 % to about 10% by weight of the pharmaceutical formulation, or from about 1 % to about
10% by weight of the pharmaceutical formulation, or from about 3% to about 5% byweight.
of the pharmaceutical formulation. The glidant/disintegrant can be selected from glidants
and disintegrants know to be useful for pharmaceutical formulations. Examples of suitable
giidant/disinlegrants include croscarmellose sodium, modified cellulose, pregelatinized''
starch, sodium starch glycolate, crospovidone, starch, alginic acid, sodium alginate, clays,
cellulose floe, ion exchange resins, effervescent systems based on food acids, Aerosil 200,
talc, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium
oxide, calcium silicate, silica, silicon dioxide, silicon dioxide aerogels and mixtures thereof.
In some embodiments, the glidant/diluent includes or consists of sodium starch glycolate.
The lubricant component is generally present in an amount of from about 0.01% to
about 10% by weight of the pharmaceutical formulation, from about 0.01% to about 3% by
weight of the pharmaceutical formulation, or from about 0.01 % to about 2% by weight of the
pharmaceutical formulation. In some embodiments, the lubricant component is present in
an amount of about 1 % by weight of the pharmaceutical formulation. The lubricant
component can be selected from the many lubricants useful in the pharmaceutical arts.
Examples of suitable lubricants include metal stearates, fatty acid esters, fatty acids, fatty
alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine,
polyethylene glycols, Aerosil 200, sodium chloride and mixtures thereof. In some preferred
embodiments, the lubricant is a metal stearate, for example, magnesium stearate.
In some embodiments, the pharmaceutical formulations and excipient systems of the
invention also contain an antioxidant component, which can be a single compou'ndf such as
ascorbic acid, or a mixture of antioxidants. A wide variety of antioxidant compound are
known in the art, and are suitable for use in the present invention. Examples of such
antioxidants that can be used, in the present invention include sodium ascorbate, ascorbyl
palmitate, BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole), each
optionally in conjunction with an amount of ascorbic acid. Generally, the antioxidant,
component, when present, is used in an amount of up to about 15% by weight of the
pharmaceutical formulation," for example from about 1% to about 10% by weight of'the
pharmaceutical formulation, or from about 2% to about 8% by weight of the pharmaceutical
formulation. ,
Additional suitable filler/diluents, antioxidants, glidant/disintegrants and lubricants.
can be found in, for example, Remington's Pharmaceutical Sciences, 17th' ed., Macjc

Publishing Company, Eastoh, Pa., 1985, .which is incorporated herein by reference-in its
entirety.
In some .embodiments", the first filler/diluent component includes one or-more of"
sugars, mannitol, lactose, sucrose, powdered cellulose, microcrystalline cellulose!
malodextrin, sorbitol, starch, xylitol, carboxymethyl cellulose, carboxyethyl cellulose,
hydroxyethyl celluloses, anhydrous dicalcium phosphate, sodium starch glycolates, or metal
aluminosilicates; the optional second filler/diluent component includes' one or more of
sugars, mannitol, lactose, sucrose, - powdered cellulose, microcrystalline cellulose,
malodextrin, sorbitol, starch, xylitol, carboxymethyl cellulose, . carboxyethyl cellulose,'
hydroxyethyl celluloses, anhydrous dicalcium phosphate, sodium starch glycolates, or metal
aluminosilicates; the optional antioxidant component,-when present, includes one or more of
ascorbic acid, sodium ascorbate or ascorbyl palmitate; the glidant/disintegrant component
includes one or. more of croscarmellose sodium, modified cellulose, pregelatinized starch,
sodium starch giycolate, crospovidone, starch, alginic acid, sodium alginate, clays, cellulose
floe, ion exchange resins, effervescent systems based on food acids,-Aerosil 200, talc,
lactose, metal stearates, dibasic calcium phosphate, magnesium carbonate, magnesium
oxide, calcium silicate, silica, silicon dioxide and silicon dioxide aerogels; and the-lubricant.
component includes one or more of metal stearates, fatty acid esters, fatty acids, fatty
alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine,
...polyethylene glycols, Aerosil 200,.and sodium chloride.'.
In some preferred embodiments, the first filler/diluent component includes or consists
of microcrystalline cellulose, for example Avicel PH101; the optional second filler/diluent
component is present, and includes or consists of a sugar,-for example lactose NF; the
optional antioxidant component is present, and includes or consists of ascorbic acid; the
glidant/disintegrant component includes or consists of sodium starch giycolate; and the
lubricant component includes or consists of a metal stearate, for example magnesium. .
stearate. ■
In some embodiments, the invention further provides non-aqueous processes for
preparing a pharmaceutical composition comprising a pharmaceutically effective 'amount of
bazedoxifene acetate and a carrier or excipient system, the carrier or excipient system
comprising:.
a) a first filler/diluent component comprising from about 5% to about 85% by
weight of the pharmaceutical formulation; ,
b)' an optional second filler/diluent component comprising from about 5% to
about 85% by weight of the pharmaceutical formulation;
• • c)' -an optional antioxidant component comprising up to about 15% by weight of
the pharmaceutical formulation;

d) a glidant/disintegrant component comprising from about 0.01%4o about 10%
by weight of the pharmaceutical formulation; and ■ '}:-'r'
e) a lubricant component comprising from about 0.01% to about 10% by weight,
of the pharmaceutical formulation. Examples of suitable non-aqueous processes include
direct blending, dry granulation and roller compaction. ' ■'■'.-'' "•
In some embodiments, the non-aqueous process is a direct blend process. In some
such embodiments, the process comprises:
i) combining the bazedoxifene-acetate, first filler/diluent, second filler/diluent,
glidant, and, optionally, the antioxidant to form a first mixture; ' . .
ii) blending the first mixture to form a blended first mixture;
iii) adding the lubricant to the blended first mixture to form a second mixture; and
iv) optionally blending the second mixture to form a blended second mixture; and
v) optionally, ' .
compressing at least a portion of said second mixture, or said blended
second mixture, to form a tablet therefrom; or
filling a capsule with said second mixture, or said blended second mixture, to
provide a capsule filled with said second mixture, or said blended second mixture. *'•
Generally, it is preferred that the bazedoxifene acetate is micronised prior to
combination-with the other components of the formulation.
The order of addition of the components (i.e., the bazedoxifene acetate, first and
second filler/diluents, antioxidant, lubricant and glidant) is not critical, although it is generally
preferred that the bazedoxifene acetate, first and second filler/diluents, antioxidant and
glidant be combined and blended prior to blending with the lubricant.
The tablets can further include one or more surface coatings, for example clear
coatings and/or color coatings. Numerous coatings and procedures for their application are
known in the art, including those disclosed in Remington's Pharmaceutical Sciences, supra.
The processes of the invention are useful, inter alia, to provide compositions of the
invention, and dosage forms containing the compositions, that include a preponderance of
one polymorphic form of bazedoxifene acetate. In some embodiments, the bazedoxifene • •
acetate is present substantially in a crystalline polymorphic form. In some embodiments, the
bazedoxifene acetate is present substantially in form A-polymorph; i.e., there is no
detectable B polymorph present, as determined by Raman spectroscopy or X-ray diffraction.
In some embodiments, at least about 90% of the bazedoxifene acetate is present in the A- .
polymorph form. In further embodiments,, at least about 80% of the bazedoxifene acetate is
present in the A polymorph form. The determination of the amount of the A or B polymorphic
form can be accomplished by, for example, Raman spectroscopy or X-ray diffraction.
The present invention also provides products of. the processes described herein.

It will be understood that the.weight percentages set forth for the bazedoxifene
acetate, first filler/diluent component,- the optional second filler component, antioxidant
component, glidant/disirvtegrant component, and lubricant component of the compositions
disclosed herein are the percentages that each component will comprise of a final
pharmaceutical composition, without reference to any surface covering, such as a tablet
coating (for example any clear or color coating) or capsule.
Oral formulations containing the present solid dispersions can comprise any
conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges,
suspensions, and the like. In some embodiments, the dosage form is a tablet. Capsules or
tablets of containing the present solid dispersion can also be combined with mixtures of
other active compounds or inert fillers and/or diluents such as the pharmaceutically .
acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening
agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours;
gelatins, gums, etc. In some preferred embodiments, the formulations are direct blend
solid dispersions compressed into tablets.
Tablet formulations can be made by conventional compression, wet granulation, or
dry granulation methods and utilize pharmaceutically acceptable diluents, (fillers)^ -binding
agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited
to, ■magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose,
carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, .,
xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose,
sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride,
talc, dry starches and powdered sugar. Oral formulations used herein may utilize standard
delay or time release formulations or spansules. Suppository formulations may be made
from traditional materials, including cocoa butter, with or without the addition of waxes to
alter the suppositories melting point, and glycerin.. Water soluble suppository bases, such as ■
polyethylene glycols of various molecular weights, may also be used.
In some embodiments, the dosage forms of the invention are direct blend tablets.
Such tablets can generally range from about 50 mg to about 1000 mg, depending upon the
dosage required for therapeutic use. In some embodiments, the dosage forms are 200 mg
tablets, containing a sufficient amount of bazedoxifene acetate to provide 20 mg of
bazedoxifene, based on the weight of the free acid. In some further embodiments, the
compositions and dosage forms of the invention include a sufficient amount of bazedoxifene-
acetate to provide 10 mg, 20 mg, 50 mg, 75 mg, 100 mg, 120 mg, 125 mg, 150 mg,175'mg,
200 mg, 225 mg or 250 mg of bazedoxifene, based on the weight of the free acid. ■:"
Film coating's' useful with the present formulations are known in the art and generally1
consist of a polymer (usually a celluiosic type of polymer), a colorant and a plasticizer.

Additional ingredients such as sugars, flavors, oils arid lubricants can be included-in film -
coating formulations to impart certain characteristics to the film coat. The compositions and
formulations herein may also be combined and.processed as a solid, then placed in a
capsule form, such as a gelatin capsule. . ,
As will be appreciated, some components of the formulations of the invention can
possess multiple, functions. For example, a given component can act as both a diluent and
a disintegrant. In some such cases, the function of a given component can be considered
singular, even though its properties may allow multiple functionality.
Additional numerous various excipients, dosage forms, dispersing agents and the like
that are suitable for use in connection with the solid dispersions of the invention are known in
the art and described in, for example, Remington's Pharmaceutical Sciences, 17th ed./Mack
Publishing Company, Easton, Pa., 1985, which is"incorporated herein by reference in its
entirety.
The materials, methods, and examples presented herein are intended to be
illustrative, and are not intended to limit.the scope of the invention. All publications, patent
applications, patents, and other references mentioned herein are incorporated by reference
in their entirety.-
Example 1
■ ■..,-:.. Procedure for Preparation of .100 mg Tablets Containing
20 mg of Bazedoxifene (as acetate)
A. Bazedoxifene acetate (2,256 g), Avicel PH101 (3,276 g), lactose NF
(fast flow; 3,276 g), ascorbic acid (680 g) and sodium starch glycolate (41.2 g) are combined
in a tumble blender and blended to form a mixture;
B. magnesium stearate (100 g) is added to the blended first mixture to
form a second mixture, which is then blended again;
C. the blended mixture is then compressed to form tablets having final
weight of 100 mg.
The composition of the tablets is shown in the Table below.



a The potency .of bazedoxifene acetate may vary, and the amount in the formula must be
adjusted accordingly with a corresponding adjustment in the amount of Avicel
b 22:56 mg of bazedoxifene acetate provides 20 mg of bazedoxifene.
• Example 2
Procedure for Preparation of. 200 mg Tablets Containing
20 mg of Bazedoxifene (as acetate).
The procedure is similar to that of Example 1, except that the amounts of the
components used are: bazedoxifene acetate (1,128 g), Avicel PH101 (4,036 g), lactose NF
(fast flow; 4,036 g), ascorbic acid (300 g), sodium starch glycolate (400 g) and magnesium
stearate(100g).
The composition of the tablets is shown in the-Table'below. -. '

a The potency of bazedoxifene acetate may vary, and the amount in the formula must be
adjusted accordingly with a corresponding adjustment in the amount of Avicel
b 22.56 mg of bazedoxifene acetate provides 20 mg of bazedoxifene.
•■• Example 3
Procedure for Preparation of Form A

A 2 gal hydrogena'tion vessel with agitator was charged with hexameihyleneimino
benzyloxyindole (250 g, 0.3841 mol; see U.S. Pat. No. 5,998,402 for a preparation), ethanol
(denatured with'5% by volume ethyl acetate) (1578 g,"2000 ml_), and palladium on carbon
10% (25 g). The reactants were hydrogenated at 25 °C and 50 psi for 20 hours. Reaction
progress was monitored by HPLC (Column: CSC-S ODS 2, 25 cm; Mobile phase: 20 % 0'.02
M NH„H2P04 (2 niL TEA/L, pH = 3) and 80 % MeCN; Flow: 2 mL/min; Detector: 220 nm).
The reaction was considered complete when less than 1% of either the hexamethyleneimino
benzyloxyindole (18.2 min retention time) or mono-debenzylaied derivative thereof (5.1 mirt' ■-'
retention time) was detected.
The mixture was filtered through a cartridge which was subsequently rinsed with
ethanol (denatured with'5% by volume ethyl acetate) (2 x 198 g; 2 x 250 ml_). The filtrate
was transferred to a 5 L multi-neck flask with agitator charged with L-ascorbic acid (2.04 g,
0.0116 mols) under nitrogen. Acetic acid ( 34.6 g, 0.5762 moles) was added at 20 °C while
stirring. The resulting reaction mixture was stirred for 2 hours (pH was about 5 and
crystallization began within about 10 minutes of addition of acetic acid). The reaction
mixture was then cooled to 0 °C and maintained at this temperature for 2 hours. The
.'.. resulting solid was collected by filtration on'a Buch.ner funnel, and washed with ethanol--
(denatured with 5% by volume ethyl acetate) (2 x 150 g, 2 x 190 mL) at 0 °C.
The solid product was further purified by charging a 3 L multineck flask (with agitator,
thermometer.-and condenser under nitrogen) with, the filtered solid, ethanol (denatured with'
5% by volume ethyl acetate) (1105 g, 1400 mL), and L-ascorbic acid (1.73 g, 0.01 mols).
The resulting mixture was heated to 75 °C and cooled to 20 °C over the course of 2. hours.
The resulting suspension was further cooled to 0 °C and held at this temperature for 2 hours.
The resulting solid product was collected by filtration with a Buchner funnel and washed with
ethanol (denatured with 5% by volume ethyl acetate) (2 x 79 g, 2 x 100 mL) at 0 °C. The
product was dried in vacuo at 60 °C, 5 mm Hg for 24 hours giving 151.3 g bazedoxifene
- acetate Form A (74.2 % yield).
Example 4
Characterization of Form A .
X-Ray Powder Diffraction (XRPD)
XRPD analyses werecarried out on a (Scintag X2) X-ray powder diffractometer using
Cu K a radiation. The instrument was equipped with tube power, and amperage was set at
45 kV and 40 mA. The divergence and scattering slits-were set at 1° and the receiving slit • -

was set at 0.2 mm. A thefa-lwo thefa continuous scan at 3°/min (0.4 sec/0.02° step) from 3
to40°29 was used.- '
.XRPD data are provided in the Table below. The corresponding XRPD pattern is
provided in Figure 1. .
<
Infrared (IR) Spectroscopy
IR spectra (e.g., see Figure 2) were acquired as follows. Samples were prepared as
potassium bromide (KBr) discs (or pellets). A small amount of each sample (about 3 mg)
was ground in a hard surface mortar unti^glossy in appearance. One half gram (0.5 g) of KBr
was'added to the sample arid the mixture was ..continuously ground until'well .mixed. The
mixture was then transferred to a die and pressed into a disc using a hydraulic press*.
The IR spectrum of Figure 2 was obtained using a DiGILAB EXCALIBU'R Series ■••
. FTS-4000 FT-IR Spectrometer operated at 4 cm"1 resolution and 16 scans between 400 -
4000 cm"1.
Differential Scanning Calorimetry (DSC) . . ,

. DSC measurements (see Figure 3) were carried out in both sealed pan and vented.
pan at a scan rate of 10 °C/min from '25 °C to 200 °C under nitrogen purge using a Pyris l
DSC,from Perkin-Elmer. " " ' •
<
Example 5
Procedure for Preparation of Form B
Preparation of Bazedoxii'ene Acetate Form B from Form A
To a stirred solution of 594 g of ethanol (denatured with 5% of acetone and. with 3%
of cyclohexane) and 184 g of ethyl acetate, 400 g of pure' bazedoxifene acetate Form A were
added under nitrogen (e.g., see Example 2). The heterogeneous mixture was kept at 30 "C
and stirred overnight under nitrogen.
The completion of the crystalline transformation was determined by DSC analysis.
The mixture was cooled to 0 °C and stirred for 2 hrs under nitrogen. The product was
filtered, washed with a mixture,of denatured ethanol-and ethyl acetate as above and dried
overnight at 60 °C under vacuum giving 391 g (97.7% yield) of bazedoxifene acetate Form B
polymorph.- "" ......
A substantially identical: result Was obtained using absolute ethanol or ethanol
denatured with 5% toluene.
Preparation of Bazedoxifene Acetate Form B from a Mixture of Form A and Form B
Bazedoxifene acetate Form A (298 g) and bazedoxifene acetate Form B (2 g) were
suspended in a degassed mixture of ethyl acetate (400 ml_) and ethyl alcohol (2400 ml_).
The resulting mixture was heated at reflux temperature for 2 hours. The suspension was
cooled to 50.°C over the course of 1 hour and then to 20°C over the course of 3 hours. The
• mixture was maintained at 20 °C for 13 hours and the product was recovered by filtration
and washing with ethyl alcohol (78.9 g divided in 2 portions). The wet material was dried
under vacuum at 60°C resulting in 276.8 g of bazedoxifene acetate Form B. •
Example 6. .
Characterization of Form B
X-Ray Powder Diffraction (XRPD)
XRPD analyses were carried out on a (Scintag X2) X-ray powder diffractometer using
'Cu K a radiation. The instrument was equipped with tube power/and amperage, was se.t at-
45 kV and'40 mA. The divergence and scattering slits were set at'1° and the receiving slit -

was set at 0.2 mm. A theta-iwo theta continuous scan at 3°/min (0.4 sec/0.02° step) from.;3 ■
to 40 °29 was used.
XRPD data,are- provided in the Table below; The corresponding XRPD pattern is
provided in Figure 4. i

Infrared (IR) Spectroscopy
IR spectra (e.g., see Figure 5) were acquired as follows. Samples were prepared as
potassium bromide (KBr) discs (or pellets). A small amount of each sample (about 3 mg)
was ground in a bard surface mortar until glossy in appearance. One half gram (0.5 g) of KBr
was added to the sample and the mixture was continuously ground until well mixed. The
mixture was then transferred to a die and pressed into a disc using a hydraulic press.
The IR spectrum of Figure 5 was obtained using a DIGILAB EXCALIBUR Series
FTS-4000. FT-IR Spectrometer operated at .4 cm resolution and 16 scans between 400 -
4000 cm"1.
Differential Scanning Calorimetry (DSC)
DSC measurements (see Figure 6) were carried but in both sealed pan and vented
pan at a scan rate of 10°C/min from 25 °C to 200 °C under nitrogen, purge using a Pyris I .
.DSC from Perkin:Elmer. '• • •

Pharmacokinetic Analysis of A Direct Blend Formulation of the Invention in Dogs''
A direct blend-tablet formulation in accordance with Example 1, supra, was compared
in female Beagle Dogs to a tablet formulation prepared by a wet granulation process.
The composition of the wet granulation formulation is shown in the Table below:'

Each of six female dogs (7.2-11.0 kg), received a single 10 mg dose of bazedoxifene
acetate from both formulations following an overnight fast in a non-randomized crossover
design. 20 mg wet granulation tablets as described above were broken in half for the 10 mg
dose from that formulation. Blood samples were drawn at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8,
12. and ZT'bours after dosing, plasma was separated and assayed for bazedoxifene acetate
content.-'
Individual dog plasma bazedoxifene concentration-time profiles were subjected to
noncompartmental pharmacokinetic analyses (WinNonlin, Model 200). The following
pharmacokinetic parameters were determined for each dog and descriptive statistics were
calculated for comparison between the two formulations: AUC0.t, Cmax, tmax. The results are
summarized in the following Table: "'■.,..■ ■ '..'•'


•Because of the variability in the plasma bazedoxifene levels typically observed in this
protocol,'terminal elimination half-lives could not be determined for the majority of the -
plasma bazedoxifene concentration-time profiles; therefore AUC0.| values were compared
between the two tablet formulations. Also, the exposure levels of bazedoxifene from the '
dfrect blend tablet appeared.to be slightly lower than those from the wet granulation tablet. •
Figure 7 shows the mean (SD) plasma bazedoxifene levels in female dogs following
single oral dose administration of 10 mg.bazedoxifene as direct blend tablet of Example 1,
and the wet granulated tablet described above. Figure 8 shows individual dog plasma
bazedoxifene levels following single oral, dose administration of the "10 mg bazedoxifene

direct blend tablets, and Figure 9 shows individual dog plasma bazedoxifene levels following
single oral dose administration of 10 mg bazedoxifene via the wet granulated tablet
described above.
As can be seen from these data, the direct blend formulation prepared in accordance
with the present invention provides administration of bazedoxifene that is comparable to that
provided by the tablets prepared by the wet granulation process.
This application claims priority benefit of U.S. Provisional Application Ser. No.
60/710,761, filed August 24, 2005, the entire content of which is incorporated by reference in
its entirety.
Various modifications of the invention, in addition to those described herein, will be
apparent to those skilled in the art from the foregoing description. Such modifications are
also intended to fall within the scope of the appended claims. Each of the publications and,
references, including books and patents, cited in the present application is incorporated
herein by reference in its entirety.

WE CLAIM:
1. A non-aqueous process for preparing a pharmaceutical composition comprising a
pharmaceutically effective amount of bazedoxifene acetate, wherein said bazedoxifene acetate
is present substantially in the A polymorph form and a carrier or excipient system, the carrier or
excipient system comprising:
a) a first filler/diluent component comprising from 5% to 85% by weight of the
pharmaceutical formulation;
b) an optional second filler/diluent component comprising from 5% to 85% by weight
of the pharmaceutical formulation;

c) an optional antioxidant component comprising up to 15% by weight of the
pharmaceutical formulation;
d) a glidant/disintegrant component comprising from 0.01 % to 10% by weight of the
pharmaceutical formulation; and
e) a lubricant component comprising from 0.01% to 10% by weight of the
pharmaceutical formulation,
the process comprising direct blending, dry granulation, or roller compaction of said
ingredients.
2. A process as claimed in claim 1 which is a dry granulation process.
3: A process as claimed in claim 1 which is a roller compaction process.
4. A process as claimed in claim 1 which is a direct blending process.
5. A process as claimed in claim 4 wherein said direct blending process comprises:
i) combining said bazedoxifene acetate, first filler/diluent, optionally said second
filler/diluent, glidant, and, optionally, the antioxidant to form a first mixture;
ii) blending the first mixture to form a blended first mixture;
iii) adding the lubricant to the blended first mixture to form a second mixture; and
iv) optionally blending the second mixture to form a blended second mixture; and
v) optionally, compressing at least a portion of said second mixture, or said blended
second mixture, to form a tablet therefrom; or filling a capsule with said second mixture, or

said blended second mixture, to provide a capsule filled with said second mixture, or said
blended second mixture.
6. A process as claimed in claim 5, wherein said bazedoxifene acetate is micronized.

ABSTRACT

A NON-AQUEOUS PROCESS FOR PREPARING A PHARMACEUTICAL
COMPOSITION COMPRISING A PHARMACEUTICALLY EFFECTIVE AMOUNT OF
BAZEDOXIFENE ACETATE
The invention is for a non-aqueous process for preparing a pharmaceutical composition
comprising a pharmaceutically effective amount of bazedoxifene acetate, wherein said
bazedoxifene acetate is present substantially in the A polymorph form and a carrier or excipient
system, the carrier or excipient system comprising: a) a first filler/diluent component comprising
from 5% to 85% by weight of the pharmaceutical formulation; b) an optional second filler/diluent
component comprising from 5% to 85% by weight of the pharmaceutical formulation; c) an
optional antioxidant component comprising up to 15% by weight of the pharmaceutical
formulation; d) a glidant/disintegrant component comprising from 0.01 % to 10% by weight of the
pharmaceutical formulation; and e) a lubricant component comprising from 0.01% to 10% by
weight of the pharmaceutical formulation, the process comprising direct blending, dry granulation,
or roller compaction of said ingredients.