U.S. patent application number 11/094627 was filed with the patent office on 2005-10-27 for benzothiophenes, formulations containing same, and methods.
Invention is credited to Arbuthnot, Gordon Nelson, Dalder, Brian Weston, Hartauer, Kerry John, Luke, Wayne Douglas, Stratford, Robert Eugene JR..
Application Number | 20050239840 11/094627 |
Document ID | / |
Family ID | 21763902 |
Filed Date | 2005-10-27 |
United States Patent
Application |
20050239840 |
Kind Code |
A1 |
Arbuthnot, Gordon Nelson ;
et al. |
October 27, 2005 |
Benzothiophenes, formulations containing same, and methods
Abstract
This invention provides compounds of formula I 1 and
pharmaceutically acceptable salts and solvates thereof,
characterized that the compound is in particulate form and having a
specific size range. The present invention further provides
pharmaceutical compositions containing or formulated using
compounds of formula I, and the use of such compounds for
alleviating human pathologies, including osteoporosis, serum lipid
lowering, and breast cancer.
Inventors: |
Arbuthnot, Gordon Nelson;
(Indianapolis, IN) ; Dalder, Brian Weston; (West
Lafayette, IN) ; Hartauer, Kerry John; (Indianapolis,
IN) ; Luke, Wayne Douglas; (West Lafayette, IN)
; Stratford, Robert Eugene JR.; (Carmel, IN) |
Correspondence
Address: |
ELI LILLY AND COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
21763902 |
Appl. No.: |
11/094627 |
Filed: |
March 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11094627 |
Mar 30, 2005 |
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10811260 |
Mar 26, 2004 |
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6894064 |
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10811260 |
Mar 26, 2004 |
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10235617 |
Sep 5, 2002 |
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6797719 |
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10235617 |
Sep 5, 2002 |
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08812896 |
Mar 10, 1997 |
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6458811 |
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60014167 |
Mar 26, 1996 |
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Current U.S.
Class: |
514/320 ;
546/202 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 333/56 20130101; A61P 19/10 20180101 |
Class at
Publication: |
514/320 ;
546/202 |
International
Class: |
A61K 031/453; C07D
049/02 |
Claims
We claim:
1. A compound of formula I 8and pharmaceutically acceptable salts
and solvates thereof, characterized in that the compound is in
particulate form, said particles having a mean particle size of
less than about 25 microns.
2. The compound of claim 1 wherein said particles have a mean
particle size of between about 5 and about 20 microns.
3. The compound of claim 2 wherein at least about 90% of said
particles have a size of less than about 50 microns.
4. The compound of claim 3 wherein at least 90% of said particles
have a size of less than about 35 microns.
5. A compound of claim 1 which is the non-solvated crystalline
6-hydroxy-2-(4-hydroxy-phenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]t-
hiophene hydrochloride having substantially the following X-ray
diffraction pattern obtained with copper radiation:
45 d-line spacing I/I.sub.o (Angstroms) (.times.100) 13.3864 71.31
9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04
6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54
5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701
9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673
22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576
3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90
3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904
11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30
6. A pharmaceutical formulation comprising or formulated using the
compound of claim 5 and one or more pharmaceutically acceptable
carriers, diluents, or excipients.
7. A pharmaceutical composition comprising or formulated using a
compound according to claim 1, or a pharmaceutically acceptable
salt or solvate thereof, in combination with one or more
pharmaceutically acceptable carriers, diluents or excipients.
8. A method of inhibiting osteoporosis comprising administering an
effective amount of a compound of formula I to a person in need
thereof.
9. A method of lowering serum lipid levels comprising administering
a compound of claim 1, or a pharmaceutically acceptable salt or
solvate thereof, to a person in need thereof.
10. A method for preventing breast cancer comprising administering
to a woman in need thereof an effective amount of a compound of
claim 1, or a pharmaceutically acceptable salt or solvate
thereof.
11. An article of manufacture comprising packaging material
containing a pharmaceutical formulation, said packaging material
further containing labelling indicating said pharmaceutical
formulation is useful for inhibiting a human pathology, said
pharmaceutical formulation comprising or formulated using a
compound of claim 1.
12. A compound of formula I 9and pharmaceutically acceptable salts
and solvates thereof, characterized in that the compound is in
particulate form, at least about 90% of said particles having a
particle size of less than about 50 microns.
13. The compound of claim 12 wherein at least about 90% of said
particles have a size of less than 35 microns.
14. The compound of claim 13 wherein said particles have a mean
particle size of less than about 25 microns.
15. The compound of claim 14 wherein said particles have a mean
particles size of between about 5 and about 20 microns.
16. A compound of claim 12 which is the non-solvated crystalline
6-hydroxy-2-(4-hydroxy-phenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]t-
hiophene hydrochloride, having substantially the following X-ray
diffraction pattern obtained with copper radiation:
46 d-line spacing I/I.sub.o (Angstroms) (.times.100) 13.3864 71.31
9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04
6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54
5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701
9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673
22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576
3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90
3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904
11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30
17. A pharmaceutical formulation comprising or formulated using the
compound of claim 16, and one or more pharmaceutically acceptable
carriers, diluents, or excipients.
18. A pharmaceutical composition comprising or formulated using a
compound according to claim 12, or a pharmaceutically acceptable
salt or solvate thereof, with one or more pharmaceutically
acceptable carriers, diluents or excipients.
19. A method of inhibiting osteoporosis comprising administering to
a person in need thereof an effective amount of a compound of claim
12, or a pharmaceutically acceptable salt or solvate thereof.
20. A method of lowering serum lipid levels, comprising
administering to a person in need thereof an effective amount of a
compound of claim 12, or a pharmaceutically acceptable salt or
solvate thereof.
21. A method for preventing breast cancer comprising administering
to a woman in need thereof an effective amount of a compound of
claim 12, or a pharmaceutically acceptable salt or solvate
thereof.
22. An article of manufacture comprising packaging material
containing a pharmaceutical formulation, said packaging material
further containing labelling indicating said pharmaceutical
formulation is useful for inhibiting a human pathology, said
pharmaceutical formulation comprising or formulated using a
compound of claim 12.
23. A compound of formula I 10and pharmaceutically acceptable salts
and solvates thereof, characterized in that the compound is in
particulate form, said particles having a mean particle size of
between about and about 20 microns, at least about 90% of said
particles having a size of less than about 35 microns.
24. A compound according to claim 23 wherein it is the
hydrochloride salt thereof.
25. A compound of claim 23 which is the non-solvated crystalline
6-hydroxy-2-(4-hydroxy-phenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]
thiophene hydrochloride, having substantially the following x-ray
diffraction pattern obtained with copper radiation:
47 d-line spacing I/I.sub.o (Angstroms) (.times.100) 13.3864 71.31
9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04
6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54
5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701
9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673
22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576
3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90
3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904
11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30
26. A pharmaceutical formulation comprising or formulated using the
compound of claim 25 and one or more pharmaceutically-acceptable
carriers, diluents, or excipients.
27. A pharmaceutical composition comprising or formulated using a
compound according to claim 23, or a pharmaceutically acceptable
salt or solvate thereof, with one or more pharmaceutically
acceptable carriers, diluents or excipients.
28. A method for inhibiting osteoporosis comprising administering
to a person in need thereof an effective amount of a compound of
claim 23, or a pharmaceutically acceptable salt or solvate
thereof.
29. A method of lowering serum lipid levels, comprising
administering an effective amount of a compound of claim 23, or a
pharmaceutically acceptable salt or solvate thereof, to a person in
need thereof.
30. A method for preventing breast cancer comprising administering
to a woman in need thereof an effective amount of a compound of
claim 23, or a pharmaceutically acceptable salt or solvate
thereof.
31. An article of manufacture comprising packaging material
containing a pharmaceutical formulation, said packaging material
further containing labelling indicating said pharmaceutical
formulation is useful for inhibiting a human pathology, said
pharmaceutical formulation comprising or formulated using a
compound of claim 23.
Description
FIELD OF THE INVENTION
[0001] This invention relates to the fields of pharmaceutical and
organic chemistry and provides a benzothiophene compound, in
particulate form, which is useful for the treatment of various
medical indications, including osteoporosis and lipid lowering.
More particularly, the benzothiophene is of a particle size range
which allows enhanced bioavailabilty and control during the
manufacturing process.
BACKGROUND OF THE INVENTION
[0002] Osteoporosis describes a group of diseases which arise from
diverse etiologies, but which are characterized by the net loss of
bone mass per unit volume. The consequence of this loss of bone
mass and resulting bone fracture is the failure of the skeleton to
provide adequate structural support for the body. One of the most
common types of osteoporosis is that associated with menopause.
Most women lose from about 20% to about 60% of the bone mass in the
trabecular compartment of the bone within 3 to 6 years after the
cessation of menses. This rapid loss is generally associated with
an increase of bone resorption and formation. However, the
resorptive cycle is more dominant and the result is a net loss of
bone mass. Osteoporosis is a common and serious disease among
post-menopausal women.
[0003] There are an estimated 25 million women in the United
States, alone, who are afflicted with this disease. The results of
osteoporosis are personally harmful and also account for a large
economic loss due its chronicity and the need for extensive and
long term support (hospitalization and nursing home care) from the
disease sequelae. This is especially true in more elderly patients.
Additionally, although osteoporosis is not generally thought of as
a life threatening condition, a 20% to 30% mortality rate is
related with hip fractures in elderly women. A large percentage of
this mortality rate can be directly associated with post-menopausal
osteoporosis.
[0004] At this time, the only generally accepted methods for
treatment of post-menopausal osteoporosis are estrogen replacement
therapy and the use of the bisphosphonate alendronate. Although
therapy is generally successful, patient compliance with the
therapy is relatively low primarily, due to undesirable side
effects.
[0005] Throughout premenopausal time, most women have less
incidence of cardiovascular disease than age-matched men. Following
menopause, however, the rate of cardiovascular disease in women
slowly increases to match the rate seen in men. This loss of
protection has been linked to the loss of estrogen and, in
particular, to the loss of estrogen's ability to regulate the
levels of serum lipids. The nature of estrogen's ability to
regulate serum lipids is not well understood, but evidence to date
indicates that estrogen can up regulate the low density lipid (LDL)
receptors in the liver to remove excess cholesterol. Additionally,
estrogen appears to have some effect on the biosynthesis of
cholesterol, and other beneficial effects on cardiovascular
health.
[0006] It has been reported in the literature that post-menopausal
women having estrogen replacement therapy have a return of serum
lipid levels to concentrations to those of the pre-menopausal
state. Thus, estrogen would appear to be a reasonable treatment for
this condition. However, the side-effects of estrogen replacement
therapy are not acceptable to many women, thus limiting the use of
this therapy. An ideal therapy for this condition would be an agent
which would regulate the serum lipid level as does estrogen, but
would be devoid of the side-effects and risks associated with
estrogen therapy.
[0007] Preclinical findings with a structurally distinct
"anti-estrogen", raloxifene, have demonstrated potential for
improved selectivity of estrogenic effects in target tissues.
Similar to tamoxifen, raloxifene was developed originally for
treatment of breast cancer; however, the benzothiophene nucleus of
raloxifene represented a significant structural deviation from the
triphenylethylene nucleus of tamoxifen. Raloxifene binds with high
affinity to the estrogen receptor, and inhibits estrogen-dependent
proliferation in MCF-7 cells (human mammary tumor derived cell
line) in cell culture. In vivo estrogen antagonist activity of
raloxifene was furthermore demonstrated in carcinogen-induced
models of mammary tumors in rodents. Significantly, in uterine
tissue raloxifene was more effective than tamoxifen as an
antagonist of the uterotrophic response to estrogen in immature
rats and, in contrast to tamoxifen, raloxifene displayed only
minimal uterotrophic response that was not dose-dependent in
ovariectomized (OVX) rats. Thus, raloxifene is unique as an
antagonist of the uterine estrogen receptor, in that it produces a
nearly complete blockage of uterotrophic responses of estrogen due
to minimal agonist effect of raloxifene in this tissue. Indeed, the
ability of raloxifene to antagonize the uterine stimulatory effect
of tamoxifen was recently demonstrated in OVX rats. Raloxifene is
more properly characterized as a Selective Estrogen Receptor
Modulator (SERM), due to its unique profile.
[0008] Raloxifene is now in Phase III clinical trials for
osteoporosis. Indications thus far from these trials and other
data, point to raloxifene's potential not only as an osteoporosis
therapy, but also of potential use in lowering LDL (serum lipid)
levels, inhibiting endometriosis and uterine fibrosis, and
preventing breast cancer. The advancement of raloxifene has been
somewhat hampered by its physical characteristics, both as to
bioavailability and in manufacturing. For example, it is generally
insoluble, and this can adversely affect the bioavailability.
Clearly, any improvement in the physical characteristics of
raloxifene, would potentially offer a more beneficial therapy and
enhanced manufacturing capability.
SUMMARY OF THE INVENTION
[0009] This invention provides a compound of formula I 2
[0010] and pharmaceutically acceptable salts and solvates thereof,
characterized in that the compound is in particulate form, said
particles having a mean particle size of less than about 25
microns, and preferably between about 5 and about 20 microns.
[0011] Further, the present invention encompasses compounds of
formula I wherein at least 90% of the particles have a particle
size of less than about 50 microns, and preferably less than about
35 microns.
[0012] The present invention further relates to pharmaceutical
compositions containing or formulated using one or more compounds
of formula I, optionally containing estrogen or progestin, and the
use of such compounds, alone, or in combination with estrogen or
progestin, for alleviating the symptoms of osteoporosis lowering
lipid levels, and inhibiting endometriosis, uterine fibrosis, and
breast cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0013] It has now been found that by processing compounds of
formula I, to bring their particle size within a specified narrow
range, pharmaceutical compositions may be prepared which exhibit
for their active ingredient both a consistent in vitro dissolution
profile and in vivo bioavailability. In addition to bringing about
these desired dissolution/bioavailability characteristics, the
control of particle size to a narrow range has also resulted in
significant improvements in manufacturing capabilities.
[0014] The mean particle size of the compounds of formula I, as set
out by the invention, is less than about 25 microns, preferably
between about 5 and about 20 microns. Further, the invention
encompasses formula I compounds with at least 90% of the particles
having a particle size of less than about 50 microns, preferably
less than about 35 microns. More preferably, the mean particle size
range is between about 5 and about 20 microns, with at least 90% of
the particles having a size of less than about 35 microns.
[0015] It will of course be understood by those familiar with
comminution process techniques that the limit set on the size of
90% or more of the particles is a limitation to further distinguish
the particulate compounds of the invention from those exhibiting a
broader size distribution, because of the wide variation in size
encountered in all matter reduced in size by a process of
comminution or particle size reduction, for example, by milling
utilizing a variety of kinds of milling equipment now available,
for example, hammer, pin or fluid energy mills.
[0016] The invention also provides pharmaceutical compositions
comprising or formulated using the said particulate compound of the
invention and one or more pharmaceutically-acceptable excipients or
carriers.
[0017] The term "inhibit" is defined to include its generally
accepted meaning which includes prohibiting, preventing,
restraining, and lowering, stopping, or reversing progression or
severity, and such action on a resultant symptom. As such the
present invention includes both medical therapeutic and
prophylactic administration, as appropriate.
[0018] The term "molar equivalents," as used herein, refers to the
number of moles of the boron trihalide reagent in relation to the
number of moles of the starting benzothiophene compound. For
example, three millimoles of boron trichloride reacted with one
millimole of the benzothiophene compound would represent three
molar equivalents of boron trichloride.
[0019] The term "solvate" represents an aggregate that comprises
one or more molecules of the solute, such as a formula I compound,
with a molecule of solvent. Representative solvates are formed with
methylene chloride, 1,2-dichloroethane, chloroform, and
1,2,3-trichloropropane.
[0020] A desirable form of raloxifene hydrochloride is the
non-solvated crystalline form described in UK published patent
application GB 2293382(A), published Mar. 27, 1996, filed Aug. 18,
1995, Application Number 9519028.6, incorporated herein by
reference.
[0021] As used herein, the term "estrogen" includes steroidal
compounds having estrogenic activity such as, for example,
17.beta.-estradiol, estrone, conjugated estrogen (Premarin.RTM.),
equine estrogen, 17.beta.-ethynyl estradiol, and the like. As used
herein, the term "progestin" includes compounds having
progestational activity such as, for example, progesterone,
norethylnodrel, nongestrel, megestrol acetate, norethindrone, and
the like.
[0022] The term "mean particle size" is defined as equivalent
spherical diameter as determined by laser light diffraction
scattering.
[0023] Raloxifene's chemical name is
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-
-piperidinoethoxy)benzoyl]benzo[b]-thiophene. "Raloxifene" also
encompasses the salts and solvates thereof, with the hydrochloride
salt being preferred.
[0024] Raloxifene is a nuclear regulatory molecule or second
generation selective estrogen receptor modulator (SERM). Raloxifene
has been shown to bind to the estrogen receptor and was originally
thought to be a molecule whose function and pharmacology was that
of a pure anti-estrogen in that it blocked the ability of estrogen
to activate uterine tissue and estrogen dependent breast cancers.
Indeed, raloxifene does block the action of estrogen in some cells;
however in other cell types, raloxifene activates the same genes as
estrogen does and displays the same pharmacology, e.g.,
osteoporosis, hyperlipidemia. The unique profile which raloxifene
displays and differs from that of estrogen is now thought to be due
to the unique activation and/or suppression of various gene
functions by the raloxifene-estrogen receptor complex as opposed to
the activation and/or suppression of genes by the estrogen-estrogen
receptor complex. Therefore, although raloxifene and estrogen
utilize and compete for the same receptor, the pharmacological
outcome from gene regulation of the two is not easily predicted and
is unique to each.
[0025] The compounds of the current invention can be made according
to established procedures, such as those detailed in U.S. Pat. Nos.
4,133,814, 4,418,068, and 4,380,635, and European Patent
Application 95306050.6, Publication No. 0699672, Kjell, et al.,
filed Aug. 30, 1995, published Mar. 6, 1996, all of which are
incorporated by reference herein. In general, the process starts
with a benzo[b]thiophene having a 6-hydroxyl group and a
2-(4-hydroxyphenyl) group. The starting compound is protected,
acylated, and deprotected to form the formula I compounds. Examples
of the preparation of such compounds are provided in the U.S.
patents discussed above.
[0026] Also, the information disclosed in the published European
Patent Application number 0670162 A1, published on Sep. 6, 1995, is
incorporated by reference.
[0027] A preferred synthesis is set out as follows. R.sup.4 is
hydrogen or C.sub.1-C.sub.4 alkoxy, R.sup.5 is hydrogen or
C.sub.1-C.sub.4 alkyl, and R.sup.6 is chloro, bromo, or hydroxyl.
HX is HCl or HBr.
[0028] The Formula II and III compounds, the starting materials for
the compounds of formula I, are prepared using standard synthetic
organic methods. The Formula II starting compound is readily
obtained by a synthesis which is exemplified below in Preparation I
and outlined in Scheme I. 3
[0029] The Formula II compounds, wherein R.sup.4 and R.sup.5 are as
defined above, are prepared by first reacting a
3-alkoxybenzenethiol with phenacyl or 4'-alkoxyphenacyl bromide in
the presence of a strong base. Suitable bases for this
transformation include, but are not limited to, potassium hydroxide
and sodium hydroxide. The reaction is typically carried out in
ethanol or a mixture of water and ethanol at a temperature of about
0.degree. C. to about 50.degree. C. The next step is cyclization of
the arylphenacylsulfide. The cyclization is conveniently carried
out by heating the arylphenacylsulfide in polyphosphoric acid. The
cyclization is typically carried out at a temperature of about
80.degree. C. to about 120.degree. C., preferably between
85.degree. C. and 90.degree. C. The Formula II benzothiophene is
typically purified by recrystallization. For example, when R.sup.4
is methoxy and R.sup.5 is methyl, the formula II compound may be
recrystallized from ethyl acetate.
[0030] The acylating agent for the present process, a Formula III
compound, is prepared as shown in Scheme II, wherein the variables
R.sup.6 and HX are as defined above and R is C.sub.1-C.sub.4 alkyl.
4
[0031] Generally, a C.sub.1-C.sub.4 alkyl 4-hydroxybenzoate is
alkylated with a chloroethylamine in the presence of an inorganic
base and the ester group hydrolyzed to produce the Formula III
compounds, wherein R.sup.6 is hydroxyl. Suitable inorganic bases
for this alkylation include potassium carbonate and sodium
carbonate. Suitable solvents for this alkylation are non-reactive
polar organic solvents such as methyl ethyl ketone and
dimethyl-formamide. The ester is hydrolyzed using standard
synthetic methods, such as by reaction of the alkylated
intermediate with an aqueous acid or base. For example, the ethyl
ester is readily hydrolyzed by reaction with 5N sodium hydroxide in
a water miscible organic solvent, such as methanol. Acidification
of the reaction with concentrated hydrochloric acid produces the
Formula III compound, wherein R.sup.6 is hydroxyl, as the
hydrochloride salt.
[0032] The Formula III compounds, wherein R.sup.6 is chloro or
bromo, are prepared by halogenating the Formula III compounds
wherein R.sup.6 is hydroxyl. Suitable halogenating agents include
oxalyl chloride, thionyl chloride, thionyl bromide, phosphorous
tribromide, triphosgene, and phosgene. Preferably, R.sup.6 is
chloro. Suitable solvents for this reaction include methylene
chloride, 1,2-dichlorobenzene, chlorobenzene, and
1,2-dichloroethane. Preferably, the halogenation reaction is
carried out in the same solvent as the subsequent acylation
reaction. A catalytic amount of dimethylformamide, from about 0.05
to about 0.25 equivalents, is added to the chlorination reaction.
When the reaction is carried out in 1,2-dichloroethane, the
reaction is complete after about 2 to 5 hours at about 47.degree.
C. The Formula III compounds, wherein R.sup.6 is chloro, may be
stored as a solid, or as a solution or mixture in methylene
chloride, chlorobenzene, 1,2-dichlorobenzene, or
1,2-dichloroethane. Preferably, the chlorination reaction and
acylation reaction are carried out successively in the same
reaction vessel.
[0033] The
2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl[b]-thiophenes can be
prepared by acylation and subsequent dealkylation of the phenolic
groups in two distinct steps, or sequentially in a "one-pot"
reaction. The step-wise synthesis is described in the following
paragraphs.
[0034] The acylated benzothiophene intermediate, a Formula IV
compound, is prepared as shown in Scheme III, wherein R.sup.4,
R.sup.5, R.sup.6, and HX are as defined above. 5
[0035] Generally, benzothiophene intermediate II is acylated with a
Formula III compound, using boron trichloride or boron tribromide
as the acylation catalyst. The reaction is carried out in an
organic solvent, such as chlorobenzene, methylene chloride,
1,2-dichloroethane, 1,2-dichlorobenzene, bromobenzene, chloroform,
1,1,2,2-tetrachloro-ethane- , 1,2,3-trichloropropane, and
fluorobenzene. Preferably, the acylation is carried out in
methylene chloride, chloro-benzene, or 1,2-dichloroethane. Most
preferably, the acylation step is carried out in methylene
chloride. The rate of acylation of the Formula II compound and the
rate of dealkylation of the phenolic ethers of the Formula II and
IV compounds varies with the choice of solvent, temperature of
reaction, and choice of boron trihalide. Because the Formula II
compounds having one or more unprotected phenolic groups will not
acylate readily under these conditions, the amount of dealkylation
must be minimized. Because boron tribromide is more preferred for
dealkylation of phenolic ethers, the preferred boron trihalide for
catalyzing acylation is boron trichloride. For boron
trichloride-catalyzed reactions in methylene chloride, the
acylation reaction can be performed at room temperature, with
minimal dealkylation of the Formula II and IV compounds. In other
solvents, the acylation reaction is carried out at lower
temperatures, such as -10.degree. C. to 10.degree. C., to minimize
the amount of dealkylation of the reaction starting material and
product. When R.sup.6 is chloro, at least 2 molar equivalents of
the boron trihalide reagent are required for acylation. When the
benzoic acid is used as an acylating agent (R.sup.6.dbd.OH), five
equivalents of the boron trihalide are typically used. The Formula
IV compound may be isolated as the hydrochloride or hydrobromide
salt, or as the free base.
[0036] In the step-wise process, the acylated intermediate (Formula
IV compound) is dealkylated to produce the Formula I compound as
shown in Scheme IV, wherein R.sup.4, R.sup.5, and HX are as defined
above. 6
[0037] The Formula I compound is produced by reacting the
hydrochloride or hydrobromide salt of the Formula IV compound with
boron tribromide or boron trichloride. The preferred boron
trihalide for dealkylation is boron tribromide. This dealkylation
reaction can be carried out in a variety of organic solvents, such
as methylene chloride, chlorobenzene, 1,2-dichloroethane,
chloroform, 1,1,2,2-tetrachloroethane, 1,2,3-trichloropropane,
1,2-dichlorobenzene, and fluorobenzene. The preferred solvent is
1,2-dichloroethane. When the acid addition salt is used as a
starting material, the amount of by-product resulting from
dealkylation of the aminoethyl group is minimized. When methylene
chloride is used as the solvent and the boron reagent is boron
trichloride, the reaction is generally carried out at a temperature
of about 55.degree. C. to about 75.degree. C., producing the
Formula I compound with no detectable cleavage of the aminoethyl
group. In other solvents, such as chloroform, 1,2-dichloroethane,
chlorobenzene, 1,2-dichlorobenzene, and fluorobenzene, the
dealkylation occurs readily at ambient temperatures. For example,
when 1,2-dichloroethane is the solvent, the reaction is generally
carried out at 25.degree. C. to 35.degree. C. with no detectable
cleavage of the aminoethyl group. At least four equivalents of the
boron trihalide reagent are typically used for complete reaction
within a reasonable time.
[0038] Preferably, the Formula I compounds are prepared by a
"one-pot" synthesis from the Formula II and III compounds as shown
in Scheme V, wherein R.sup.4, R.sup.5, R.sup.6, and HX are as
defined above. 7
[0039] The benzothiophene Formula II compound is acylated with the
Formula III compound in the presence of boron trichloride or boron
tribromide; boron trichloride is preferred for the "one-pot"
process. The reaction can be carried out in a variety of organic
solvents, such as chloroform, methylene chloride,
1,2-dichloroethane, 1,2,3-dichloropropane,
1,1,2,2-tetrachloroethane, 1,2-dichloro-benzene, chlorobenzene, and
fluorobenzene. The preferred solvent for this synthesis is
1,2-dichloroethane. The reaction is carried out at a temperature of
about -10.degree. C. to about 25.degree. C., preferably at
0.degree. C. The reaction is best carried out at a concentration of
the benzothiophene Formula II compound of about 0.2 M to about 1.0
M. The acylation reaction is generally complete after about two
hours to about eight hours.
[0040] The acylated benzothiophene, the Formula IV compound, is
converted to a Formula I compound without isolation. This
conversion is performed by adding additional boron trihalide and
heating the reaction mixture. Preferably, two to five molar
equivalents of boron trichloride are added to the reaction mixture,
most preferably three molar equivalents. This reaction is carried
out at a temperature of about 25.degree. C. to about 40.degree. C.,
preferably at 35.degree. C. The reaction is generally complete
after about 4 to 48 hours. The acylation/dealkylation reaction is
quenched with an alcohol or a mixture of alcohols. Suitable
alcohols for use in quenching the reaction include methanol,
ethanol, and isopropanol. Preferably, the acylation/ dealkylation
reaction mixture is added to a 95:5 mixture of ethanol and methanol
(3A). The 3A ethanol can be at room temperature or heated to
reflux, preferably at reflux. When the quench is performed in this
manner, the Formula I compound conveniently crystallizes from the
resulting alcoholic mixture. Generally, 1.25-3.75 mL of alcohol per
millimole of the benzothiophene starting material are used.
[0041] The preparation of a solvate of the Formula I compound,
wherein HX is HCl, was described previously. Jones et al., J. Med.
Chem., 27, 1057 (1984). The crystalline product of this "one-pot"
process, when BCl.sub.3 is used, is isolated as the solvate of the
hydrochloride salt. These crystalline solvates are obtained under a
variety of conditions. Generally, the form of the product of the
present process is determined by choice of acylation/dealkylation
solvent, boron trihalide, and work-up conditions.
[0042] A particularly useful solvate of the formula I compound is
the 1,2-dichloroethane solvate. This solvate is prepared by
carrying out the "one-pot" acylation/dealkylation process in
1,2-dichloroethane. When HX is HCl, the 1,2-dichloroethane solvate
of a compound of formula I can exist in two distinct forms. One
crystalline solvate form, termed crystal form I, is prepared by
quenching the boron trichloride-catalyzed acylation/dealkylation
reaction with ethanol. Preferably, a mixture of ethanol and
methanol (95:5) is used in the preparation of this crystal form.
This particular crystal form is characterized by the X-ray
diffraction pattern shown in Table 1.
1TABLE 1 X-ray Diffraction Pattern for Crystal Form 1. d-line
spacing I/I.sub.o (Angstroms) (.times.100) 16.1265 3.80 10.3744
8.63 8.3746 5.29 7.9883 36.71 7.2701 5.06 6.5567 70.77 6.2531 6.79
5.5616 24.05 5.3879 100.00 5.0471 89.64 4.7391 85.96 4.6777 39.36
4.6332 62.60 4.5191 77.56 4.2867 36.82 4.2365 41.66 4.1816 49.60
4.0900 11.28 3.9496 11.85 3.7869 36.25 3.7577 56.16 3.6509 40.62
3.5751 15.65 3.5181 21.52 3.4964 18.53 3.4361 33.60 3.3610 6.21
3.3115 4.95 3.2564 7.36 3.2002 3.80 3.1199 15.77 3.0347 14.84
2.8744 9.67 2.8174 10.82 2.7363 11.51
[0043] The amount of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride present in the
crystalline material is about 87.1%, as determined using the high
performance liquid chromatography (HPLC) assay described below. The
amount of 1,2-dichloroethane present in the crystalline material is
about 0.55 molar equivalents, as determined by proton nuclear
magnetic resonance spectroscopy.
[0044] A large, analytically pure single crystal of the form I
1,2-dichloroethane solvate was prepared for single crystal X-ray
analysis. This single crystal was prepared by placing a saturated
methanolic solution of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoet-
hoxy)benzoyl]benzo[b]thiophene hydrochloride in an atmosphere
saturated with 1,2-dichloroethane (see Example 8). A total of 8419
reflections with 2.theta. less than 116.degree. were collected, and
used to solve the structure. The X-ray structure clearly shows that
the crystalline material is a 1,2,-dichloroethane solvate having a
1:2 ratio of solvent to solute molecules. The theoretical X-ray
powder diffraction pattern spectrum, calculated from the single
crystal X-ray data, is identical to that listed in Table 1,
indicating that both solvates are identical.
[0045] A second crystalline solvate form, termed crystal form II,
is similar to crystal form I. This second form is prepared by
quenching the boron trichloride-catalyzed acylation/dealkylation
reaction carried out in 1,2-dichloroethane with methanol.
Alternatively, the boron trichloride-catalyzed acylation/
dealkylation reaction using 1,2,3-trichloropropane as the solvent,
produces a 1,2,3-trichloropropane solvate of this form. This
particular crystal form is characterized by the X-ray diffraction
pattern shown in Table 2.
2TABLE 2 X-ray Diffraction Pattern for Crystal Form II. d-line
spacing I/I.sub.o (Angstroms) (.times.100) 10.4311 22.64 8.9173
10.73 8.4765 5.31 8.0095 50.39 7.3068 4.23 6.6094 79.23 5.6196
22.34 5.4223 89.86 5.1959 11.81 5.0746 74.90 4.8017 100.00 4.7262
57.97 4.6569 53.35 4.5378 96.75 4.4376 10.83 4.3397 56.89 4.2782
48.23 4.2129 40.94 4.1037 12.80 3.9880 14.76 3.8863 8.17 3.7999
42.13 3.7662 57.09 3.6738 38.58 3.5701 18.50 3.5393 19.00 3.4622
39.57 3.3867 5.02 3.3321 4.33 3.2686 6.79 3.1535 14.86 3.0450 13.58
2.9028 12.30 2.8302 19.59 2.7544 12.30 2.6366 6.89
[0046] The amount of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride present in the
crystalline material is about 86.8%. The amount of
1,2-dichloroethane present in the crystalline material is about
6.5%, as determined by gas chromatography.
[0047] The formula I compounds form a variety of distinct solvates
with aromatic solvents. A useful aromatic solvate of this compound
is the chlorobenzene solvate, which exists in a distinct form
termed crystal form III. This particular crystal form is
characterized by the X-ray diffraction pattern shown in Table
3.
3TABLE 3 X-ray Diffraction Pattern for Crystal Form III. d-line
spacing I/I.sub.o (Angstroms) (.times.100) 14.3518 7.24 10.3335
6.17 8.8305 4.29 7.9475 38.16 6.5904 64.25 6.2848 6.52 5.6048 28.06
5.4107 100.00 5.1544 11.26 5.0493 53.26 5.0224 46.11 4.8330 76.94
4.7694 34.23 4.6461 50.22 4.5754 38.61 4.4953 72.65 4.3531 49.15
4.2940 41.64 4.2425 35.75 4.1856 21.63 4.1338 9.47 4.0793 12.69
3.9960 18.50 3.9037 9.03 3.7854 40.39 3.7521 54.16 3.6787 28.60
3.6509 17.96 3.5444 31.72 3.4679 41.55 3.3899 7.69 3.3101 5.72
3.2561 7.42 3.1784 15.19 3.0445 11.17 3.0146 8.94 2.9160 11.89
2.8217 18.23 2.7500 12.06 2.6436 9.65 2.6156 6.97
[0048] The amount of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride present in the
crystalline material is about 78.6%. The amount of chlorobenzene
present in the crystalline material is about 12.3%, as determined
by HPLC.
[0049] A fourth crystalline solvated form is termed crystal form
IV. This particular form is prepared by the boron
trichloride-catalyzed acylation/dealkylation process using
methylene chloride or chloroform as the solvent. This particular
crystal form is characterized by the X-ray diffraction pattern
shown in Table 4.
4TABLE 4 X-ray Diffraction Pattern for Crystal Form IV. d-line
spacing I/I.sub.o (Angstroms) (.times.100) 10.3696 14.40 8.9032
10.19 8.3125 7.61 7.9818 41.03 7.2036 7.34 6.5411 74.18 6.2367 6.39
5.5539 20.11 5.3689 100.00 5.0272 95.92 4.7085 89.13 4.6406 73.37
4.6199 77.58 4.5347 69.70 4.4818 49.86 4.2589 47.69 4.2067 44.43
4.1659 44.16 4.0957 11.96 3.9347 11.28 3.7818 40.90 3.7614 53.53
3.6375 36.68 3.5773 20.11 3.5037 25.14 3.4409 32.34 3.4270 39.54
3.3088 12.64 3.2611 9.65 3.1046 12.77 3.0263 17.53 2.8536 8.29
2.8131 12.09 2.7309 8.97
[0050] The amount of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride present in the
crystalline material is about 80.4%, as determined by HPLC
analysis. The amount of chloroform present in the crystalline
material is about 0.42 molar equivalents, as determined by proton
nuclear magnetic resonance spectroscopy.
[0051] A preferred crystalline form of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4--
(2-piperidinoethoxy)benzoyl]benzo[b]-thiophene hydrochloride is a
non-solvated crystal form. This particular form is preferred for
use in the preparation of pharmaceutical formulations because of
the absence of solvent that could affect the patient. This
particular crystal form is prepared by recrystallization of the
solvated hydrochloride salt produced by the boron
trichloride-catalyzed acylation/ dealkylation process. Generally,
the solvated hydrochloride salt is added to a solution of sodium
hydroxide in methanol or a mixture of methanol and water. At least
one equivalent of base is used for dissolution and to ensure that
the hydrochloride salt is converted to the free base. Activated
carbon is optionally added to the resulting solution to facilitate
removal of impurities. The mixture is filtered to remove the
activated carbon, if present, and any insoluble impurities. The
filtrate is extracted with an aliphatic hydrocarbon solvent, such
as hexane or heptane, to remove the organic solvent used in the
acylation/ dealkylation reaction. The methanol solution is
acidified with hydrochloric acid, such as gaseous or aqueous
hydrochloric acid, causing crystallization of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]-t-
hiophene as the non-solvated hydrochloride salt. The resulting
crystalline slurry is preferably stirred at ambient temperature for
about one to about two hours to ensure complete crystallization.
The non-solvated crystalline form is isolated by filtration,
followed by drying in vacuo. This particular crystal form is
characterized by the X-ray diffraction pattern shown in Table
5.
5TABLE 5 X-ray Diffraction Pattern for Non-solvated Crystal Form.
d-line spacing I/I.sub.o (Angstroms) (.times.100) 13.3864 71.31
9.3598 33.16 8.4625 2.08 7.3888 7.57 6.9907 5.80 6.6346 51.04
6.1717 29.57 5.9975 5.67 5.9135 9.87 5.6467 38.47 5.4773 10.54
5.2994 4.74 4.8680 4.03 4.7910 5.98 4.6614 57.50 4.5052 5.75 4.3701
9.03 4.2516 69.99 4.2059 57.64 4.1740 65.07 4.0819 12.44 3.9673
22.53 3.9318 100.00 3.8775 9.07 3.7096 33.38 3.6561 21.65 3.5576
3.36 3.5037 7.97 3.4522 18.02 3.4138 4.65 3.2738 10.23 3.1857 8.90
3.1333 6.24 3.0831 9.43 3.0025 12.13 2.9437 4.96 2.8642 7.70 2.7904
11.95 2.7246 3.05 2.6652 3.32 2.5882 7.30
[0052] The amount of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride present in the
crystalline material is at least 95%.
[0053] This non-solvated crystalline material is more pure than the
material produced by the processes described in the
above-referenced patents. This material is free of aluminum
impurities, as well as, chlorinated aliphatic hydrocarbon solvents
and aromatic solvents. This non-solvated crystalline form is
particularly preferred for use in the manufacture of pharmaceutical
compositions.
[0054] The following examples further illustrate the processes
described. The examples are not intended to be limiting to the
scope of the invention in any respect, and should not be so
construed. All experiments were run under positive pressure of dry
nitrogen. All solvents and reagents were used as obtained. The
percentages are generally calculated on a weight (w/w) basis;
except for HPLC solvents which are calculated on a volume (v/v)
basis. Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
obtained on a Bruker AC-300 FTNMR spectrometer at 300.135 MHz.
Melting points were determined by differential scanning calorimetry
(DSC) in a TA Instrument DCS 2920 using a closed cell and a heating
rate of 2.degree. C./minute. The X-ray powder diffraction spectra
were obtained in a Siemens D5000 X-Ray Powder Diffraktometer, using
copper radiation and a Si(Li) detector.
[0055] The reactions were generally monitored for completion using
high performance liquid chromatography (HPLC). The reaction
producing the acid chloride, the Formula III compound wherein
R.sup.6 is chloro, was monitored using a Zorbax Rx-C8 column, (25
cm.times.4.6 mm ID, 5.mu. particle) eluting with a mixture of 60 mM
phosphate (KH.sub.2PO.sub.4) and 10 mM octanesulfonate (pH
2.0)/acetonitrile (60:40). The Formula III compound was derivatized
with aniline, and analyzed using a carbanilide reference standard,
derived from reaction of phosgene with aniline. A carbanilide
standard stock solution was prepared by dissolving carbanilide (10
mg) and aniline (3 mL). This solution was diluted to a volume of
100 mL with the eluent described above. The reaction was monitored
by the addition of about 0.3 mL of the acid chloride solution to 1
mL of HPLC grade methanol. The resulting mixture was shaken
vigorously and allowed to derivatize. After 30 minutes,
acetonitrile (6 mL) was added followed by dilution to 100 mL with
the eluent described above.
[0056] The acylation, dealkylation, or acylation/dealkylation
reactions are also monitored for completion by HPLC. A sample of
the reaction mixture was assayed using a Zorbax Rx-C8 column, (25
cm.times.4.6 mm ID, 5.mu. particle), eluting with a gradient as
shown below:
6 Gradient Solvent System Time (min.) A (%) B (%) 0 60 40 5 60 40
10 45 55 20 38 62 25 45 55 32 45 55 37 60 40 42 60 40 A: 0.05 M
HClO.sub.4 (pH = 2.0) B: acetonitrile
[0057] The reaction mixture was analyzed by diluting a 0.1 to 0.2
mL sample to 50 mL with a 60:40 mixture of A/B. Similarly, the
mother liquor of the recrystallizations was sampled in a similar
manner.
[0058] The amount (percentages) of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-p-
iperidinoethoxy)benzoyl)benzo[b]thiophene hydrochloride in the
crystalline material (potency) was determined by the following
method. A sample of the crystalline solid (5 mg) was weighed into a
100-mL volumetric flask, and dissolved in a 70/30 (v/v) mixture of
75 mM potassium phosphate buffer (pH 2.0) and acetonitrile. An
aliquot of this solution (10 .mu.L) was assayed by high performance
liquid chromatography, using a Zorbax Rx-C8 column (25 cm.times.4.6
mm ID, 5.mu. particle) and UV detection (280 nm). The following
gradient solvent system is used:
7 Gradient Solvent System (Potency) Time (min) A (%) B (%) 0 70 30
12 70 30 14 25 75 16 70 30 25 70 30 A: 75 mM KH.sub.2PO.sub.4
buffer (pH 2.0) B: acetonitrile
[0059] The percentage of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoe-
thoxy)benzoyl]benzo[b]thiophene hydrochloride in the sample is
calculated using the peak area, slope (m), and intercept (b) of the
calibration curve with the following equation: 1 % potency = peak
area - b m .times. sample volume ( mL ) sample weight ( mg )
[0060] The amount (percentage) of solvent, such as methanol,
ethanol, or 1,2-dichloroethane, present in the crystalline material
is determined by gas chromatography. A sample of the crystalline
solid (50 mg) was weighed into a 10-mL volumetric flask, and
dissolved in a solution of 2-butanol (0.025 mg/mL) in
dimethylsulfoxide. A sample of this solution was analyzed on a gas
chromatograph using a DB Wax column (30 m.times.0.53 mm ID, 1.mu.
particle), with a column flow of 10 mL/min and flame ionization
detection. The column temperature was heated from 35.degree. C. to
230.degree. C. over a 12 minute period. The amount of solvent was
determined by comparison to the internal standard (2-butanol),
using the following formula: 2 % solvent = C D .times. E F .times.
G H .times. I
[0061] wherein:
[0062] C=ratio of solvent in sample
[0063] D=average ratio of standard for specific solvent
[0064] E=average weight of standard
[0065] F=weight of sample (mg)
[0066] G=volume of sample (10 mL)
[0067] H=volume of standard (10,000 mL)
[0068] I=purity of standard (%)
Preparation 1
6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene
[0069] A solution of 3-methoxybenzenethiol (100 grams) and
potassium hydroxide (39.1 grams) in water (300 mL) was added to
denatured ethanol (750 mL), and the resulting mixture cooled to
about 0.degree. C. The cold mixture was treated with
4'-methoxyphenacyl bromide (164 grams) in several small portions.
Upon complete addition, the mixture was cooled for an additional
ten minutes, then allowed to warm to room temperature. After three
hours, the mixture was concentrated in vacuo, and the residue
treated with water (200 mL). The resulting mixture was treated with
ethyl acetate, and the phases were separated. The organic phase was
washed with water (2.times.), sodium bicarbonate solution
(2.times.), and sodium chloride solution (2.times.). The organic
phase was then dried over magnesium sulfate, filtered, and
evaporated to dryness in vacuo to give 202 grams of
.alpha.-(3-methoxyphenylthio)-4-methoxyacetophenone. This crude
product was crystallized from methanol and washed with hexane to
give 158 grams. Melting point 53.degree. C.
[0070] Polyphosphoric acid (930 grams) was heated to 85.degree. C.
and treated with the intermediate product from above (124 grams) in
small portions over 30 minutes. Upon complete addition, the
resulting mixture was stirred at 90.degree. C. After an additional
45 minutes, the reaction mixture was allowed to cool to room
temperature. This mixture was treated with crushed ice while the
mixture was cooled in an ice bath. The resulting mixture was
treated with water (100 mL) producing a light pink precipitate. The
precipitate was isolated by filtration, washed with water and
methanol, and dried in vacuo at 40.degree. C. to give 119 grams of
6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. This crude product
was slurried in hot methanol, filtered, and washed with cold
methanol. The resulting solid material was recrystallized from
ethyl acetate (4 liters), filtered, washed with hexane, and dried
in vacuo to 68 grams of the title compound. Melting point
187-190.5.degree. C.
Preparation 2
Ethyl 4-(2-Piperidinoethoxy)benzoate
[0071] A mixture of ethyl 4-hydroxybenzoate (8.31 g),
1-(2-chloroethyl)piperidine monohydrochloride (10.13 g), potassium
carbonate (16.59 g), and methyl ethyl ketone (6.0 mL) was heated to
80.degree. C. After one hour, the mixture was cooled to about
55.degree. C. and treated with additional
1-(2-chloroethyl)piperidine mono-hydrochloride (0.92 g). The
resulting mixture was heated to 80.degree. C. The reaction was
monitored by thin layer chromatography (TLC), using silica-gel
plates and ethyl acetate/acetonitrile/ triethylamine (10:6:1, v/v).
Additional portions of 1-(2-chloroethyl)piperidine hydrochloride
are added until the starting 4-hydroxybenzoate ester is consumed.
Upon complete reaction, the reaction mixture was treated with water
(60 mL) and allowed to cool to room temperature. The aqueous layer
was discarded and the organic layer concentrated in vacuo at
40.degree. C. and 40 mm Hg. The resulting oil was used in the next
step without further purification.
Preparation 3
4-(2-Piperidinoethoxy)benzoic Acid Hydrochloride
[0072] A solution of the compound prepared as described in
Preparation 2 (about 13.87 g) in methanol (30 mL) was treated with
5 N sodium hydroxide (15 mL), and heated to 40.degree. C. After
41/2 hours, water (40 mL) was added. The resulting mixture was
cooled to 5-10.degree. C., and concentrated hydrochloric acid (18
mL) was added slowly. The title compound crystallized during
acidification. This crystalline product was collected by
filtration, and dried in vacuo at 40-50.degree. C. to give 83%
yield of the title compound. Melting point 270-271.degree. C.
Preparation 4
4-(2-Piperidinoethoxy)benzoyl Chloride Hydrochloride
[0073] A solution of the compound prepared as described in
Preparation 3 (30.01 g) and dimethylformamide (2 mL) in methylene
chloride (500 mL) was treated with oxalyl chloride (10.5 mL) over a
30-35 minute period. After stirring for about 18 hours, the
reaction was assayed for completion by HPLC analysis. Additional
oxalyl chloride may be added to the reaction if the starting
carboxylic acid is present. Upon completion, the reaction solution
was evaporated to dryness in vacuo. The residue was dissolved in
methylene chloride (200 mL), and the resulting solution evaporated
to dryness. This dissolution/evaporation procedure was repeated to
give the title compound as a solid. The title compound may be
stored as a solid or as a 0.2 M solution in methylene chloride (500
mL).
EXAMPLE 1
6-Methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride
[0074] A mixture of the compound prepared as described in
Preparation 1 (8.46 grams) and the acid chloride prepared as
described in Preparation 3 (10.0 grams) in methylene chloride (350
mL) was cooled to about 20-25.degree. C. The cool mixture was
treated with boron trichloride (2.6 mL), and the resulting mixture
mechanically stirred. The reaction was monitored by HPLC using the
assay described above. After 85 minutes, the in situ HPLC yield
based on a 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piper-
idinoethoxy)benzoyl]benzo[b]thiophene standard was 88%.
EXAMPLE 2
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride 1,2-Dichloroethane Solvate (Crystal Form
I)
[0075] A solution of
6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethox-
y)benzoyl]benzo[b]thiophene hydrochloride (2.0 g) in
1,2-dichloroethane (20 mL) was treated with boron trichloride (2.0
mL). The resulting mixture was stirred at 35.degree. C. for about
18 hours. A mixture of ethanol and methanol (10 mL, 95:5, 3A) was
treated with the reaction mixture from above, causing the alcoholic
mixture to reflux. Upon complete addition, the resulting
crystalline slurry was stirred at 25.degree. C. After one hour, the
crystalline product was filtered, washed with cold ethanol (10 mL),
and dried at 40.degree. C. in vacuo to give 1.78 g of the title
compound. The X-ray powder diffraction pattern is identical to that
reported in Table 1.
[0076] Potency: 80.2%
[0077] 1,2-Dichloroethane: 7.5% (gas chromatography)
EXAMPLE 3
6-Hydroxy-2-(4-hydroxyphenyl)-3-(4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride Methylene Chloride Solvate (Crystal Form
IV)
[0078] A mixture of the compound prepared as described in
Preparation 1 (7.54 grams) in methylene chloride (10 mL) and the
acid chloride prepared as described in Preparation 4 (140 mL, 0.21
M solution in methylene chloride) was placed in a sealed reaction
vessel (Hastalloy Parr). The solution was cooled to 0.degree. C.
and treated with boron trichloride (7.2 mL). The resulting reaction
mixture was stirred at room temperature. After three hours, the
reaction was cooled in an ice bath for 10 minutes. A second portion
of boron trichloride (4.8 mL) was added to the reaction mixture,
and the mixture was heated to 75.degree. C. After 2.5 hours, the
reaction mixture was cooled to about 15.degree. C. The cool mixture
was treated with tetrahydrofuran (15 mL) and methanol (45 mL). This
mixture was stirred for about one hour at 18.degree. C., producing
a crystalline solid. The crystalline solid was removed by
filtration, rinsed with cold methanol (45 mL), and dried in vacuo
at 40.degree. C. for 18 hours, to give 12.5 grams of the title
compound. The X-ray powder diffraction pattern is identical to that
reported in Table 4. Melting point 207.degree. C.
[0079] Potency: 81.8%
[0080] Methylene chloride: 0.4 molar equivalents (.sup.1H NMR)
EXAMPLE 4
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride 1,2-Dichloroethane Solvate (Crystal Form
I)
[0081] A mixture of the compound prepared as described in
Preparation 2 (15 g) and dimethylformamide (0.2 mL) in
1,2-dichloroethane (250 mL) was cooled to 0.degree. C. Phosgene
(8.25 mL) was condensed in a cold, jacketed addition funnel
(-10.degree. C.), and added to the cold mixture over a period of
two minutes. The resulting mixture was heated to about 47.degree.
C. After about two and one half hours, the reaction was assayed by
HPLC for completion. Additional phosgene may be added to drive the
reaction to completion. Excess phosgene was removed by vacuum
distillation at 30-32.degree. C. and 105-110 mm Hg.
[0082] After about three to four hours, the reaction solution was
treated with the compound prepared as described in Preparation 1
(13.52 g). The resulting solution was cooled to 0.degree. C. Boron
trichloride (12.8 mL) was condensed in a graduated cylinder, and
added to the cold reaction mixture. After eight hours at 0.degree.
C., the reaction solution was treated with additional boron
trichloride (12.8 mL). The resulting solution was heated to
30.degree. C. After 15 hours, the reaction was monitored for
completion by HPLC.
[0083] A mixture of ethanol and methanol (125 mL, 95:5, 3A) was
heated to reflux, and treated with the reaction solution from above
over a 60 minute period. Upon complete addition, the
acylation/demethylation reaction flask was rinsed with additional
ethanol (30 mL). The resulting slurry was allowed to cool to room
temperature with stirring. After one hour at room temperature, the
crystalline product was filtered, washed with ethanol (75 mL), and
dried at 40.degree. C. in vacuo to give 25.9 g of the title
compound. The X-ray powder diffraction pattern is reported in Table
1. Melting point 261.degree. C.
[0084] Potency: 87.1%
[0085] 1,2-Dichloroethane: 0.55 molar equivalents (.sup.1H NMR)
EXAMPLE 5
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride Chlorobenzene Solvate (Crystal Form 3)
[0086] A solution of the compound prepared as described in
Preparation 1 (2.92 grams) and the acid chloride prepared as
described in Preparation 4 (3.45 grams) in chlorobenzene (52 mL)
was cooled to about 0.degree. C. The cold solution was treated with
boron trichloride (2.8 mL). The resulting mixture was mechanically
stirred at about 0.degree. C. After three hours, additional boron
trichloride (2.8 mL) was added, and the reaction mixture was
allowed to warm to room temperature. After about 16-20 hours, the
reaction mixture was cooled to 0.degree. C. The cold reaction was
quenched by the slow addition of ethanol (26 mL) over 30 minutes.
During the addition of the alcohol, a crystalline solid formed.
Upon complete addition of the alcohol, the resulting mixture was
stirred at room temperature for one hour. The crystalline solid was
removed by filtration, washed with cold ethanol (25 mL), and dried
in vacuo at 40.degree. C. to give 5.94 grams of the title compound
as a yellow solid. The X-ray powder diffraction pattern is
identical to that reported in Table 3. Melting point 247.degree.
C.
[0087] Potency: 78.6%
[0088] Chlorobenzene: 12.3% (HPLC)
EXAMPLE 6
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride 1,2-Dichloroethane Solvate (Crystal Form
II)
[0089] A mixture of the compound prepared as described in
Preparation 1 (2.92 g), the compound prepared as described in
Preparation 4 (3.45 g), and 1,2-dichloroethane (52 mL) was cooled
to about 0.degree. C. Boron trichloride gas was condensed into a
cold graduated cylinder (2.8 mL), and added to the cold mixture
described above. After eight hours at 0.degree. C., the reaction
mixture was treated with additional boron trichloride (2.8 mL). The
resulting solution was heated to 35.degree. C. After 16 hours, the
reaction was complete.
[0090] Methanol (30 mL) was treated with the reaction mixture from
above over a 20-minute period, causing the methanol to reflux. The
resulting slurry was stirred at 25.degree. C. After one hour, the
crystalline product was filtered, washed with cold methanol (8 mL),
and dried at 40.degree. C. in vacuo to give 5.14 g of the title
compound. The X-ray powder diffraction pattern is reported in Table
2. Melting point 225.degree. C.
[0091] Potency: 86.8%
[0092] 1,2-Dichloroethane: 6.5% (gas chromatography)
EXAMPLE 7
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]th-
iophene Hydrochloride
[0093] The compound prepared as described in Example 4 (4.0 grams)
and activated carbon (0.4 grams, Darco G-60, Aldrich Chem. Co.,
Inc., Milwaukee, Wis.) were slurried in methanol (50 mL) at room
temperature. The resulting mixture was treated with a solution of
sodium hydroxide (0.313 grams) in methanol (10 mL). After 30
minutes, the slurry was filtered through Whatman #1 filter paper
precoated with diatomaceons earth (Hyflo Super Cel.RTM., Aldrich
Chem. Co.). The filter cake was rinsed with methanol (5 mL). The
combined filtrate was treated (dropwise) with 2N hydrochloric acid
(4 mL). The resulting slurry was stirred for 30 minutes at room
temperature, then cooled to about 9.degree. C. After one hour, the
cool mixture was filtered. The filter cake was rinsed with cold
methanol (10 mL, 0.degree. C.), and dried in vacuo at 60.degree. C.
for about 18 hours to give 2.06 grams of an off-white free flowing
powder.
[0094] Potency: 96.8%
[0095] Related substances: 1.41%
EXAMPLE 8
6-Hydroxy-2-(4-hydroxyphenyl)-3-(4-(2-piperidinoethoxy)-benzoyl]benzo[b]th-
iophene Hydrochloride 1,2-Dichloroethane Solvate (Crystal Form
II)
[0096] A saturated solution of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piper-
idinoethoxy)benzoyl]benzo[b]thiophene hydrochloride was produced by
stirring a slurry of the compound prepared as described in Example
7 in methanol at room temperature overnight. This mixture was
filtered (Whatman #1 filter paper). A portion of the filtrate
(20-25 mL) was placed in a 50 mL Erlenmeyer flask. This flask was
placed within a glass jar (3.5 in..times.4 in.) containing
1,2-dichloroethane (about 10 mL). The jar was sealed and the
combination was allowed to stand at room temperature. After 24
hours, single crystals had crystallized from the methanol solution.
These crystals were filtered and dried in vacuo. The crystal
structure was determined with a Siemens R3m/V automated four-circle
diffractometer using monochromatic copper radiation
(.lambda.=1.54178 .ANG.). The crystal structure was solved using
the direct methods routine TREF of the SHELXTL PLUS program
library. Full-matrix least-squares refinement was conducted with
anisotropic temperature factors for all atoms except hydrogens,
which were included at calculated positions with isotropic
temperature factors. The final R-factor was 8.02%. The crystal data
is shown below.
8 Crystal Data Space group C2/C Unit all dimensions a = 20.720(7)
.ANG. b = 9.492(2) .ANG. c = 28.711(4) .ANG. .beta. =
96.50(2).degree. Volume 5610(2) .ANG..sup.3 Density (calc.) 1.409
mg/m.sup.3 Absorption coefficient 3.951 mm.sup.-1
[0097] The X-ray structure clearly shows that the crystalline
material is a 1,2-dichloroethane solvate having a 1:2 ratio of
molecules of 1,2-dichloroethane to molecules of
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2--
piperidinoethoxy)benzoyl]-benzo[b]-thiophene hydrochloride.
EXAMPLE 9
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]th-
iophene Hydrochloride 1,2,3-Trichloropropane Solvate (Crystal Form
II)
[0098] A mixture of the compound prepared as described in
Preparation 1 (2.70 g), the compound prepared as described in
Preparation 4 (3.60 g), and 1,2,3-trichloropropane (50 mL) was
treated with boron trichloride (2.6 mL). After three hours at
20-25.degree. C., the reaction mixture was treated with additional
boron trichloride (2.6 mL). After about 18 hours, the reaction
mixture was treated with tetrahydrofuran (15 mL) followed by the
slow addition of methanol (15 mL). After these additions were
complete, the resulting mixture was stirred at room temperature.
After one hour, the crystalline solid was collected by filtration,
washed with cold methanol (10 mL), and dried at 50.degree. C. in
vacuo to give 4.13 g of the title compound. The X-ray powder
diffraction pattern was identical to that reported in Table 2.
Melting point 236.degree. C.
[0099] Potency: 78.9%
[0100] 1,2,3-Trichloropropane: 0.5 molar equivalents (.sup.1H
NMR)
EXAMPLE 10
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]th-
iophene Hydrochloride Chloroform Solvate (Crystal Form IV)
[0101] The title compound (4.42 g) was prepared using the procedure
described in Example 9, except the reaction solvent was chloroform
(50 mL). The X-ray powder diffraction pattern was identical to that
reported in Table 4. Melting point 258.degree. C.
[0102] Potency: 80.4%
[0103] Chloroform: 0.42 molar equivalents (.sup.1H NMR)
EXAMPLE 11
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]th-
iophene Hydrochloride
[0104] A solution of sodium hydroxide (0.313 g) in methanol (10 mL)
was diluted with additional methanol (50 mL). This solution was
treated with the compound prepared as described in Example 6 (4.0
g). After 45 minutes at room temperature, the solution was filtered
(Whatman #1 filter paper) and the filter paper rinsed with methanol
(3 mL). The filtrate was treated with 2 N hydrochloric acid (4 mL),
producing a crystalline slurry. After 11/2 hours, this crystalline
product was filtered, washed with methanol (5 mL), and dried at
45-50.degree. C. in vacuo to give 2.103 g of the title compound.
The X-ray powder diffraction pattern was identical to that reported
in Table 5. Potency: 96.5%
EXAMPLE 12
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]th-
iophene Hydrochloride
[0105] A solution of sodium hydroxide (0.313 g) in methanol (10 mL)
was diluted with additional methanol (40 mL) and water (10 mL).
This solution was treated with the compound prepared as described
in Example 5 (4.0 g). The resulting solution was extracted with
hexane (2.times.50 mL) to remove the chlorobenzene. The methanolic
phase was treated with 2 N hydrochloric acid (4 mL), producing a
crystalline slurry. After one hour, the crystalline product was
filtered, washed with methanol (5 mL), and dried at 60.degree. in
vacuo to give 2.23 g of the title compound. The X-ray powder
diffraction pattern was identical to that reported in Table 5.
[0106] Often, compounds which have poor solubility profiles can
have their bioavailability enhanced by increasing the surface area
of the formulated particles. The surface area generally increases
per unit volume as the particle size decreases. Various techniques
for grinding or milling a drug substance are well known in the art
and each of these techniques are commonly used to decrease particle
size and increase the surface area of the particle. It would seem
reasonable that the best way to deal with any slightly soluble
compound would be to mill it to the smallest size possible;
however, this is not always practical or desirable. The milling
process has an economic cost not only it the direct cost of the
process, itself, but also with other associated factors. For
example, very finely divided material presents difficulties and
cost in capsule filling or tablet preparation, because the material
will not flow, but becomes caked in finishing machinery. Such
finishing difficulties generate non-homogeneity in the final
product, which is not acceptable for a drug substance.
Additionally, the milling process, physically generates heat and
pressure on the material, such conditions lead to chemical
degradation of the compound, thus such milling techniques are
usually kept to a minimum.
[0107] Therefore, there is always dynamic between the properties
which yield the maximum bioavailability (particle surface area) and
the practical limits of manufacture. The point of compromise which
marks this "best solution" is unique to each situation and unique
as to its determination.
[0108] Methods for determining the size of particles are known in
the art. The following is a description of one method, but is not
intended to be limiting. For example, the general method of U.S.
Pat. No. 4,605,517 could be employed.
[0109] In preparing the particulate compound of the invention a
compound of formula I, in its raw state, is first characterized for
size using an instrument adapted to measure equivalent spherical
volume diameter, that is to say a Horiba LA900 Laser Scattering
Particle Size Distribution Analyzer or equivalent instrument.
Typically a representative sample of a compound of formula I would
be expected to comprise in its raw state particles having a mean
equivalent spherical volume diameter of about 110-200 microns and
with a broad size distribution.
[0110] After being characterized for size in its raw state, the raw
compound is then milled, preferably using a pin mill under suitable
conditions of mill rotation rate and feed rate, to bring the
particle size value within the above mentioned limits according to
the invention. The efficiency of the milling is checked by sampling
using a Horiba LA900 Laser Scattering Particle Size Distribution
Analyzer and the final particle size is checked in a similar
manner. If the first pass through the mill does not produce the
required size distribution, then one or more further passes are
effected.
[0111] The compound of formula I in its particulate form within the
above mentioned limits according to the invention may then be mixed
with an excipient or carrier as necessary and, for example,
compressed into tablets. Thus, for example, the particulate
compound may be mixed with anhydrous lactose, lactose monohydrate,
a portion of crospovidone and granulated in an aqueous dispersion
of povidone and polysorbate 80. After drying and milling into
granules the material can be terminally blended with magnesium
stearate and remaining crospovidone to be compressed into
tablets.
[0112] Because the particles in the raw state as well as after
milling or other particle size reduction techniques are irregular
in shape, it is necessary to characterize them not by measurement
of an actual size such as thickness or length, but by measurement
of a property of the particles which is related to the sample
property possessed by a theoretical spherical particle. The
particles are thus allocated an "equivalent spherical
diameter".
[0113] The values found from characterizing a large number of
"unknown" particles can be plotted frequency vs. diameter or in
other methods weight vs. diameter, usually adopting percentage
undersize values for frequency or weight. This gives a
characteristic curve representing size distribution of the sample,
i.e., cumulative percentage undersize distribution curve. Values
from this can be read off directly or plotted on log-probability
paper to give an appropriate straight line. The mean equivalent
spherical volume diameter is the 50% undersize value.
[0114] The mean equivalent spherical volume diameter found is thus
a statistical representation of a theoretical particle having the
same property as the "unknown" particle.
[0115] As indicated above the mean equivalent sphere volume
diameter of the particles of the milled compound of formula I may
be evaluated using a Horiba LA900 Laser Scattering Particle Size
Distribution Analyzer. Using such an instrument values for a
suspension of the particle of unknown size may be obtained and the
instrument may be monitored using a control sample having particles
within the size range expected based on statistical analysis of the
sample. Multiple runs of the control sample established the
standard deviation in measurement of the mean to be 1.3
microns.
[0116] Following is a description by way of example of the
preparation of compositions in accordance with the invention. In
all of the Examples the compound was prepared from raw form using a
pin mill and consisted of particles having a mean equivalent
spherical volume diameter of between about 5 and 20 microns, at
least 90% of the particles having a particle size of less than
about 35 microns.
[0117] The particle size of the reduced raloxifene HCl was measured
as follows. The laser scattering particle size distribution
analysis was effected on a small sample of the reduced material
which is suspended in approximately 180 ml of dispersant solution.
Sample is added to the dispersant until an acceptable level of
laser light obscuration achieved at which point the particle size
distribution is measured. Prior to the sample suspension the
dispersant solution was prepared by adding 20 drops of Coulter 1A
dispersant to a saturated aqueous solution of raloxifene HCl. The
dispersant solution was filtered through a 0.2 micron microporous
membrane filter to provide the necessary particle-free suspending
dispersant.
[0118] Within five minutes of the preparation of the dispersion,
triplicate particle size measurements were performed. Triplicate
measurements are effected as a minimum check a) to produce more
reliable measurements and b) to check the equivalent sampling of
the suspended material has been reproducible i.e., the suspension
has not settled.
[0119] The results were automatically recorded and displayed
graphically to give a frequency percentage vs. undersize and a
cumulative percentage vs. undersize characteristic curves for the
sample. From this, the mean equivalent spherical volume diameter
value was derived (50% undersize value) together with the standard
deviation of the distribution calculated as above.
[0120] Several physical properties of raloxifene hydrochloride have
been investigated during the progression of the compound through
development. These include particle size, surface area, and powder
bulk density.
[0121] A primary determinant in the potential influence of such
properties on drug product performance is the aqueous solubility of
the drug substance. Raloxifene hydrochloride has a water solubility
of approximately 0.3 mg/mL at 25.degree. C. and significantly lower
values in Simulated Gastric Fluid, USP (0.003 mg/mL) and Simulated
Intestinal Fluid, USP (0.002 mg/mL) at 37.degree. C. The aqueous
value falls into the USP classification of "very slightly soluble",
while according to the recent SUPAC guidance ("Industry Guidance
Immediate Release Solid Oral Dosage Forms Pre- and Post-Approval
Changes: Chemistry, Manufacturing and Controls, In Vitro
Dissolution Testing, and In Vivo Bioequivalence Documentation",
Prepared by the Immediate Release Scale-Up and Post Approval Change
(SUPAC), Expert Working Group of the Chemistry Manufacturing
Controls Coordinating Committee (CMC CC) of the Center for Drug
Evaluation and Research at the FDA) on immediate release solid oral
dosage forms, the compound has low solubility with a dose
solubility volume of greater than 250 mL. Given the low solubility,
the rate at which the dosage form dissolves in the gastrointestinal
tract can potentially impact the rate and extent of absorption of
the active compound. Two related physical properties of the bulk
drug which can alter the dissolution rate of the dosage form are
particle size and surface area. The impact of surface area which is
a function of particle size is illustrated in the Noyes-Whitney
equation given below.
dC/dt=(D/h)*(S)*(Cs-C)
[0122] Here, C is the concentration of drug at time t, D is the
diffusion coefficient of drug in the medium, h is the thickness of
diffusion layer, Cs is the saturation solubility of drug in the
diffusion layer and S is the effective surface area of the drug
particles. To ascertain the effect of particle size/surface area of
raloxifene HCl on in vitro dissolution, lots with varying particle
size distributions were obtained via recrystallization and further
modified through various milling technologies. The following table
contains pertinent data on four bulk lots produced in this effort,
which includes particle size data generated utilizing laser light
diffraction, and surface area data collected by nirogen adsorption,
and analyzed through the BET (Brunauer, Emmett, Teller)
equation.
9TABLE 6 Bulk Milling Surface Area Mean Particle 90% less Lot #
Technology m.sup.2/gm Size (.mu.m) than (.mu.m) #1 Micronized 6.09
3.9 6.8 #2 Recrystallized 2.28 8.4 13.9 #3 Ball Milled 2.10 23.3
55.3 #3 Slurry Milled 0.45 48.1 89
[0123] These four bulk lots were handfilled into capsules to
provide 60.0 mg of raloxifene hydrochloride and submitted for
dissolution testing in a 0.1% aqueous polysorbate 80 medium
utilizing USP Apparatus II, with a paddle speed of 50 rpm. Data was
collected at 10, 20, 30 and 45 minutes to produce a dissolution
profile.
10 TABLE 7 Lot #1 (micronized) Time (min.) Lot #2 (Control)
Dissolved % Dissolved Time (min.) % 10 51 10 41 20 68 20 60 30 78
30 68 45 88 45 74 Lot #3 (Ball-milled) Time (min.) Lot #4 (Slurry
Milled) Dissolved % Dissolved Time (min.) % 10 31 10 15 20 45 20 27
30 54 30 35 45 64 45 49
[0124] It was observed that a range of dissolution profiles
resulted from the various particle size distributions of the bulk
drug substance, with values ranging from 25% to approximately 80%
dissolved at 30 minutes. In an attempt to evaluate these
differences upon in vivo absorption, a study was conducted in
Fischer 344 rats. In the study, rats were dosed with the same four
bulk raloxifene lots in their diet (0.4% w/w) for seven days.
Plasma concentrations of unconjugated raloxifene were quantitated
by HPLC for the four bulk lots. The following table shows the
excellent linear correlations obtained between the percent
raloxifene hydrochloride dissolved at 10 minutes or 30 minutes in
the in vitro dissolution test to the average area under-the curve
(AUC, ng-h/mL) values obtained in rats for each of the bulk drug
lots.
11TABLE 8 % Dissolved at % Dissolved at Lot 10 Minutes 30 Minutes
AUC (ng - h/mL) #1 - Micronized 50 78 10056 #2 - As 41 68 8037
Recrystallized #3 - Ball Milled 31 55 5743 #4 - Slurry Milled 15 35
3329
[0125] This in vitro to in-vivo correlation supports the
discriminating ability of the dissolution method, as well as
emphasizing the need for a control strategy for either the particle
size distribution or surface area of the bulk drug substance.
Further evaluation of this data indicated that the particle size
data correlates better to the differences noted in the dissolution
data and in vivo absorption. This can be explained based upon the
Noyes-Whitney equation, which relates dissolution to the effective
surface area. It is postulated that the surface area as measured by
nitrogen adsorption for the various types of milled raloxifene does
not predict the effective surface area accessible to the
dissolution medium. This is demonstrated when comparing the
recrystallized (control) lot (lot #2) and ball milled lot (lot #3).
While they have very similar surface area values, 2.28 and 2.10
m.sup.2/gm respectively, the control lot has a finer mean particle
size, 8.4 microns compared to 23.3 microns for the ball milled lot.
SEM photomicrographs of the ball milled particles show very
irregular surfaces with numerous cracks and fissures which would
result in increased surface area as measured by nitrogen
adsorption, but may not provide surface area accessible to the
dissolution medium, resulting in a lower effective surface area.
This reasoning can explain the better correlation of the
differences in particle size to the differences in in vitro
dissolution and in vivo absorption, compared to the similarity of
the surface areas for the two lots. Based upon these findings, the
decision was made to pursue particle size distribution as a control
parameter to ensure consistent performance of the drug product with
regards to release of the drug component.
[0126] To further investigate the impact of particle size of
raloxifene HCl on drug product performance as measured by in vitro
dissolution and in vivo absorption, a single dose, plasma
concentration versus time study was designed in cynomolgus monkeys.
The study compared absorption from two bulk lots of raloxifene
which possessed mean particle sizes of 48.1 and 9.0 microns. The
lots were formulated into granulation matrices representative of
granulations being compacted into tablets for human use. In
addition, the bulk lot with the 9.0 mean particle size was
generated through pin milling technology which represents the
desired commercial milling route. The table below summarizes the
particle size data of the two bulk lots.
12TABLE 9 Bulk Lot/ Mean Granulation Milling 10% Less 50% Less 90%
Less Particle Lot # Technology Than .mu.m Than .mu.m Than .mu.m
Size Lot 5A Slurry 11.4 44.1 90 48.1 Lot 5B Pin 3.2 8.6 15.1
9.0
[0127] For the purposes of producing a dissolution profile, the
granulations were handfilled into capsules to provide the
equivalent of 60 mg of raloxifene hydrochloride. The dissolution
data produced in 0.1% aqueous Tween medium, utilizing the paddle
method at 50 rpm, are shown below.
13 TABLE 10 Time (min.) % Dissolved Lot 5A (slurry milled) 10 33 20
55 30 65 45 74 Lot 5B (pin milled) 10 63 20 91 30 95 45 97
[0128] These differences in particle size distribution again
produced significant differences in the dissolution profile in the
aqueous 0.1% polysorbate 80 dissolution medium. In the study
monkeys received each formulation according to a crossover study
design and incorporating a replicate period to allow for
intrasubject variability. The following Table 11 shows the mean
average plasma concentrations of total raloxifene after the
administration of a 25 mg/kg oral dose to the monkeys.
14TABLE 11 Lot 5A (slurry milled) ng Total Raloxifene/ Time (hrs.)
ml plasma 1.4 78 3.6 67 8.2 81 12.1 60 24.3 45 30 32 36.4 22 48.6
14 Lot 5B (pin milled) ng Raloxifene/ Time (hrs.) ml plasma 1.4 108
3.6 84 8.2 121 12.1 95 24.3 70 30 51 36.4 34 48.6 23
[0129] As seen from the plasma concentration versus time profiles
given in Table 11, the formulation with the finer particle size
bulk drug substance provided higher plasma concentrations of total
raloxifene at all of the timepoints sampled. The superior
absorption from the formulation with the finer particle size is
reflected in both the rate and extent of absorption as illustrated
in the following summary of pharmacokinetic parameters from the
study.
15 Lot Number Cmax (ng/mL) AUC (ng - h/mL) 5A (9.0 microns) 131
3608 5B (48.1 microns) 96 2357
[0130] The differences shown were found to be significant upon
statistical analysis (AUC, p<0.005 and Cmax, p<0.02). This
data is further evidence of the critical nature of the particle
size distribution on its impact on bioavailability. The study also
confirms the discriminating ability of the in vitro dissolution
method and its relationship to in vivo absorption. Once again, the
differences observed in the in vitro dissolution profiles
translated into in vivo absorption differences.
[0131] Based upon the above work and physical property data
generated, a particle size specification was established. The
invention provides that the mean particle size, as determined by
laser light diffraction, should be less than about 25 microns. In
addition, 90% of the particles by volume should be under 50
microns, which allows for characterization of the distribution.
Preferably, the size is between about 5 and about 20 microns, and
90% of the particles have a size of less than about 35 microns. To
justify this range, bulk lots were produced by pin milling and
samples of the available extremes were manufactured into formulated
tablets and in vitro dissolution testing. In one study, six bulk
lots of raloxifene hydrochloride (ca. 1 kg) were received and
manufactured into formulated 60 mg raloxifene HCl tablets
representative of the tablets being utilized in Phase III clinical
testing. The particle size data for the lots utilized is summarized
in the following Table 12.
16TABLE 12 (all particle size in microns) 10% Less 50% Less 90%
Less Lot # Than Than Than Mean 6 2 6 12 6 7 3 8 21 10 8 3 11 31 15
9 3 12 30 14 10 2 5 10 6 11 3 9 23 11
[0132] The dissolution profile in 0.1% aqueous polysorbate 80 for
all of these 6 bulk lots formulated into tablets are comparable in
all cases. In addition, all lots displayed a relatively fast
dissolution profile, with values greater than 90% dissolved at 20
minutes. To statistically assess the dissolution as a function of
particle size, JMP Statistical and Graphics Guide software (SAS
Institute, Inc., Cary, N.C.) was utilized and a plot was generated
where the percent dissolved at 20 minutes was plotted as a function
of the average particle size of each lot. Table 13 sets out the
data.
17TABLE 13 % Dissolved - Raloxifene Hydrochloride from Core Tablets
Time Lot Number (Min) 6 7 8 9 10 11 10 89.2 88.1 81.1 74.5 84.1
80.5 20 92.3 92.6 95.4 91.3 96.0 93.7 30 93.2 93.9 97.0 93.3 96.3
94.0 45 93.0 94.1 98.4 93.9 96.1 94.6
[0133] The scatter observed in the plot, along with the high
p-value (0.81) support the conclusion of a non-significant effect
of particle size on dissolution over this range of particle sizes.
Similar analyses were performed at the other timepoint, 10, 30 and
45 minutes, with calculated p-values of 0.11, 0.76, and 0.40
respectively. These high p-values along with the observation of
both negative and positive slopes at the various timepoints again
support the appropriateness of the range for the particle size.
[0134] Another similar study was performed with 7 different
particle size distributions of bulk drug, with each again being
formulated into 60 mg tablets. The particle size data for these
lots is summarized in Table 14.
18TABLE 14 (all particle size in microns) 10% Less 50% Less 90%
Less Lot Than Than Than Mean 70B 3.3 14.5 39.3 18.8 70E 2.8 10.5
26.3 13.0 70F 3.4 16.0 50.2 22.9 71B 3.1 12.9 38.9 17.8 71D 2.8
10.1 25.6 12.6 71G 3.3 14.6 42.1 19.6 71H 2.9 11.1 28.2 13.7
[0135] The dissolution data collected in 0.1% aqueous polysorbate
80 for these seven bulk lots formulated into tablets is given in
the following table.
19TABLE 15 % Dissolved - Raloxifene Hydrochloride Time Lot Number
(Min) 70B 70E 70F 71B 71D 71G 71H 10 76 81 73 76 75 61 68 20 94 96
91 93 88 85 91 30 98 99 95 98 91 88 95 45 99 99 97 99 97 97 98
[0136] As with the previous set of particle size distributions, the
comparable dissolution profiles obtained with these particle size
distributions support the ranges for particle size given in this
invention.
[0137] Given the relationship shown between in vitro dissolution
and in vivo absorption, it follows that the particle size
distribution range claimed in this patent will provide surprisingly
consistent in vivo absorption/bioavailability characteristics.
[0138] In addition to the role of particle size in vitro
dissolution and in vivo absorption, another important aspect is its
role on the various unit operations of the drug product
manufacturing process. While the particle size specification
ensures consistent delivery of the drug molecule to the sites of
absorption in the gastrointestinal tract, it also allows for better
control during the wet granulation step of the tablet manufacturing
process. By controlling the particle size, the variations in
quantity of water needed to elicit the appropriate progression of
the granulation power consumption curve is reduced. By maintaining
the particle size within the previous mentioned constraints,
established quantities of water can be dictated in the
manufacturing ticket for routine lot manufacture. The granulation
step is common to many tablet and capsule manufacturing operations
and is typically driven by the addition of water to bring about the
desired endpoint of the granulation. A downstream unit operation
dependent upon the granulation endpoint is the milling of the dried
granulation and the resulting particle size distribution obtained
on the granulation. It has been discovered that the incoming
particle size of the active ingredient also effects the ultimate
particle size distribution of the dry milled agglomerates formed
during granulations. For a fixed water quantity, a coarser
distribution will result in a finer size distribution of the dry
milled agglomerates. Too fine a granulation distribution can lead
to poor granulation flow and poor control of individual tablet
weight during the compression step. Thus the narrow particle size
constraints previously mentioned have also resulted in making the
process more amenable to automation by reducing the variations in
water required during the granulation step and producing dry milled
granules of the appropriate distribution to prevent the rejection
of tablets during compression due to unacceptable tablet
weight.
[0139] The present invention also provides methods of use in
inhibiting compounds of Formula I. Such uses include inhibiting
osteoporosis, treating or prevent breast cancer, inhibiting uterine
fibrosis, inhibiting endometriosis, and lowering serum
cholesterol.
[0140] As used herein, the term "effective amount" means an amount
of compound of formula I which is capable of alleviating the
symptoms of the various pathological conditions herein described.
The specific dose of a compound administered according to this
invention will, of course, be determined by the particular
circumstances surrounding the case including, for example, the
compound administered, the route of administration, the state of
being of the patient, and the pathological condition being treated.
A typical daily dose will contain a nontoxic dosage level of from
about 10.0 mg to about 1000 mg/day of a compound of the present
invention. Preferred daily doses generally will be from about 50 mg
to about 150 mg/day.
[0141] Besides the hydrochloride salt, the compounds of this
invention form pharmaceutically acceptable acid and base addition
salts with a wide variety of organic and inorganic acids and bases
and include the physiologically acceptable salts which are often
used in pharmaceutical chemistry. Such salts are also part of this
invention. Typical inorganic acids used to form such salts include
hydrobromic, hydroiodic, nitric, sulfuric, phosphoric,
hypophosphoric and the like. Salts derived from organic acids, such
as aliphatic mono and dicarboxylic acids, phenyl substituted
alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids,
aromatic acids, aliphatic and aromatic sulfonic acids, may also be
used. Such pharmaceutically acceptable salts thus include acetate,
phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide,
isobutyrate, phenylbutyrate, .beta.-hydroxybutyrate,
butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride,
cinnamate, citrate, formate, fumarate, glycollate, heptanoate,
hippurate, lactate, malate, maleate, hydroxymaleate, malonate,
mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate,
phthalate, teraphthalate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,
propionate, phenylpropionate, salicylate, sebacate, succinate,
suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
sulfonate, benzene-sulfonate, p-bromophenylsulfonate,
chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,
methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,
p-toluenesulfonate, xylenesulfonate, tartarate, and the like. Of
course, the preferred salt is the hydrochloride salt.
[0142] The pharmaceutically acceptable acid addition salts are
typically formed by reacting a compound of formula I with an
equimolar or excess amount of acid. The reactants are generally
combined in a mutual solvent such as diethyl ether or benzene. The
salt normally precipitates out of solution within about one hour to
10 days and can be isolated by filtration or the solvent can be
stripped off by conventional means.
[0143] Bases commonly used for formation of salts include ammonium
hydroxide and alkali and alkaline earth metal hydroxides,
carbonates, as well as aliphatic and primary, secondary and
tertiary amines, aliphatic diamines. Bases especially useful in the
preparation of addition salts include ammonium hydroxide, potassium
carbonate, methylamine, diethylamine, ethylene diamine and
cyclohexylamine.
[0144] The compounds of this invention can be administered by a
variety of routes including oral, rectal, transdermal,
subucutaneus, intravenous, intramuscular, and intranasal. These
compounds preferably are formulated prior to administration, the
selection of which will be decided by the attending physician.
Thus, another aspect of the present invention is a pharmaceutical
composition comprising an-effective amount of a compound of Formula
I, or a pharmaceutically acceptable salt thereof, optionally
containing an effective amount of estrogen or progestin, and a
pharmaceutically acceptable carrier, diluent, or excipient.
[0145] The total active ingredients in such formulations comprises
from 0.1% to 99.9% by weight of the formulation. By
"pharmaceutically acceptable" it is meant the carrier, diluent,
excipients and salt must be compatible with the other ingredients
of the formulation, and not deleterious to the recipient
thereof.
[0146] Pharmaceutical formulations of the present invention can be
prepared by procedures known in the art using well known and
readily available ingredients. For example, the compounds of
formula I, with or without an estrogen or progestin compound, can
be formulated with common excipients, diluents, or carriers, and
formed into tablets, capsules, suspensions, powders, and the like.
Examples of excipients, diluents, and carriers that are suitable
for such formulations include the following: fillers and extenders
such as starch, sugars, mannitol, and silicic derivatives; binding
agents such as carboxymethyl cellulose and other cellulose
derivatives, alginates, gelatin, and polyvinyl-pyrrolidone;
moisturizing agents such as glycerol; disintegrating agents such as
calcium carbonate, sodium bicarbonate and cross-linked povidone
(cross povidone); agents for retarding dissolution such as
paraffin; resorption accelerators such as quaternary ammonium
compounds; surface active agents such as cetyl alcohol, polysorbate
80, glycerol monostearate; adsorptive carriers such as kaolin and
bentonite; and lubricants such as talc, calcium and magnesium
stearate, and solid polyethyl glycols.
[0147] The compounds also can be formulated as elixirs or solutions
for convenient oral administration or as solutions appropriate for
parenteral administration, for example, by intramuscular,
subcutaneous or intravenous routes. Additionally, the compounds are
well suited to formulation as sustained release dosage forms and
the like. The formulations can be so constituted that they release
the active ingredient only or preferably in a particular
physiological location, possibly over a period of time. The
coatings, envelopes, and protective matrices may be made, for
example, from polymeric substances or waxes.
[0148] Compounds of formula I, alone or in combination with another
pharmaceutical agent, generally will be administered in a
convenient formulation. The following formulation examples only are
illustrative and are not intended to limit the scope of the present
invention.
Formulations
[0149] In the formulations which follow, "Raloxifene" means a
compound of formula I, including salts and solvates thereof.
[0150] Formulation 1: Gelatin Capsules Hard gelatin capsules are
prepared using the following:
20 Ingredient Quantity (mg/capsule) Raloxifene 10.0-1000 Starch, NF
0-650 Starch flowable powder 0-650 Silicone fluid 350 centistokes
0-15
[0151] The formulation above may be changed in compliance with the
reasonable variations provided.
[0152] A tablet formulation is prepared using the ingredients
below:
[0153] Formulation 2: Tablets
21 Ingredient Quantity (mg/tablet) Raloxifene 2.5-1000 Cellulose,
microcrystalline .sup. 200-650.sup. Silicon dioxide, fumed 10-650
Stearic acid 5-15
[0154] The components are blended and compressed to form
tablets.
[0155] Alternatively, tablets each containing 2.5-1000 mg of
Raloxifene are made up as follows:
[0156] Formulation 3: Tablets
22 Ingredient Quantity (mg/tablet) Raloxifene 25-1000 Starch 45
Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as 10%
solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium
stearate 0.5 Talc 1
[0157] Raloxifene, starch, and cellulose are passed through a No.
45 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinylpyrrolidone is mixed with the resultant powders which are
then passed through a No. 14 mesh U.S. sieve. The granules so
produced are dried at. 50.degree.-60.degree. C. and passed through
a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 60
U.S. sieve, are then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets.
[0158] Suspensions each containing 0.1-1000 mg of medicament per 5
ml dose are made as follows:
[0159] Formulation 4: Suspensions
23 Ingredient Quantity (mg/5 ml) Raloxifene 0.1-1000 mg Sodium
carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution
0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL
[0160] The medicament is passed through a No. 45 mesh U.S. sieve
and mixed with the sodium carboxymethyl cellulose and syrup to form
a smooth paste. The benzoic acid solution, flavor, and color are
diluted with some of the water and added, with stirring. Sufficient
water is then added to produce the required volume.
[0161] An aerosol solution is prepared containing the following
ingredients:
[0162] Formulation 5: Aerosol
24 Quantity (% by Ingredient weight) Raloxifene 0.25 Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 70.00
[0163] Raloxifene is mixed with ethanol and the mixture added to a
portion of the propellant 22, cooled to 30.degree. C., and
transferred to a filling device. The required amount is then fed to
a stainless steel container and diluted with the remaining
propellant. The valve units are then fitted to the container.
[0164] Suppositories are prepared as follows:
[0165] Formulation 6: Suppositories
25 Quantity Ingredient (mg/suppository) Raloxifene 250 Saturated
fatty acid glycerides 2,000
[0166] Raloxifene is passed through a No. 60 mesh U.S. sieve and
suspended in the saturated fatty acid glycerides previously melted
using the minimal necessary heat. The mixture is then poured into a
suppository mold of nominal 2 g capacity and allowed to cool.
[0167] An intravenous formulation is prepared as follows:
[0168] Formulation 7: Intravenous Solution
26 Ingredient Quantity Raloxifene 50 mg Isotonic saline 1,000
mL
[0169] The solution of Raloxifene is intravenously administered to
a patient at a rate of about 1 mL per minute.
[0170] Formulation 8: Combination Capsule I
27 Ingredient Quantity (mg/capsule) Raloxifene 50 Premarin 1 Avicel
pH 101 50 Starch 1500 117.50 Silicon Oil 2 Tween 80 0.50 Cab-O-Sil
0.25
[0171] Formulation 9: Combination Capsule II
28 Ingredient Quantity (mg/capsule) Raloxifene 50 Norethylnodrel 5
Avicel pH 101 82.50 Starch 1500 90 Silicon Oil 2 Tween 80 0.50
[0172] Formulation 10: Combination Tablet
29 Ingredient Quantity (mg/capsule) Raloxifene 50 Premarin 1 Corn
Starch NF 50 Povidone, K29-32 6 Avicel pH 101 41.50 Avicel pH 102
136.50 Crospovidone XL10 2.50 Magnesium Stearate 0.50 Cab-O-Sil
0.50
[0173] Formulation 11:
30 Ingredient Quantity (mg/capsule) Raloxifene HCl 60-150
Polyvinylpyrrolidone 15.75 Polysorbate 80 5.25 Lactose Anhydrous
264.62 Cross-linked 31.5 polyvinylpyrrolidone Stearic Acid 5.25
Magnesium Stearate 2.63
[0174] The mixture of raloxifene HCl, lactose, and a portion of the
cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of the polyvinylpyrrolidone and polysorbate 80. The
granules are dried, reduced to a suitable size, and mixed with
stearic acid, magnesium stearate, and remaining cross-linked
polyvinylpyrrolidone. The mixture is compressed into individual
tablets.
[0175] Formulation 12:
31 Ingredient Quantity (mg/capsule) Raloxifene HCl 60-150
Polyvinylpyrrolidone 15.75 Polysorbate 80 5.75 Lactose Anhydrous
132.06 Dextrose 132.06 Cross-linked 31.5 polyvinylpyrrolidone
Stearic Acid 5.25 Magnesium Stearate 2.63
[0176] The mixture of raloxifene HCl, lactose anhydrous, dextrose,
and a portion of the cross-linked polyvinylpyrrolidone is
granulated with an alcoholic solution of polyvinylpyrrolidone and
polysorbate 80. The granules are dried, reduced to a suitable size,
and mixed with magnesium stearate, stearic acid, and remaining
cross-linked polyvinylpyrrolidone. The mixture is compressed into
individual tablets.
[0177] Formulation 13:
32 Ingredient Quantity (mg/capsule) Raloxifene HCl 60-150
Hydroxypropyl Cellulose 16.00 Sodium Laurylsulfate 10.00 Dextrose
154.00 Cross-linked sodium 16.00 carboxymethylcellulose Magnesium
Stearate 4.00
[0178] The mixture of raloxifene HCl, dextrose, and cross-linked
sodium carboxymethylcellulose is granulated with an aqueous
solution of hydroxypropyl cellulose and sodium laurylsulfate. The
granules are dried, reduced to a suitable size, and mixed with
magnesium stearate. The mixture is compressed into individual
tablets.
[0179] Formulation 14:
33 Ingredient Quantity (mg/capsule) Raloxifene HCl 30.00 Lactose
Anhydrous 144.00 Lactose, Hydrous spray 36.00 Dried
Polyvinylpyrrolidone 12.00 Polysorbate 80 2.40 Cross-linked 14.40
polyvinylpyrrolidone Magnesium Stearate 1.20
[0180] The mixture of raloxifene HCl, lactose anhydrous,
spray-dried hydrous lactose, and a portion of the cross-linked
polyvinylpyrrolidone is granulated with an aqueous solution of
polyvinylpyrrolidone and polysorbate 80. The granules are dried,
reduced to a suitable size, and mixed with magnesium stearate and
remaining cross-linked polyvinylpyrrolidone. The mixture is
compressed into individual tablets yielding a tablet weight of 240
mg.
[0181] Formulation 15:
34 Ingredient Quantity (mg/capsule) Raloxifene HCl 30.00 Lactose
Anhydrous 160.00 Hydroxypropyl Cellulose 11.00 Poloxamer 7.00
Cross-linked sodium 23.00 carboxymethylcellulose Stearic Acid 2.00
Magnesium Stearate 4.00
[0182] The mixture of raloxifene HCl, anhydrous lactose, and
cross-linked sodium carboxymethylcellulose is granulated with an
aqueous solution of poloxamer and hydroxypropyl cellulose. The
granules are dried, reduced to a suitable size, and mixed with
stearic acid and magnesium stearate. The mixture is then compressed
into individual tablets yielding a tablet weight of 240 mg.
[0183] Formulation 16:
35 Ingredient Quantity (mg/capsule) Raloxifene HCl 30.00 Lactose
89.00 Dextrose 89.00 Hydroxypropyl 10.00 methylcellulose Sodium
Laurylsulfate 5.00 Cross-linked sodium 12.00 polyvinylpyrrolidone
Stearic Acid 5.00
[0184] The mixture of raloxifene HCl, lactose, dextrose, and
cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of hydroxypropyl methylcellulose and sodium laurylsulfate.
The granules are dried, reduced to a suitable size, and mixed with
the stearic acid. The mixture is then compressed into individual
tablets yielding a tablet weight of 240 mg.
[0185] Formulation 17:
36 Ingredient Quantity (mg/capsule) Raloxifene HCl 60.00 Lactose
Anhydrous 156.00 Polyvinylpyrrolidone 7.20 Polysorbate 80 7.20
Cross-linked sodium 7.20 polyvinylpyrrolidone Magnesium Stearate
2.40
[0186] The mixture of raloxifene HCl, lactose anhydrous, and
cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of polyvinylpyrrolidone and polysorbate 80. The granules
are dried, reduced to a suitable size, and mixed with magnesium
stearate. The mixture is then compressed into individual tablets
yielding a tablet weight of 240 mg.
[0187] Formulation 18:
37 Ingredient Quantity (mg/capsule) Raloxifene HCl 60.00 Lactose
Anhydrous 120.00 Lactose, hydrous spray-dried 30.00
Polyvinylpyrrolidone 12.00 Polysorbate 80 2.40 Cross-linked sodium
14.40 polyvinylpyrrolidone Magnesium Stearate 1.20
[0188] The mixture of raloxifene HCl, lactose anhydrous,
spray-dried hydrous lactose, and a portion of the cross-linked
polyvinylpyrrolidone is granulated with an aqueous solution of
polyvinylpyrrolidone and polysorbate 80. The granules are dried,
reduced to a suitable size, and mixed with magnesium stearate and
remaining cross-linked polyvinylpyrrolidone. The mixture is then
compressed into individual tablets yielding a tablet weight of 240
mg.
[0189] Formulation 19:
38 Ingredient Quantity (mg/capsule) Raloxifene HCl 60.00 Mannitol
77.00 Dextrose 73.00 Hydroxypropyl 7.00 methylcellulose Polysorbate
80 4.00 Sodium Starch Glycolate 14.00 Stearic Acid 4.00 Magnesium
Stearate 1.00
[0190] The mixture of raloxifene HCl, mannitol, dextrose and sodium
starch glycolate is granulated with an aqueous solution of
polysorbate 80 and hydroxypropyl methylcellulose. The granules are
dried, reduced to a suitable size, and mixed with stearic acid and
magnesium stearate. The mixture is then compressed into individual
tablets yielding a tablet weight of 240 mg.
[0191] Formulation 20:
39 Ingredient Quantity (mg/capsule) Raloxifene HCl 150.00 Lactose
Anhydrous 41.00 Lactose, hydrous spray-dried 10.25
Polyvinylpyrrolidone 11.50 Polysorbate 80 2.30 Cross-linked sodium
13.80 polyvinylpyrrolidone Magnesium Stearate 1.15
[0192] The mixture of raloxifene HCl, anhydrous lactose, hydrous
spray-dried lactose, and a portion of the cross-linked
polyvinylpyrrolidone is granulated with an aqueous solution of
polyvinylpyrrolidone and polysorbate 80. The granules are dried,
reduced to a suitable size, and mixed with magnesium stearate and
the remaining cross-linked polyvinylpyrrolidone. The mixture is
then compressed into individual tablets yielding a tablet weight of
230 mg.
[0193] Formulation 21:
40 Ingredient Quantity (mg/capsule) Raloxifene HCl 150.00 Lactose,
hydrous spray-dried 56.00 Polyvinylpyrrolidone 7.00 Polysorbate 80
1.20 Cross-linked sodium 13.80 polyvinylpyrrolidone Magnesium
Stearate 2.00
[0194] The mixture of raloxifene HCl, hydrous spray-dried lactose,
and a portion of the cross-linked polyvinylpyrrolidone is
granulated with an aqueous solution of polyvinylpyrrolidone and
polysorbate 80. The granules are dried, reduced to a suitable size
and mixed with magnesium stearate and remaining cross-linked
polyvinylpyrrolidone. The mixture is then compressed into
individual tablets yielding a tablet weight of 230 mg.
[0195] Formulation 22:
41 Ingredient Quantity (mg/capsule) Raloxifene HCl 150.00 Lactose,
anhydrous 52.40 Polyvinylpyrrolidone 11.50 Polysorbate 80 4.60
Polyethylene Glycol 8000 11.50
[0196] The mixture of raloxifene HCl and anhydrous lactose is
granulated with an aqueous solution of polysorbate 80 and
polyvinylpyrrolidone. The granules are dried, reduced to a suitable
size, and mixed with the polyethylene glycol 8000. The mixture is
then compressed into individual tablets yielding a tablet weight of
230 mg.
[0197] Capsules may be prepared using the ingredients and
procedures as described below:
[0198] Formulation 23:
42 Ingredient Quantity (mg/capsule) Raloxifene HCl 30.00 Lactose,
hydrous spray-dried 178.30 Sodium laurylsulfate 4.60 Cross-linked
9.20 polyvinylpyrrolidone Hydroxypropyl 6.90 methylcellulose
Colloidal Silicon Dioxide 1.00
[0199] The mixture of raloxifene HCl, hydrous spray-dried lactose,
and cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of sodium laurylsulfate and hydroxypropyl methylcellulose.
The granules are dried, reduced to a suitable size, and mixed with
colloidal silicon dioxide. This mixture is then filled into Size 3
hard-shell gelatin capsules utilizing conventional encapsulating
equipment, with each capsule containing 230 mg of the final
mixture.
[0200] Formulation 24:
43 Ingredient Quantity (mg/capsule) Raloxifene HCl 60.00 Lactose,
hydrous spray-dried 148.30 Sodium laurylsulfate 4.60 Cross-linked
9.20 polyvinylpyrrolidone Hydroxypropyl 6.90 methylcellulose
Colloidal Silicon Dioxide 1.00
[0201] The mixture of raloxifene HCl, hydrous spray-dried lactose,
and cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of sodium laurylsulfate and hydroxypropyl methylcellulose.
The granules are dried, reduced to a suitable size, and mixed with
colloidal silicon dioxide. This mixture is then filled into Size 3
hard-shell gelatin capsules utilizing conventional encapsulating
equipment, with each capsule containing 230 mg of the final
mixture.
[0202] Formulation 25:
44 Ingredient Quantity (mg/capsule) Raloxifene HCl 150.00 Lactose,
hydrous spray-dried 58.30 Sodium laurylsulfate 4.60 Cross-linked
9.20 polyvinylpyrrolidone Hydroxypropyl 6.90 methylcellulose
Colloidal Silicon Dioxide 1.00
[0203] The mixture of raloxifene HCl, hydrous spray-dried lactose,
and cross-linked polyvinylpyrrolidone is granulated with an aqueous
solution of sodium laurylsulfate and hydroxypropyl methylcellulose.
The granules are dried, reduced to a suitable size, and mixed with
colloidal silicon dioxide. This mixture is then filled into Size 3
hard-shell gelatin capsules utilizing conventional encapsulating
equipment, with each capsule containing 230 mg of the final
mixture.
* * * * *