METHODS OF SEPARATION AND DETECTION OF BAZEDOXIFENE ACETATE
IN PHARMACEUTICAL COMPOSITIONS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 U.S.C. §119(e) to United
States Provisional Patent Application No. 60/909,113 filed on March 30. 2007, which is
hereby incorporated by reference in its entirety.
FIELD
[0002] The disclosure relates to methods of separating and detecting bazedoxifene
acetate from pharmaceutical compositions containing a mixture of bazedoxifene acetate and
one or more other components. Methods of separating and detecting crystalline
bazedoxifene acetate Form A and/or Fomn B in pharmaceutical compositions are disclosed.
BACKGROUND
[0003] Bazedoxifene is an estrogenic agent which is useful in treating a variety of
conditions, disorders or diseases, particularly those associated with menopause.
Bazedoxifene salts, particularly, bazedoxifene acetate is used in pharmaceutical
formulations. Bazedoxifene acetate {1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-
phenyl)-3-methyl-1H-indol-5-ol acetic acid) has the chemical formula shown below.
[0004] Bazedoxifene 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. Bazedoxifene acetate has demonstrated estrogenic activity on bone and
cardiovascular lipid parameters and antiestrogenic activity on uterine and mammary tissue
and thus has the potential for treating a number of different disease or disease-like states
involving the estrogen receptor.
[0005] U.S. Pat. Nos. 5.998.402 and 6,479.535 report the preparation of bazedoxifene
acetate. The synthetic preparation of bazedoxifene acetate has also appeared in the general
literature. See, for example, Miller et al., J. Med. Chem., 2001, 44, 1654-1657. 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). In addition, pharmaceutical compositions
containing bazedoxifene acetate is disclosed in WO 02/03987. Further, co-administration of
bazedoxifene acetate and conjugated estrogens is disclosed in US 6,479,535 and US
2007/0003623, as well as in commonly assigned and co-pending Patent Application Serial
Nos. US 11/946.586, filed on November 28, 2007, and US 12/013,109, filed on Jan. 11,
2008.
[0006] The crystalline polymorph form of a particular drug often affects 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 polymorphs
can be produced, it may be desirable to have a method to make each polymorph in pure
fomn.
[0007] Polymorphic Form A of bazedoxifene acetate is disclosed in US 2005/0227965
while polymorphic Form B of bazedoxifene acetate is disclosed in US 2005/0250762.
Methods of preparing polymorphic Form A of bazedoxifene acetate are also disclosed in
commonly assigned and co-pending Patent Application Serial Nos. 61/027,607 and
61/027,634, filed on February 11, 2008. Form A has higher solubility in both aqueous and
organic solvent systems than Form B. This can be advantageous in formulations or doses
where the solubility of the particular composifion is of concern. For example, higher
solubility can influence bioavailability, which can affect biological absorption and distribution
of the drug and can facilitate formulation in liquid can-iers. However, Form A is the kinetic (or
meta-stable) polymorph while Form B is the thermodynamicaily more stable polymorph.
Form A can easily convert to Fomn B upon contact with a solvent or solvent mixture (e.g.,
ethyl acetate and ethanol), which presents a challenge to the preparation of pure Form A
that is substantially free of Form B. Further, under various conditions, and over time. Form A
can convert to Form B.
[0008] Accordingly, it is useful to detect levels of Form A and Form B in pharmaceutical
compositions, for example, to detect the presence of Form B in pharmaceutical compositions
of Form A, to monitor the levels, if any, of conversion from Form A to Form B under various
conditions and/or over time.
SUMMARY
[0009] It has been discovered that some excipients commonly found in pharmaceutical
compositions of bazedoxifene acetate, for example, lactose and sucrose, interfere with
bazedoxifene acetate polymorphs in temis of X-ray diffraction (XRD) pattern. If
bazedoxifene acetate tablets are tested using previous methods, i.e., without performing the
extraction methods described herein, the detection limits for Form B are estimated at about
10% by weight relative to total bazedoxifene acetate for tablets containing 45.1mg of
bazedoxifene acetate (40 mg of bazedoxifene as free base) and 20% by weight relative to
total bazedoxifene acetate for tablets containing 22.6mg of bazedoxifene acetate (20 mg of
bazedoxifene as free base), based on bazedoxifene acetate weight percentage in the tablets
and instalment noise levels. If interfering excipients, such as lactose and sucrose, can be
removed while crystalline bazedoxifene acetate Form A and Form B are retained, Form B
can, be detected with greater sensitivity.
[0010] Disclosed herein are improved methods of separating and detecting crystalline
bazedoxifene acetate Form A and/or Form B in phamnaceutical compositions.
[0011] In one aspect, methods are provided for separating a pharmaceutical
composition comprising bazedoxifene acetate and one or more components that produce X-
Ray diffraction patterns having one or more interfering peaks at or near the characteristic
peak or peaks for bazedoxifene acetate. The method includes:
(a) contacting the pharmaceutical composition with an extraction medium to
produce a suspension, wherein bazedoxifene acetate is substantially insoluble in the
extraction medium and wherein the one or more components having one or more interfering
peaks are substantially soluble in the extraction medium;
(b) filtering the suspension to produce a filtrate and a filtrand, wherein the one or
more components are substantially contained in the filtrate; and
(c) drying the filtrand to produce a composition substantially free of the one or
more components that produce X-Ray diffraction patterns having one or more interfering
peaks.
[0012] In certain embodiments, the bazedoxifene acetate is substantially contained in
the filtrand. In certain embodiments, the method further comprises washing the filtrand.
[0013] In certain embodiments, the method further comprises fonming the composition
obtained in step (c) mentioned above into a tablet or pellet for X-Ray diffraction
measurement.
[0014] In certain embodiments, the bazedoxifene acetate is bazedoxifene acetate Form
A and/or bazedoxifene acetate Fonm B. In certain embodiments, the characteristic peak for
bazedoxifene acetate Form A is at about 12.8±0.2° in 2theta angular degree by Cu radiation,
and the characteristic peaks for bazedoxifene acetate Form B are at about 12.0±0.2° and
13.3±0.2° in 2theta angular degree by Cu radiation.
[0015] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include, without limitation, pharmaceutically
acceptable diluents, fillers, excipients, binding agents, lubricants, disintegrants, suspending
or stabilizing agents, and mixtures thereof. In certain embodiments, the one or more
components that produce X-Ray diffraction patterns having interfering peaks include lactose,
sucrose, or mixtures thereof. In some embodiments, the one or more components that
produce X-Ray diffraction patterns having interfering peaks include lactose.
[0016] In certain embodiments, the interfering peaks are at from about 11.6*0.2° to
about 13.7±0.2° in 2theta angular degree by Cu radiation.
[0017] In certain embodiments, the extraction medium is a solution including one or
more acetate salts. In certain embodiments, the solution includes ammonium acetate,
sodium acetate, potassium acetate, magnesium acetate, calcium acetate, or mixtures
thereof. In certain embodiments, the solution comprises ammonium acetate, sodium
acetate, or mixtures thereof. In some cases, the solution comprises sodium acetate.
[0018] In certain embodiments, the solution has a concentration of about 0.05 M to
about 1 M with respect to acetate. In certain embodiments, the solution has a concentration
of about 0.25 M to about 0.75 M with respect to acetate. In some embodiments, the solution
has a concentration of about 0.45 M to about 0.55 M with respect to acetate.
[0019] In certain embodiments, the solution has a pH range from about 5 to about 10. In
certain embodiments, the solution has a pH range from about 6 to about 9.2. In some
embodiments, the solution has a pH range from about 6.2 to about 8.5.
[0020] In certain embodiments, the pharmaceutical composition is provided as at least
one unit dosage forn. Examples of unit dosage forms include, without limitation, tablet,
capsule, gel cap, buccal form, troche, and lozenge. In certain embodiments, the unit dosage
form is tablet.
[0021] In certain embodiments, the method further comprises removing any coating from
the pharmaceutical composition prior to contacting the composition with the extraction
medium.
[0022] In certain embodiments, the amount of the extraction medium used during the
contacting of the pharmaceutical composition with the extraction medium to produce the
suspension is from about 0.2 ml per dosage (e.g., tablet) unit to about 10 ml per dosage unit.
In certain embodiments, the phannaceutical composition is contacted with the extraction
medium for about 1 to about 120 minutes. In some embodiments, the pharmaceutical
composition is contacted with the extraction medium for about 5 to about 30 minutes. In
some embodiments, the pharmaceutical composition is contacted with the extraction
medium for about 5 to about 15 minutes.
[0023] In another aspect, methods are provided for separating a pharmaceutical
composition comprising bazedoxifene acetate Form A and/or Form B and one or more
components that produce X-Ray diffraction patterns having one or more interfering peaks at
or near the characteristic peak or peaks for bazedoxifene acetate Form A and/or Form B.
The method includes:
(a) contacting the pharmaceutical composition with a solution comprising at least
one acetate salt to produce a suspension, wherein bazedoxifene acetate Form A and/or
Form B is substantially insoluble in the solution and wherein the one or more components
are substantially soluble in the solution;
(b) filtering the suspension to produce a filtrate and a filtrand, wherein the one or
more components are substantially contained in the filtrate; and(c) washing and drying the
filtrand to produce a composition substantially free of the one or more components that
produce X-Ray diffraction patterns having one or more interfering peaks.
[0024] In certain embodiments, the pharmaceutical composition is provided as tablet
form, and the method further includes removing any coating from the tablet prior to
contacting the tablet with the solution.
[0025] In certain embodiments, the one or more components that produce X-Ray
diffraction pattems having interfering peaks include, without limitation, lactose, sucrose, and
mixtures thereof.
[0026] In certain embodiments, the characteristic peak for bazedoxifene acetate Fomi A
is at about 12.8±0.2° in 2theta angular degree by Cu radiation. In certain embodiments, the
characteristic peaks for bazedoxifene acetate Form B are at about 12.0±0.2° and about
13.3±0.2° in 2theta angular degree by Cu radiation, in some embodiments, the interfering
peaks are at from about 11.6±0.2° to about 13.7±0.2° in 2theta angular degree by Cu
radiatbn.
[0027] In yet another aspect, a method is provided for detecting bazedoxifene acetate
Form A and/or Form B in a pharmaceutical composition comprising bazedoxifene acetate
Form A and/or Fomn B and one or more components (e.g., lactose) that produce X-Ray
diffraction patterns having one or more interfering peaks at or near the characteristic peak or
peaks for bazedoxifene acetate Form A and/or Form B. The method includes:
(a) producing a composition containing bazedoxifene acetate Form A and/or
Form B by a method as described hereinabove, wherein the composition is substantially free
of the components (e.g., lactose) that produce X-Ray diffraction patterns having one or more
interfering peaks;
(b) forming the composition containing bazedoxifene acetate Form A and/or
Form B into a tablet or pellet for X-Ray diffraction measurement; and
(c) analyzing the tablet or pellet using X-Ray diffraction.
[0028] In a further aspect, a method is provided for separating a pharmaceutical
composition comprising bazedoxifene acetate and one or more components that produce X-
Ray diffraction patterns having one or more interfering peaks at or near the characteristic
peak or peaks for bazedoxifene acetate. The method includes:
(a) contacting the pharmaceutical composition with an extraction medium to
produce a suspension, wherein bazedoxifene acetate is substantially insoluble in the
extraction medium and wherein the one or more components are substantially soluble in the
extraction medium;
(b) centrifuging the suspension to produce a solid and a supernatant solution,
wherein the one or more components are substantially contained in the supernatant solution;
and
(c) collecting and drying the solid to produce a composition substantially free of
the one or more components that produce X-Ray diffraction patterns having one or more
interfering peaks.
[0029] In certain embodiments, the pharmaceutical composition further includes
conjugated estrogens. In certain embodiments, the pharmaceutical composition includes a
core containing conjugated estrogens and an outer layer containing bazedoxifene acetate.
In certain embodiments, the contacting of the pharmaceutical composition with an extraction
medium in step (a) is stopped when a filler coating between the conjugated estrogen core
and the bazedoxifene outer layer is exposed.
[0030] In certain embodiments, the bazedoxifene acetate is substantially contained in
the solid provided by the centrifugation. In some embodiments, the method further
comprises removing the supematant solution produced in step (b). In some instances, the
supernatant solution can be removed by decanting or through pipette. In some
embodiments, the method further includes washing the solid produced in step (b).
[0031] In certain embodiments, the solid is collected by filtration. In certain
embodiments, the method further comprises forming the composition obtained in step (c)
into powder or a tablet or pellet for X-Ray diffraction measurement. In some embodiments,
the method further includes analyzing the composition obtained in step (c) or the powder,
tablet or pellet prepared from the composition using X-Ray diffraction.
[0032] In certain embodiments, the bazedoxifene acetate is bazedoxifene acetate Form
A and/or bazedoxifene acetate Form B.
[0033] In certain embodiments, the characteristic peak for bazedoxifene acetate Form A
is at about 12.8±0.2° in 2theta angular degree by Cu radiation, and the characteristic peaks
for bazedoxifene acetate Form B are at about 12.0±0.2° and about 13.3±0.2° in 2theta
angular degree by Cu radiation.
[0034] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include, without limitation, pharmaceutically
acceptable diluents, fillers, excipients, binding agents, lubricants, disintegrants, suspending
or stabilizing agents, and mixtures thereof. In certain embodiments, the one or more
components that produce X-Ray diffraction patterns having interfering peaks include, without
limitation, lactose, sucrose, or mixtures thereof. In some embodiments, the one or more
components that produce X-Ray diffraction patterns having interfering peaks include, without
limitation, sucrose.
[0035] In certain embodiments, the interfering peaks are at from about 11.9±0.2° to
about 13.3±0.2° in 2theta angular degree by Cu radiation.
[0036] In certain embodiments, the extraction medium is a solution comprising one or
more acetate salts. In certain embodiments, the solution includes ammonium acetate,
sodium acetate, potassium acetate, magnesium acetate, calcium acetate, or mixtures
thereof. In certain embodiments, the solution includes ammonium acetate, sodium acetate,
or mixtures thereof.
[0037] In certain embodiments, the solution has a concentration of about 0.05 M to
about 1 M with respect to acetate. In certain embodiments, the solution has a concentration
of about 0.1 M to about 0.75 M with respect to acetate. In some embodiments, the solution
has a concentration of about 0.1 M to about 0.3 M with respect to acetate.
[0038] In certain embodiments, the solution has a pH between about 5 and about 10. In
certain embodiments, the solution has a pH between about 6 and about 9.2. In some
embodiments, solution has a pH between about 6.2 and about 8.5.
[0039] In certain embodiments, the pharmaceutical composition is provided as at least
one unit dosage fonm. Non-limiting examples of the unit dosage form include tablet, capsule,
gel cap, buccal form, troche, and lozenge. In certain embodiments, the pharmaceutical
composition is provided as a tablet. In some embodiments, the tablet form includes a core
and an outer layer. In certain embodiments, the core contains conjugated estrogens and the
outer layer contains bazedoxifene acetate.
[0040] In certain embodiments, the method further includes removing any coating from
the pharmaceutical composition prior to contacting the composition with the extraction
medium. In certain embodiments, the amount of the extraction medium used during the
contacting of the pharmaceutical composition with the extraction medium to produce the
suspension is from about 0.2 ml per dosage unit to about 10 ml per dosage unit (e.g., lOmg,
20mg or 40mg bazidoxifene tablet, optionally containing conjugated estrogens). In some
embodiments, the pharmaceutical composition is contacted with the extraction medium for
about 1 to about 120 minutes. In some embodiments, the pharmaceutical composition is
contacted with the extraction medium for about 1 to about 30 minutes. In some
embodiments, the pharmaceutical composition is contacted with the extraction medium for
about 1 to about 5 minutes. In some embodiments, the pharmaceutical composition is
contacted with the extraction medium for about 2 minutes.
[0041] In another aspect, a method is provided for separating a phamnaceutical
composition comprising bazedoxifene acetate Form A and/or Form B and one or more
components that produce X-Ray diffraction patterns having one or more interfering peaks at
or near the characteristic peak or peaks for bazedoxifene acetate Form A and/or Fomn B.
The method includes:
(a) contacting the pharmaceutical composition with a solution comprising at least
one acetate salt to produce a suspension, wherein bazedoxifene acetate Form A and/or
Form B is substantially insoluble in the solution and wherein the one or more components
are substantially soluble in the solution;
(b) centrifuging the suspension to produce a solid and a supernatant solution,
wherein the one or more components are substantially contained in the supernatant solution;
and
(c) collecting and drying the solid to produce a composition substantially free of
the one or more components that produce X-Ray diffraction patterns having one or more
interfering peaks.
[0042] In certain embodiments of, the pharmaceutical composition is provided as a
tablet. In certain embodiments, the tablet includes a core and an outer layer. In some
instances, the core contains conjugated estrogens and the outer layer contains
bazedoxifene acetate Form A and/or Form B. In certain embodiments, the method further
includes removing any coating from the tablet prior to contacting the tablet with the solution.
[0043] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include lactose, sucrose, or mixtures thereof. In
certain embodiments, the one or more components that produce X-Ray diffraction patterns
having interfering peaks include sucrose.
[0044] In certain embodiments, the characteristic peak for bazedoxifene acetate Form A
is at about 12.8±0.2° in 2theta angular degree by Cu radiation. In certain embodiments, the
characteristic peaks for bazedoxifene acetate Fonm B are at about 12.0±0.2° and 13.3±0.2°
in 2theta angular degree by Cu radiation. In some embodiments, the interfering peaks are at
from about 11.9±0.2° to about 13.3±0.2° in 2theta angular degree by Cu radiation.
[0045] In a further aspect, a method is provided for detecting bazedoxifene acetate Form
A and/or Form B in a pharmaceutical composition comprising bazedoxifene acetate Form A
and/or Form B and one or more components (e.g., sucrose) that produce X-Ray diffraction
pattems having one or more interfering peaks at or near the characteristic peak or peaks for
bazedoxifene acetate Form A and/or Form B. The method includes:
(a) producing a composition containing bazedoxifene acetate Fonm A and/or
Form B by a method as described herein above, wherein the composition is substantially
free of the one or more components (e.g., sucrose) that produce X-Ray diffraction patterns
having one or more interfering peaks;
(b) forming the composition containing bazedoxifene acetate Form A and/or
Form B into a tablet or pellet for X-Ray diffraction measurement; and
(c) analyzing the tablet or pellet using X-Ray diffraction.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] Figure 1 shows the X-Ray diffraction (XRD) patterns of bazedoxifene acetate
Forms A and B, and lactose.
[0047] Figure 2 shows the XRD patterns of bazedoxifene acetate Forms A and B, and
sucrose.
DETAILED DESCRIPTION
[0048] One aspect provides methods of separating a pharmaceutical composition
comprising bazedoxifene acetate and one or more components that produce X-Ray
diffraction patterns having one or more interfering peaks at or near the characteristic peak or
peaks for bazedoxifene acetate. The method includes: (a) contacting the phannnaceutical
composition with an extraction medium to produce a suspension, in which bazedoxifene
acetate is substantially insoluble in the extraction medium and in which the one or more
components are substantially soluble in the extraction medium; (b) filtering the suspension to
produce a filtrate and a filtrand, in which the one or more components are substantially
contained in the filtrate; and (c) drying the filtrand to produce a composition substantially free
of the one or more components that produce X-Ray diffraction patterns having one or more
interfering peaks.
[0049] In certain embodiments, the bazedoxifene acetate is substantially contained in
the filtrand. In certain embodiments, the method further includes washing the filtrand.
[0050] In certain embodiments, the method further includes forming the composition
obtained in step (c) mentioned above into powder or tablet or pellet for X-Ray diffraction
measurement.
[0051] In certain embodiments, the bazedoxifene acetate is bazedoxifene acetate Fomn
A and/or bazedoxifene acetate Form B. In some cases, the bazedoxifene acetate is a
mixture of bazedoxifene acetate Form A and bazedoxifene acetate Form B. In certain
embodiments, the characteristic peak for bazedoxifene acetate Form A is at about 12.8±0.2°
in 2theta angular degree by Cu radiation, and the characteristic peaks for bazedoxifene
acetate Form B are at about 12.0±0.2° and about 13.3±0.2° in 2theta angular degree by Cu
radiation.
[0052] In certain embodiments, the one or more components ("interfering components")
that produce X-Ray diffraction patterns having interfering peaks include, without limitation,
pharmaceutically acceptable diluents, fillers, excipients, binding agents, lubricants,
disintegrants, suspending or stabilizing agents, and mixtures thereof. In some
embodiments, the one or more components that produce X-Ray diffraction patterns having
interfering peaks include, but are not limited to, one or more of magnesium stearate, stearic
acid, talc, sodium lauryl sulfate, microcrystalline cellulose, ascorbic acid, sodium starch
glycolate, pregelled starch, carboxymethylceliulose calcium, polyvinylpynrolidone, 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, dry starches and powdered sugar. In certain embodiments, the
one or more components that produce X-Ray diffraction patterns having interfering peaks
include, without limitation, lactose, sucrose, or mixtures thereof. In some embodiments, the
one or more components that produce X-Ray diffraction patterns having interfering peaks
include, without limitation, lactose. In certain embodiments, the interfering peaks are at from
about 11.6±0.2° to about 13.7±0.2° in 2theta angular degree by Cu radiation.
[0053] Figure 1 illustrates the interference with the characteristic peaks of bazedoxifene
acetate Forms A and B caused by lactose. In some embodiments, the peak of lactose at
about 12.5±0.2° interferes with the characteristic peak of bazedoxifene acetate Form A at
about 12.8±0.2° and the characteristic peaks of bazedoxifene acetate Form B at about
12.0±0.2°. In certain embodiments, the interfering peaks are at from about 11.9±0.2° to
about 13.3±0.2°.
[0054] Figure 2 illustrates the interference with the characteristic peaks of bazedoxifene
acetate Forms A and B caused by sucrose. In some embodiments, the peak of sucrose at
about 12.9±0.2° interferes with the characteristic peak of bazedoxifene acetate Form A at
about 12.8±0.2°. In some other embodiments, the peak of sucrose at about 11.9±0.2° and
13.3±0.2° interferes with the characteristic peak of bazedoxifene acetate Form B at about
12.0±0.2° and 13.3±0.2° respectively.
[0055] In some embodiments of the methods described herein, bazedoxifene acetate is
substantially insoluble in the extraction medium and the components that produce XRD
pattems having interfering peaks at or near the characteristic peaks of bazedoxifene acetate
are substantially soluble in the extraction medium.
[0056] The term "substantially insoluble" as used herein means "sparingly soluble,"
"slightly soluble," "very slightly soluble," or "practically insoluble, or insoluble" as described in
USP 25, The United States Pharmacopeia, page 2363 (2002). In certain embodiments, the
term "substantially insoluble" with respect to bazedoxrfene acetate means that less than
about 1 mg of bazedoxifene acetate can dissolve in one mL of extraction solution, for
example, less than about 0.5 mg of bazedoxrfene acetate can dissolve in one mL of
extraction solution, less than about 0.1 mg of bazedoxrfene acetate can dissolve in one mL
of extraction solution, less than about 0.05 mg of bazedoxrfene acetate can dissolve in one
mL of extraction solution, less than about 0.01 mg of bazedoxifene acetate can dissolve in
one mL of extraction solution, or less than about 0.005 mg of bazedoxifene acetate can
dissolve in one mL of extraction solution.
[0057] The term "substantially soluble" as used herein means "very soluble," "freely
soluble," or "soluble" as described in USP 25, The United States Pharmacopeia, page 2363
(2002). In certain embodiments, the term "substantially soluble" as used herein with respect
to an interfering component means that greater than about 20 mg of the interfering
component can dissolve in one mL of extraction solution, for example, greater than about 50
mg of the interfering component can dissolve in one mL of extraction solution, greater than
about 100 mg of the interfering component can dissolve in one mL of extraction solution,
greater than about 200 mg of the interfering component can dissolve in one mL of extraction
solution, greater than about 350 mg of the interfering component can dissolve in one mL of
extraction solution, greater than about 500 mg of the interfering component can dissolve in
one mL of extraction solution, greater than about 1000 mg of the interfering component can
dissolve in one mL of extraction solution, greater than about 1500 mg of the interfering
component can dissolve in one mL of extraction solution, greater than about 1800 mg of the
interfering component can dissolve in one mL of extraction solution; or greater than about
2000 mg of the interfering component can dissolve in one mL of extraction solution.
[0058] Bazedoxifene acetate or one or more other components is identified as
substantially contained in, e.g., a filtrand, filtrate, or supernatant solution or solid produced
by centrifugation. The term "substantially contained" as used herein means that at least
about 70% by weight of the identified bazedoxifene acetate or other component is contained
in the specified filtrate, filtrand, supernatant solution or solid compared to the amount of the
corresponding component contained in the initial pharmaceutical composition being
analyzed. In some instances, at least about 80% or at least 90% of the identified
bazedoxifene acetate or other component is contained in the specified filtrate, filtrand,
supernatant solution or solid.
[0059] The term "substantially free" as used herein means that the interfering component
makes up no more than about 25% by weight of the final composition as prepared according
to a method described herein. In certain embodiments, the interfering component makes up
no more than about 20%, about 10%, about 5%, or about 1 % by weight of the final
composition.
[0060] In certain embodiments, the extraction medium is a solution comprising one or
more acetate salts. In certain embodiments, the solution includes ammonium acetate,
sodium acetate, potassium acetate, magnesium acetate, calcium acetate, or mixtures
thereof. In certain embodiments, the solution includes ammonium acetate, sodium acetate,
or mixtures thereof. In some cases, the solution includes sodium acetate. Certain
embodiments provide methods to extract bazedoxifene acetate from formulations, without
altering the bazedoxifene acetate crystal form. While not to be bound by theory, it is
believed that high concentrations of acetate (Ac) may suppress the dissociation and
dissolution of bazedoxifene acetate.
[0061] In certain embodiments, the solution has a concentration of about 0.05 M to
about 1 M with respect to acetate. In certain embodiments, the solution has a concentration
of about 0.1 M to about 0.9 M with respect to acetate. In some embodiments, the solution
has a concentration of about 0.15 M to about 0.85 M with respect to acetate. In some
embodiments, the solution has a concentration of about 0.2 M to about 0.8 M with respect to
acetate. In some embodiments, the solution has a concentration of about 0.25 M to about
0.75 M with respect to acetate. In some embodiments, the solution has a concentration of
about 0.3 M to about 0.7 M with respect to acetate. In some embodiments, the solution has
a concentration of about 0.35 M to about 0.65 M with respect to acetate. In some
embodiments, the solution has a concentration of about 0.4 M to about 0.6 M with respect to
acetate. In some embodiments, the solution has a concentration of about 0.45 M to about
0.55 M with respect to acetate. In some embodiments, the solution has a concentration of
about 0.5 M with respect to acetate.
[0062] In some embodiments, the extraction medium has a pH of about 1 to about 13.
In some embodiments, the extraction medium has a pH of about 5 to about 12. In certain
embodiments, the solution has a pH of about 5 to about 10. In some embodiments, the
extraction medium has a pH of about 6 to about 11. In some embodiments, the extraction
medium has a pH of about 6.5 to about 10.5. In certain embodiments, the extraction
medium has a pH of about 6 to about 9.2. In some embodiments, the extraction medium
has a pH of about 6.2 to about 8.5. In some embodiments, the extraction medium has a pH
of about 7 to about 10. In some embodiments, the extraction medium has a pH of about 7.5
to about 9.5. In some embodiments, the extraction medium has a pH of about 8 to about 9.
In some embodiments, the extraction medium has a pH of about 8.2 to about 8.5. in some
embodiments, the extraction medium has a pH of about 8.3 to about 8.4.
[0063] In some embodiments, the extraction medium includes a solution of ammonium
acetate. In some embodiments, the extraction medium includes about 0.5 M ammonium
acetate. In some embodiments, the extraction medium includes about 0.5 M ammonium
acetate and has a pH of about 6.2.
[0064] In some embodiments, the extraction medium includes a mixture of ammonium
acetate and sodium acetate. In some embodiments, the extraction medium includes a
solution of: about 0.05 M to about 0.5 M ammonium acetate; and about 0.05 M to about 0.5
M sodium acetate. In some embodiments, the extraction medium includes ammonium
acetate and sodium acetate and has a pH of about 6.5 to about 7.5.
[0065] In some embodiments, the extraction medium includes about 0.1 M ammonium
acetate and about 0.4 M sodium acetate. In some embodiments, the extraction medium
includes about 0.15 M ammonium acetate and about 0.35 M sodium acetate. In some
embodiments, the extraction medium includes about 0.2 M ammonium acetate and about
0.3 M sodium acetate. In some embodiments, the extraction medium includes about 0.25 M
ammonium acetate and about 0.25 M sodium acetate. In some embodiments, the extraction
medium includes about 0.3 M ammonium acetate and about 0.2 M sodium acetate. In some
embodiments, the extraction medium includes about 0.35 M ammonium acetate and about
0.15 M sodium acetate. In some embodiments, the extraction medium includes about 0.4 M
ammonium acetate and about 0.1 M sodium acetate. In some embodiments, the extraction
medium includes about 0.45 M ammonium acetate and about 0.05 M sodium acetate.
[0066] In some embodiments, the extraction medium includes about 0.125 M ammonium
acetate and about 0.375 M sodium acetate. In some embodiments, the extraction medium
includes about 0.125 M ammonium acetate and about 0.375 M sodium acetate has a pH of
about 6.85. In some embodiments, the extraction medium includes about 0.05 M
ammonium acetate and about 0.45 M sodium acetate. In some embodiments, the extraction
medium includes about 0.05 M ammonium acetate and about 0.45 M sodium acetate has a
pH of about 7.18.
[0067] In some embodiments, the extraction medium includes sodium acetate. In some
embodiments, the extraction medium includes about 0.5 M sodium acetate. In some
embodiments, the extraction medium includes about 0.5 M sodium acetate and has a pH of
about 8.34.
[0068] In certain embodiments, the pharmaceutical composition is provided as at least
one unit dosage form. Examples of unit dosage forms include, without limitation, tablet,
capsule, gel cap, buccal form, troche, and lozenge. In certain embodiments, the unit dosage
form is a tablet. In certain embodiments, the dosage units described herein can utilize
standard delay or time release formulations or spansules.
[0069] In certain embodiments, any coating is removed from the dosage unit prior to
contacting it with the extraction medium. In some embodiments, the pharmaceutical dosage
unit is broken apart prior to and/or during mixing with the extraction medium.
[0070] In certain embodiments, the amount of the extraction medium used during the
contacting of the pharmaceutical composition with the extraction medium to produce the
suspension is from about 0.2 ml per dosage unit to about 10 ml per dosage unit (e.g., tablet).
In some embodiments, the amount of the extraction medium used during the mixing of the
pharmaceutical composition and the extraction medium is about 0.8 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
pharmaceutical composition and the extraction medium is about 1 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
phamriaceutical composition and the extractbn medium is about 1.67 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
phamnaceutical composition and the extraction medium is about 2.5 ml per dosage unit. In
some embodiments, the amount of extraction medium used is inversely related to the molar
concentration of acetate ion in the extraction medium.
[0071] In certain embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 1 to about 120 minutes. In some embodiments, the
pharmaceutical composition is contacted with the extraction medium for about 5 to about 30
minutes. In some embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 5 to about 10 minutes. In some embodiments, the
phamnaceutical composition is contacted with the extraction medium for about 2 to about 5
minutes. In some embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 2 minutes.
[0072] In some embodiments, a mixture of the pharmaceutical composition and the
extraction medium is filtered to produce a filtrand. In some instances, washing is performed
with additional extraction medium. In some embodiments, the filtrand is dried. In some
embodiments, the filtrand is dried ovemight. In some embodiments, the fiitrand is dried at an
elevated temperature, for example, at about 40°C. In some embodiments, the filtrand is
dried at an elevated temperature, for example, at about 40°C ovemight. In some
embodiments, the filtrand is dried at room temperature. In some embodiments, the filtrand is
dried under vacuum. In some embodiments, the filtrand is dried under vacuum and at an
elevated temperature, for example, at about 40°C.
[0073] Another aspect provides methods of separating a pharmaceutical composition
comprising bazedoxifene acetate Form A and/or Form B and one or more components (e.g.,
lactose) that produce X-Ray diffraction pattems having one or more interfering peaks at or
near the characteristic peak or peaks for bazedoxifene acetate Form A and/or Form B. The
method includes: (a) contacting the pharmaceutical composition with a solution comprising
at least one acetate salt to produce a suspension, in which the bazedoxifene acetate Form A
and/or Form B is substantially insoluble in the solution and in which the one or more
components (e.g., lactose) are substantially soluble in the solution; (b) filtering the
suspension to produce a filtrate and a filtrand, in which the one or more components are
substantially contained in the filtrate; and (c) washing and drying the filtrand to produce a
composition substantially free of the one or more components (e.g., lactose) that produce X-
Ray diffraction patterns having one or more interfering peaks.
[0074] In certain embodiments, the pharmaceutical composition is provided as tablet
form, and the method further includes removing any coating from the tablet prior to
contacting the tablet with the solution.
[0075] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include, without limitation, lactose, sucrose, or
mixtures thereof.
[0076] In certain embodiments, the characteristic peak for bazedoxifene acetate Form A
is at about 12.8±0.2° in 2theta angular degree by Cu radiation. In certain embodiments, the
characteristic peaks for bazedoxifene acetate Fomn B are at about 12.0±0.2° and 13.3±0.2°
in 2theta angular degree by Cu radiation. In some embodiments, the interfering peaks are at
from about 11.610.2° to about 13.7±0.2° in 2theta angular degree by Cu radiation.
[0077] Yet another aspect provides a method of detecting bazedoxifene acetate Form A
and/or Form B in a pharmaceutical composition comprising bazedoxifene acetate Form A
and/or Form B and one or more components that produce X-Ray diffraction pattems having
one or more interfering peaks at or near the characteristic peak or peaks for bazedoxifene
acetate Form A and/or Form B. The method includes: producing a composition containing
bazedoxifene acetate Form A and/or Form B by a method as described hereinabove,
wherein the composition is substantially free of the one or more components that produce X-
Ray diffraction patterns having one or more interfering peaks; forming the composition
containing bazedoxifene acetate Form A and/or Form B into powder or tablet or pellet for X-
Ray diffraction measurement; and analyzing the powder or tablet or pellet using X-Ray
diffraction.
[0078] A further aspect provides a method of separating a pharmaceutical composition
comprising bazedoxifene acetate and one or more components that produce X-Ray
diffraction patterns having one or more interfering peaks at or near the characteristic peak or
peaks for bazedoxifene acetate. The method includes: (a) contacting the pharmaceutical
composition with an extraction medium to produce a suspension, in which the bazedoxifene
acetate is substantially insoluble in the extraction medium and in which the one or more
components are substantially soluble in the extractbn medium; (b) centrifuging the
suspensbn to produce a solid and a supernatant solution, in which the one or more
components are substantially contained in the supernatant solution; and (c) collecting and
drying the solid to produce a composition substantially free of the one or more components
that produce X-Ray diffraction patterns having one or more interfering peaks.
[0079] In certain embodiments, the pharmaceutical composition further includes
conjugated estrogens. In certain embodiments, the pharmaceutical composition includes a
core containing conjugated estrogens and an outer layer containing bazedoxifene acetate.
In certain embodiments, the contacting of the pharmaceutical composition with an extraction
medium in step (a) is stopped when a filler coating between the conjugated estrogen core
and the bazedoxefene outer layer is exposed.
[0080] In certain embodiments, the bazedoxifene acetate is substantially contained in
the solid produced by centrifugation. In some embodiments, step (b) is repeated as needed.
In some embodiments, the method further includes removing the supernatant solution
provided in step (b). In some instances, the supernatant solution can be removed by
decanting or through pipette. In some embodiments, the method further includes washing
the solid provided in step (b).
[0081] In certain embodiments, the solid is collected by filtration. In certain
embodiments, the method further includes forming the composition obtained in step (c) into
powder or a tablet or pellet for X-Ray diffractbn measurement. In some embodiments, the
method further includes analyzing the composition obtained in step (c) or the powder, tablet
or pellet prepared from the composition using X-Ray diffraction
[0082] In certain embodiments, the bazedoxifene acetate is bazedoxifene acetate Fomn
A and/or bazedoxifene acetate Fonnn B.
[0083] In certain embodiments, the characteristic peak for bazedoxifene acetate Fomn A
is at about 12-8±0.2° in 2theta angular degree by Cu radiation, and the characteristic peaks
for bazedoxifene acetate Form B are at about 12.0±0.2° and about 13.3±0.2° in 2theta
angular degree by Cu radiation.
[0084] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include, without limitation, pharmaceutically
acceptable diluents, fillers, excipients, binding agents, lubricants, disintegrants, suspending
or stabilizing agents, and mixtures thereof. In certain embodiments, the one or more
components that produce X-Ray diffraction pattems having interfering peaks include lactose,
sucrose, or mixtures thereof. In some embodiments, the one or more components that
produce X-Ray diffraction patterns having interfering peaks include sucrose.
[0085] In certain embodiments, the interfering peaks are at from about 11.9±0.2° to
about 13.3±0.2° in 2theta angular degree by Cu radiation.
[0086] In certain embodiments, the extraction medium is a solution comprising one or
more acetate salts. In certain embodiments, the solution includes ammonium acetate,
sodium acetate, potassium acetate, magnesium acetate, calcium acetate, or mixtures
thereof. In certain embodiments, the solution includes ammonium acetate, sodium acetate,
or mixtures thereof.
[0087] In certain embodiments, the solution has a concentration of about 0.05 M to
about 1 M with respect to acetate. In certain embodiments, the solution has a concentration
of about 0.1 M to about 0.9 M with respect to acetate. In some embodiments, the solution
has a concentratbn of about 0.15 M to about 0.85 M with respect to acetate, in some
embodiments, the solution has a concentration of about 0.2 M to about 0.8 M with respect to
acetate. In some embodiments, the solution has a concentration of about 0.25 M to about
0.75 M with respect to acetate. In some embodiments, the solution has a concentration of
about 0.3 M to about 0.7 M with respect to acetate. In some embodiments, the solution has
a concentration of about 0.35 M to about 0.65 M with respect to acetate. In some
embodiments, the solution has a concentration of about 0.4 M to about 0.6 M with respect to
acetate. In some embodiments, the solution has a concentration of about 0.45 M to about
0.55 M with respect to acetate. In some embodiments, the solution has a concentration of
about 0.5 M with respect to acetate.
[0088] In some embodiments, the extraction medium has a pH of about 1 to about 13.
In some embodiments, the extraction medium has a pH of about 5 to about 12. In certain
embodiments, the extraction medium has a pH of about 5 to about 10. In some
embodiments, the extraction medium has a pH of about 6 to about 11. In some
embodiments, the extraction medium has a pH of about 6.5 to about 10.5. In certain
embodiments, the extraction medium has a pH of about 6 to about 9.2. In some
embodiments, the extraction medium has a pH of about 6.2 to about 8.5. In some
embodiments, the extraction medium has a pH of about 7 to about 10. In some
embodiments, the extraction medium has a pH of about 7.5 to about 9.5. In some
embodiments, the extraction medium has a pH of about 8 to about 9. In some
embodiments, the extraction medium has a pH of about 8.2 to about 8.5. In some
embodiments, the extraction medium has a pH of about 8.3 to about 8.4.
[0089] In certain embodiments, the pharmaceutical composition is provided as at least
one unit dosage form. Non-limiting examples of the unit dosage form include tablet, capsule,
gel cap, buccal form, troche, and lozenge. In certain embodiments, the pharmaceutical
composition is provided as a tablet. In some embodiments, the tablet includes a core and an
outer layer. In some embodiments, the core contains conjugated estrogens and the outer
layer contains bazedoxifene acetate.
[0090] In certain embodiments, the amount of the extraction medium used during the
contacting of the pharmaceutical composition with the extraction medium to produce the
suspensbn is from about 0.2 ml per dosage unit (e.g., tablet) to about 10 ml per dosage unit.
In some embodiments, the amount of the extraction medium used during the mixing of the
pharmaceutical composition and the extraction medium is about 0.8 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
phamnaceutical composition and the extraction medium is about 1 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
phamiaceutical composition and the extraction medium is about 1.67 ml per dosage unit. In
some embodiments, the amount of the extraction medium used during the mixing of the
phamnaceutical composition and the extraction medium is about 2.5 ml per dosage unit. In
some embodiments, the amount of extraction medium used is inversely related to the molar
concentration of acetate ion in the extraction medium.
[0091] In certain embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 1 to about 120 minutes. In some embodiments, the
pharmaceutical composition is contacted with the extraction medium for about 5 to about 30
minutes. In some embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 5 to about 10 minutes. In some embodiments, the
pharmaceutical composition is contacted with the extraction medium for about 2 to about 5
minutes. In some embodiments, the pharmaceutical composition is contacted with the
extraction medium for about 2 minutes.
[0092] Another aspect provides a method of separating a pharmaceutical composition
comprising bazedoxifene acetate Form A and/or Form B and one or more components that
produce X-Ray diffraction patterns having one or more interfering peaks at or near the
characteristic peak or peaks for bazedoxifene acetate Form A and/or Fomi B. The method
includes: (a) contacting the pharmaceutical composition with a solution comprising at least
one acetate salt to produce a suspension, wherein bazedoxifene acetate Form A and/or
Form B is substantially insoluble in the solution and wherein the one or more components
are substantially soluble in the solution; (b) centrifuging the suspension to produce a solid
and a supernatant solution, wherein the one or more components are substantially contained
in the supernatant solution; and (c) collecting and drying the solid to produce a composition
substantially free of the one or more components that produce X-Ray diffraction patterns
having one or more interfering peaks.
[0093] In certain embodiments, the pharmaceutical composition is provided as a tablet.
IN some embodiments, the tablet includes a core and an outer layer. In some instances, the
core contains conjugated estrogens and the outer layer contains bazedoxifene acetate Form
A and/or Form B. In certain embodiments, the method further includes removing any coating
from the tablet prior to contacting the tablet with the solution.
[0094] In certain embodiments, the one or more components that produce X-Ray
diffraction patterns having interfering peaks include lactose, sucrose, or mixtures thereof. In
certain embodiments, the one or more components that produce X-Ray diffraction patterns
having interfering peaks include sucrose.
[0095] In certain embodiments, the characteristic peak for bazedoxifene acetate Form A
is at about 12.8±0.2° in 2theta angular degree by Cu radiation. In certain embodiments, the
characteristic peaks for bazedoxifene acetate Fomn B are at about 12.0±0.2° and 13.3±0.2°
in 2theta angular degree by Cu radiation. In some embodiments, the interfering peaks are at
from about 11.9±0.2° to about 13.3±0.2° in 2theta angular degree by Cu radiation.
[0096] A further aspect provides a method of detecting bazedoxifene acetate Form A
and/or Form B in a pharmaceutical composition comprising bazedoxifene acetate Form A
and/or Form B and one or more components (e.g., sucrose) that produce X-Ray diffraction
patterns having one or more interfering peaks at or near the characteristic peak or peaks for
bazedoxifene acetate Form A and/or Form B. The method includes:
(a) producing a composition containing bazedoxifene acetate Form A and/or
Form B by a method as described herein above, wherein the composition is substantially
free of the one or more components (e.g., sucrose) that produce X-Ray diffraction patterns
having one or more interfering peaks;
(b) forming the composition containing bazedoxifene acetate Form A and/or
Form B into a tablet or pellet for X-Ray diffraction measurement; and
(c) analyzing the tablet or pellet using X-Ray diffraction.
[0097] In some embodiments, the pharmaceutical composition comprising bazedoxifene
acetate and one or more components that produce XRD patterns having interfering peaks at
or near the characteristic peaks of bazedoxifene acetate includes a mixture of bazedoxifene
acetate Form A and bazedoxifene acetate Form B.
[0098] In some embodiments, the methods described herein includes: preparing a final
composition that is substantially free of interfering components (e.g., lactose or sucrose) for
XRD analysis. In some embodiments, the final composition is ground and pressed into a
tablet or pellet for XRD measurement. In some embodiments, the analysis of the final
composition is canried out using a Phillips X-Pert PW3040-MPD diffractometer. In some
embodiments, the analysis of the final composition is carried out using a Bruker D8 Discover
X-ray diffractometer with GADDS.
[0099] The embodiments of the methods described above can be combined in any
manner. Thus, features from one embodiment can be combined with features from any
other embodiment. For example, the embodiments described above can be combined in a
manner to produce methods of detecting bazedoxifene acetate Form A and/or Form B in a
phamnaceutical composition comprising bazedoxifene acetate and one or more components
that produce XRD patterns having interfering peaks at or near the characteristic peaks of
bazedoxifene acetate Form A and/or Form B, comprising: removing any coating from at least
one dosage unit comprising bazedoxifene acetate and one or more pharmaceutically
acceptable diluents, fillers, excipients, binding agents, lubricants, disintegrants, or
suspending or stabilizing agents (e.g., lactose); adding sodium acetate solution (about 0.5
M) to the phamnaceutical composition to produce a suspension with stirring for about 2 to
about 15 minutes; filtering and washing the suspension with additional sodium acetate
solution to produce a filtrand; drying the filtrand; grinding and pressing the fillrand into pellets
for XRD measurement; and analyzing the prepared pellets using an XRD diffractometer,
e.g., Bruker D8 Discover X-ray diffractometer with GADDS.
[0100] Furthermore, the embodiments described above can be combined in a manner to
produce methods of detecting bazedoxifene acetate Form A and/or Fonn B in a
pharmaceutical composition comprising bazedoxifene acetate and one or more components
that produce XRD patterns having interfering peaks at or near the characteristic peaks of
bazedoxifene acetate Form A and/or Form B. The method includes: removing any coating
from at least one dosage unit comprising bazedoxifene acetate and one or more
phamnaceutically acceptable diluents, fillers, excipients, binding agents, lubricants,
disintegrants, or suspending or stabilizing agents (e.g., sucrose); adding an appropriate
amount of sodium acetate solution (about 0.2 M) to the pharmaceutical composition to
produce a suspension with stirring for about 2 to about 10 minutes; centrifuging the
suspension to produce a solid and a supernatant solution; removing the supernatant
solution; adding additional sodium acetate solution to the solid to produce another
suspensbn with shaking; centrifuging the suspension to produce another solid and another
supernatant solution; removing the supernatant solution; filtering and drying the solid;
grinding and pressing the solid into pellets for XRD measurement; and analyzing the
prepared pellets using an XRD diffractometer, e.g., Bruker D8 Discover X-ray diffractometer
with GADDS.
[0101] The methods disclosed according to certain embodiments herein advantageously
allow for detecting bazedoxifene acetate Form B that is present in a pharmaceutical
composition in low levels. For example, about 2% by weight of bazedoxifene acetate Form
B relative to the total bazedoxifene acetate can be detected after the application of the
extraction procedure as described according to certain embodiments herein due to the
increase of the detectable bazedoxifene acetate signals in X-Ray diffraction upon removal of
interfering component(s).
[0102] The following examples are for illustrative purposes only and are not to be
construed as limiting. The tablets used in the examples can be prepared by a method
described in, e.g., WO 02/03987, US 6,479,535, US 2007/0003623, and Patent Application
Serial Nos. US 11/946,586. filed on November 28, 2007, and US 12/013,109, filed on Jan.
11, 2008.
EXAMPLES
Example 1: Extraction Procedure For Tablets Containing Bazedoxifene Acetate (BZA)
[0103] Tablets used herein comprise BZA Form A, lactose monohydrate, ascorbic acid,
microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, colloidal silicon
dioxide, magnesium stearate, and sodium lauryl sulfate. The tablets further comprise a
coating containing Opadry® White and Opadry® Clear.
[0104] The coatings of three of the tablets were removed. The resulting tablets were
then placed in a small bealcer. About 3.0 ml of extraction medium solution was added to the
beaker to produce a mixture. The mixture was broken up and stirred for about 5 to about 15
minutes. The resulting mixture was filtered and washed with an additional 3.0 ml of
extraction medium solution three times to produce a solid (filtrand). The recovered solid was
dried at about 40°C overnight. The dried solid was grinded and pressed into pellets for XRD
measurement. This procedure can be scaled up or down for various quantities of BZA
tablets. This procedure was employed for the samples found in Table 1.
Example 2: Extraction Procedure for Tablets Containing Bazedoxifene Acetate (BZA)
and Conjugated Estrogens (CE)
[0105] Tablets used herein comprise a core comprising CE, lactose monohydrate,
microcrystalline cellulose, and hypromellose; an outer layer conmprising BZA Form A,
ascorbic acid, sucrose, hypromellose, and sucrose palmitic acid ester; and a filler coat
between the core and the outer layer, which filler coat containing sucrose, microcrystalline
cellulose, hypromellose, polyethylene glycol. The tablets further comprise a coating
containing Opadry® Pink and Opadry® 2 Clear.
[0106] The coatings of twenty of the BZA/CE tablets were removed by razor blades or
other appropriate means. The resulting tablets were placed in a 50 ml beaker. About 20-25
ml of 0.2 M sodium acetate solution was added to the beaker to produce a mixture. The
mixture was stin-ed with a magnetic stirring bar to produce a suspension. The resulting
suspension was transferred into a 50 ml centrifuge tube. About another 10~25 ml of 0.2 M
sodium acetate solution was added to the beaker containing residual tablets to produce a
mixture. The mixture was stinred to produce a suspension, which was again transferred into
the same centrifuge tube. (This step may be repeated as needed until a filler coating
between the CE core and the BZA outer layer was exposed. The filler coating between the
BZA outer layer and the CE core usually looks smooth and whitish.) The resulting

suspension was centrifuged to produce a supernatant solution and a solid. The supernatant
solution was removed. The solid remained in the centrifuge tube was added about 40 ml of
0.2 M sodium acetate, then shaken, centrifuged and the resulting supernatant solution
removed again. (This step may be repeated as needed.) The remaining solid in the
centrifuge tube was filtered to remove any leftover extraction medium. The recovered solid
produced by filtration was dried at about 40 °C overnight (12 to 18 hours).
[0107] The dried solid was grinded and pressed into pellets using an IR hydraulic
presser for XRD measurement.
Example 3: X-Ray Powder Diffraction
[0108] X-Ray Powder Diffraction analyses were carried out on samples prepared
according to Examples 1 and 2 using a Bruker D8 Discover X-ray diffractometer with
GADDS. The diffractometer power was set at 40 kV and 40 mA. The collimator diameter of
the instrument was about 0.8 mm and the detector-to-sample distance was set at about 30
cm. The X-ray incident angle relative to the pellet/tablet surface was about 4° and the
detection angle relative to the pellet/tablet surface was about 16±0.2°. Data were collected
at about 120 minutes to about 240 minutes.
[0109] Altematively, X-Ray Diffraction analyses on powder samples can be carried out
on a (Philips X'Pert MPD) X-ray diffractometer using Cu radiation x-ray beams. The
diffractometer power was set at 40 kV and 40 mA. A continuous scan at 0.02
degree/second from 4 to 40 ° was used. Figure 1 and 2 show the XRD patterns collected
from bazedoxifene acetate Form A and Form B, lactose and sucrose powders.
Example 4: Bazedoxifene Acetate (BZA) Solubility Study
[0110] To examine potential bazedoxifene acetate loss during extraction, a
bazedoxifene acetate solubility study was performed. Tablets (same as those used in
Example 1) were placed in an extraction medium (0.5 M of sodium acetate). The solution
part was tested by High Pressure Liquid Chromatography (HPLC) to detemnine how much
bazedoxifene acetate had dissolved in the extraction medium. Known amount of BZA was
dissolved in and diluted with acetonitrile/water (1:1) into different concentrations (standard
bazedoxifene acetate solutions), and then chromatographed on a reversed phase C1 8
column to provide a standard chromatogram as a reference. A calibration curve between
the bazedoxifene concentration and the UV peak area at 220nm was established from these

standard bazedoxifene acetate solutions. Bazedoxifene acetate concentration of a given
sample is determined by its UV peak area at 220nm using the calibration curve . The
identification of bazedoxifene by HPLC is determined by comparing the retention time of the
bazedoxifene peak in the sample preparation chromatogram to that of the bazedoxifene
peak in the standard preparation. HPLC Column: C18. 5 µm, 150 x 4.6 mm; detector
wavelength: 220 nm; flow rate: about 1.5 mL per minute; injection volume: 10 µL; mobile
phase: constant 68:32 (v/v) - 25 mM phosphate buffer, pH 3.0 : acetonitrile; run time: about
10 minutes.
[0111] Less than 0.5% of bazedoxifene acetate by weight dissolved in 2 hours or longer.
Since the extraction procedures typically contact the bazedoxifene acetate formulation with
the extraction medium for less than about two hours, for example, less than about half an
hour, bazedoxifene acetate loss and solution-mediated transformation during the extraction
procedure are typically not significant.
Example 5: Bazedoxifene acetate Recovery in Different Extraction K/ledia
[0112] The following table illustrates the results of experiments using the extraction
methods of Example 1. The extractions were perfomned using different extraction media and
the results were measured in terms of peak area of bazedoxifene using XRD as described in
Example 3. As can be seen from Table 1, the extraction medium with the highest recovery
rate for this particulare set of experiments was 0.50 M Sodium Acetate, at a pH of about
8.34.
*Peak at 12.8° for bazedoxifene acetate Form A is used to indicate the bazedoxifene acetate
recovery.
[0113] Various modifications, in addition to those described herein, will be apparent to
those si