U.S. patent application number 11/284157 was filed with the patent office on 2006-04-06 for novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof.
This patent application is currently assigned to Wyeth. Invention is credited to Kadum Abdul Nabi Ali, Jun Han, Yong Jai Lee.
Application Number | 20060074131 11/284157 |
Document ID | / |
Family ID | 23313356 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060074131 |
Kind Code |
A1 |
Ali; Kadum Abdul Nabi ; et
al. |
April 6, 2006 |
Novel crystalline polymorph of venlafaxine hydrochloride and
methods for the preparation thereof
Abstract
This invention relates to a highly thermally stable novel
anhydrous crystalline polymorphic form of venlafaxine
hydrochloride, methods for the preparation thereof, and its
use.
Inventors: |
Ali; Kadum Abdul Nabi;
(Congers, NY) ; Han; Jun; (Park City, IL) ;
Lee; Yong Jai; (Monroe, NY) |
Correspondence
Address: |
WYETH;PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
23313356 |
Appl. No.: |
11/284157 |
Filed: |
November 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10308480 |
Dec 3, 2002 |
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11284157 |
Nov 21, 2005 |
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60335822 |
Dec 5, 2001 |
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Current U.S.
Class: |
514/649 |
Current CPC
Class: |
A61P 25/24 20180101;
C07C 217/64 20130101; C07C 2601/14 20170501; A61P 25/00 20180101;
A61K 31/137 20130101; A61P 25/22 20180101 |
Class at
Publication: |
514/649 |
International
Class: |
A61K 31/137 20060101
A61K031/137 |
Claims
1. A method of treating depression in a mammal in need thereof
comprising administering to the mammal an effective amount of a
crystalline polymorph of venlafaxine hydrochloride exhibiting an
X-ray powder diffraction pattern having characteristic peaks
expressed in degrees 2.theta. at about 5.67, 7.28, 9.14, 9.67,
10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
2. A method of treating generalized anxiety disorder in a mammal in
need thereof comprising administering to the mammal an effective
amount of a crystalline polymorph of venlafaxine hydrochloride
exhibiting an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
3. A method of treating social anxiety disorder in a mammal in need
thereof comprising administering to the mammal an effective amount
of a crystalline polymorph of venlafaxine hydrochloride exhibiting
an X-ray powder diffraction pattern having characteristic peaks
expressed in degrees 2.theta. at about 5.67, 7.28, 9.14, 9.67,
10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
4. A method of treating post traumatic stress disorder in a mammal
in need thereof comprising administering to the mammal an effective
amount of a crystalline polymorph of venlafaxine hydrochloride
exhibiting an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
5. A method of treating panic disorder in a mammal in need thereof
comprising administering to the mammal an effective amount of a
crystalline polymorph of venlafaxine hydrochloride exhibiting an
X-ray powder diffraction pattern having characteristic peaks
expressed in degrees 2.theta. at about 5.67, 7.28, 9.14, 9.67,
10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
6. A method of preventing relapse or recurrence of depression
disorder in a mammal in need thereof comprising administering to
the mammal an effective amount of a crystalline polymorph of
venlafaxine hydrochloride exhibiting an X-ray powder diffraction
pattern having characteristic peaks expressed in degrees 2.theta.
at about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69,
and 20.74.
7. A method of treating depression, generalized anxiety disorder,
social anxiety disorder, post traumatic stress disorder or panic
disorder, or preventing the relapse or recurrence of depression,
comprising administering to a mammal in need thereof an effective
amount of a crystalline polymorph of venlafaxine hydrochloride
exhibiting an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81,
16.17, 16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74,
21.86, 22.33, 22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62,
26.97, 27.64, 28.25, 29.01, 29.96, 31.01, 31.61, 32.75, 34.54,
35.50, 35.95 and 36.91.
8. A method of treating depression, generalized anxiety disorder,
social anxiety disorder, post traumatic stress disorder or panic
disorder, or preventing the relapse or recurrence of depression,
comprising administering to a mammal in need thereof an effective
amount of a crystalline polymorph of venlafaxine hydrochloride
having an X-ray powder diffraction pattern substantially the same
as that shown in FIG. 1.
9. A method of treating depression, generalized anxiety disorder,
social anxiety disorder, post traumatic stress disorder or panic
disorder, or preventing the relapse or recurrence of depression,
comprising administering to a mammal in need thereof an effective
amount of substantially pure anhydrous venlafaxine
hydrochloride.
10. The method of claim 9 wherein the anhydrous venlafaxine
hydrochloride has a melting point of about 219.degree. C.
11. Substantially pure anhydrous venlafaxine hydrochloride.
12. A method of preparing anhydrous venlafaxine hydrochloride, the
method comprising heating form I or II of venlafaxine hydrochloride
or a mixture thereof to at least about 197.degree. C. for a time
sufficient to form the anhydrous venlafaxine hydrochloride.
13. The method of claim 12, wherein the venlafaxine hydrochloride
is heated to at least about 200.degree. C.
14. The method of claim 12, wherein the venlafaxine hydrochloride
is heated for at least about 60 minutes.
15. The method of claim 13, wherein the venlafaxine hydrochloride
is heated for at least 150 minutes.
16. The method of claim 12 wherein the anhydrous venlafaxine
hydrochloride exhibits an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
17. The method of claim 12 wherein the anhydrous venlafaxine
hydrochloride exhibits an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81,
16.17, 16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74,
21.86, 22.33, 22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62,
26.97, 27.64, 28.25, 29.01, 29.96, 31.01, 31.61, 32.75, 34.54,
35.50, 35.95 and 36.91.
18. The method of claim 12 wherein the anhydrous venlafaxine
hydrochloride exhibits an X-ray powder diffraction pattern
substantially as that shown in FIG. 1.
19. The method of claim 12 wherein the anhydrous venlafaxine is
substantially pure.
20. Anhydrous venlafaxine hydrochloride prepared according to claim
12.
21. Anhydrous venlafaxine hydrochloride prepared according to claim
20 which is substantially pure.
22. Anhydrous venlafaxine hydrochloride prepared according to claim
12 having a melting point of 219.
23. Anhydrous venlafaxine hydrochloride prepared according to claim
22 which is substantially pure.
24. Anhydrous venlafaxine hydrochloride prepared according to claim
12 exhibiting an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
25. Anhydrous venlafaxine hydrochloride prepared according to claim
24 which is substantially pure.
26. Anhydrous venlafaxine hydrochloride prepared according to claim
12 exhibiting an X-ray powder diffraction pattern having
characteristic peaks expressed in degrees 2.theta. at about 5.67,
7.28, 9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81,
16.17, 16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74,
21.86, 22.33, 22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62,
26.97, 27.64, 28.25, 29.01, 29.96, 31.01, 31.61, 32.75, 34.54,
35.50, 35.95 and 36.91.
27. Anhydrous venlafaxine hydrochloride prepared according to claim
26 which is substantially pure.
28. Anhydrous venlafaxine hydrochloride prepared according to claim
12 exhibiting an X-ray powder diffraction pattern substantially as
that shown in FIG. 1.
29. Substantially pure anhydrous venlafaxine hydrochloride prepared
according to claim 12 exhibiting an X-ray powder diffraction
pattern substantially as that shown in FIG. 1.
30. A method of preparing a crystalline polymorph of venlafaxine
hydrochloride in substantially pure form, the method comprising:
(a) obtaining venlafaxine hydrochloride having an X-ray powder
diffraction pattern substantially the same as that shown in FIG. 1
in substantially pure form; and (b) converting the venlafaxine
hydrochloride of step (a) into a different crystalline polymorphic
form.
31. The method of claim 30, wherein the venlafaxine hydrochloride
formed in step (b) is Form I of venlafaxine hydrochloride.
32. The method of claim 30 wherein the venlafaxine hydrochloride
formed in step (b) is Form II of venlafaxine hydrochloride.
Description
[0001] This application is a divisional of copending U.S.
application Ser. No. 10/308,480, filed on Dec. 3, 2002, which
claims benefit to Provisional Application No. 60/335,822, filed on
Dec. 5, 2001, the entire disclosure of which is hereby incorporated
by reference.
FIELD OF THE INVENTION
[0002] This invention relates to a novel highly thermally stable
anhydrous crystalline polymorphic form of venlafaxine
hydrochloride, methods for the preparation thereof, and its
use.
BACKGROUND OF THE INVENTION
[0003] Venlafaxine
(1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol) and
its therapeutically acceptable salts (collectively referred to as
venlafaxine herein) are inhibitors of monoamine neurotransmitter
uptake, a mechanism associated with clinical antidepressant
activity. This mechanism has also been associated with reproductive
function by affecting indirectly the hypothalamic-pituitary-ovarian
axis. It is believed that venlafaxine's mechanism of action is
related to potent inhibition of the uptake of the monoamine
neurotransmitters serotonin and norepinephrine. To a lesser degree,
venlafaxine also inhibits dopamine reuptake. However, it has no
inhibitory activity on monoamine oxidase.
[0004] In contrast to classical tricyclic antidepressant drugs,
venlafaxine has virtually no affinity for muscaranic,
histaminergic, or adrenergic receptors in vitro. Pharmacologic
activity at these receptors is associated with the various
anticholinergic, sedative, and cardiovascular effects seen with the
tricyclic antidepressant drugs.
[0005] Hypothalamic amenorrhea in depressed and non-depressed human
females may also be treated with venlafaxine as taught in U.S. Pat.
No. 5,506,270.
[0006] U.S. Pat. No. 5,530,013 teaches that venlafaxine induces
cognition enhancement and treats cognitive impairment in a
mammal.
[0007] U.S. Pat. No. 5,744,474 discloses that venlafaxine can treat
urinary incontinence in humans.
[0008] More recently, as discussed in U.S. Pat. No. 5,916,923,
venlafaxine has been found to treat, prevent, and control obesity,
generalized anxiety disorder, post-traumatic stress disorder, late
luteal phase disphoric disorder (premenstrual syndrome), attention
deficit disorder (with and without hyperactivity), Gilles de la
Tourette syndrome, bulimia nervosa, and Shy Drager Syndrome in
mammals (e.g., humans).
[0009] Extended release formulations of venlafaxine are disclosed
in U.S. Pat. No. 6,274,171 and International Patent Publication No.
WO 94/27589. As discussed in U.S. Pat. No. 6,274,171, venlafaxine
hydrochloride is known to exist in two polymorphic forms, Forms I
and II. Characteristic X-ray powder diffraction patterns for Forms
I and II are shown in FIGS. 2 and 3, respectively.
SUMMARY OF THE INVENTION
[0010] The present invention provides a novel anhydrous crystalline
polymorph of venlafaxine hydrochloride. This crystalline polymorph
is more thermally stable than known forms of venlafaxine
hydrochloride. While forms I and II of venlafaxine hydrochloride
have melting points of 209 and 211.degree. C. .DELTA.H=125.8 and
130.3 J/g), respectively, the melting point of the crystalline
polymorph of the present invention is about 219.degree. C.
.DELTA.H=116 J/g). Because of this stability, a mixture of various
polymorphs of venlafaxine hydrochloride can be formed into a pure
form of this new polymorph. Furthermore, residual solvents used in
the preparation of this new polymorph or the precursor venlafaxine
hydrochloride can be easily removed.
[0011] The crystalline polymorph of the present invention exhibits
characteristic XRPD peaks (expressed in degrees 2.theta.) at about
5.67, 7.28, 9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48,
15.81, 16.17, 16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46,
20.74, 21.86, 22.33, 22.67, 22.95, 23.17, 24.06, 24.61, 25.13,
26.62, 26.97, 27.64, 28.25, 29.01, 29.96, 31.01, 31.61, 32.75,
34.54, 35.50, 35.95 and 36.91.
[0012] The crystalline polymorph of the present invention can be
administered to a mammal to treat depression (including, but not
limited to, major depressive disorder, bipolar disorder, and
dysthymia), fibromyalgia, anxiety, panic disorder, agorophobia,
post traumatic stress disorder, premenstrual dysphoric disorder
(premenstrual syndrome), attention deficit disorder (with and
without hyperactivity), obsessive compulsive disorder (including
trichotillomania), social anxiety disorder, generalized anxiety
disorder, autism, schizophrenia, obesity, anorexia nervosa, bulimia
nervosa, Gilles de la Tourette Syndrome, vasomotor flushing,
cocaine and alcohol addiction, sexual dysfunction (including
premature ejaculation), borderline personality disorder, chronic
fatigue syndrome, urinary incontinence, pain (including, but not
limited to, migraine, chronic back pain, phantom limb pain, central
pain, neuropathic pain such as diabetic neuropathy, and
postherpetic neuropathy), Shy Drager Syndrome, or Raynaud's
syndrome. The crystalline polymorph can also be administered to
prevent relapse or recurrence of depression, to induce cognitive
enhancement, to treat cognitive impairment, and in regimens for
cessation of smoking or other tobacco uses. Additionally, the
crystalline polymorph can be administered to treat hypothalamic
amenorrhea in depressed and non-depressed human females. These
methods involve administering to a mammal (e.g., a human) in need
thereof an effective amount of the crystalline polymorph of the
present invention or a mixture of venlafaxine polymorphs that
contains the crystalline polymorph of the present invention.
Preferably, the venlafaxine is administered orally.
[0013] Another embodiment is a pharmaceutical composition
comprising the crystalline polymorph of the present invention and,
optionally, a pharmaceutically acceptable carrier or diluent.
Typically, the pharmaceutical composition comprises an amount of
the crystalline polymorph effective to treat depression or any of
the aforementioned indications in an animal, such as a mammal (e.g.
human). According to one preferred embodiment, the pharmaceutical
composition comprises at least about 20, 30, 40, 50, 60, 70, 80,
90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7,
99.8, or 99.9% by weight of the crystalline polymorph of the
present invention, based upon 100% total weight of venlafaxine
hydrochloride in the pharmaceutical composition. According to
another preferred embodiment, the pharmaceutical composition
comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96,
97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or
99.9% by weight of the crystalline polymorph of the present
invention, based upon 100% total weight of venlafaxine
hydrochloride in the pharmaceutical composition.
[0014] The pharmaceutical composition may be incorporated into a
dosage form, such as a tablet or capsule.
[0015] The crystalline polymorph of the present invention can be
prepared by heating venlafaxine hydrochloride of form I or II or
mixtures thereof to a temperature of at least about 197.degree. C.
and more preferably at least about 200.degree. C. According to one
embodiment, the venlafaxine hydrochloride is heated to about
200.degree. C. Generally, the venlafaxine hydrochloride is heated
for at least about 60 minutes and more preferably for at least
about 150 minutes. The crystals formed may be recovered by any
method known in the art.
[0016] Another embodiment is a method of preparing a substantially
pure crystalline polymorphic form of venlafaxine hydrochloride. The
method includes obtaining the venlafaxine hydrochloride crystalline
polymorph of the present invention in substantially pure form and
then converting the substantially pure venlafaxine hydrochloride
into another polymorphic form, such as form I. The substantially
pure venlafaxine hydrochloride product can be incorporated into
pharmaceutical compositions and dosage forms as known in the
art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a characteristic X-ray Powder Diffraction (XRPD)
pattern of the anhydrous venlafaxine hydrochloride crystalline
polymorph of the present invention.
[0018] FIG. 2 is a characteristic XRPD pattern of Form I of
venlafaxine hydrochloride.
[0019] FIG. 3 is a characteristic XRPD pattern of Form II of
venlafaxine hydrochloride.
[0020] FIG. 4 is a differential scanning calorimetry (DSC) scan of
the anhydrous venlafaxine hydrochloride crystalline polymorph of
the present invention carried out in a sealed pan at a scan rate of
10.degree. C./minute from 25 to 240.degree. C. under a nitrogen
purge.
[0021] FIG. 5 is a thermogravimetric analysis (TGA) of the
anhydrous crystalline polymorph of the present invention heated
from 28 to 238.degree. C. at a scan rate of 10.degree. C./minute
under a nitrogen purge.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The term "about" generally means within 10%, preferably
within 5%, and more preferably within 1% of a given value or range.
With regard to a given value or range in degrees 22 from XRPD
patterns, the term "about" generally means within 0.2.degree.
2.theta. and preferably within 0.10, 0.05.degree., or 0.01.degree.
2.theta. of the given value or range. Alternatively, the term
"about" means within an acceptable standard error of the mean, when
considered by one of ordinary skill in the art.
[0023] The term "treat" as used herein refers to preventing,
ameliorating, controlling, or curing the desired symptoms or
disorders.
[0024] The term "venlafaxine hydrochloride" as used herein refers
to racemic mixtures of R and S-venlafaxine and their optically pure
enantiomers. The crystalline polymorph of the present invention may
be R, S, or a racemic mixture of R and S-venlafaxine
hydrochloride.
[0025] The crystalline polymorph has an XRPD pattern substantially
identical to that shown in FIG. 1. Peak locations and intensities
for the XRPD pattern in FIG. 1 are provided in Table 1 below.
TABLE-US-00001 TABLE 1 Characteristic XRPD Peaks (expressed in
degrees 2.theta.) D-spacing in Angstrom (.ANG.) and Intensities of
Diffraction Lines in CPS for the Polymorphic Form of Venlafaxine
Hydrochloride Degrees 2.theta. d (.ANG.) I (Counts per Second (CPS)
5.67 15.57 309.09 7.28 12.14 828.73 9.14 9.67 766.93 9.67 9.14
262.26 10.77 8.21 303.39 11.31 7.82 728.55 14.01 6.31 224.07 14.54
6.09 807.87 14.85 5.96 887.19 15.48 5.72 830.41 15.81 5.60 617.50
16.17 5.48 357.33 16.94 5.23 728.55 17.68 5.01 338.29 18.02 4.92
312.91 18.48 4.80 753.93 19.29 4.60 1069.82 19.69 4.50 963.51 20.46
4.34 866.61 20.74 4.28 1084.34 21.86 4.06 365.61 22.33 3.98 187.75
22.67 3.92 259.14 22.95 3.87 240.39 23.17 3.84 343.83 24.06 3.70
264.69 24.61 3.62 403.19 25.13 3.54 498.24 26.62 3.35 479.23 26.97
3.30 783.01 27.64 3.23 338.01 28.25 3.16 294.56 29.01 3.08 452.07
29.96 2.98 237.53 31.01 2.88 348.88 31.61 2.83 478.42 32.75 2.73
332.38 34.54 2.60 347.78 35.50 2.53 338.55 35.95 2.50 315.92 36.91
2.43 221.30
In particular, the peaks (expressed in degrees 2.theta.) at about
5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and
20.74 are unique to this crystalline polymorph. The crystalline
polymorph also has a melting endotherm, according to differential
scanning calorimetry, at 219.degree. C.
[0026] The crystalline polymorph of the present invention is useful
for treating, preventing, or controlling depression and the
aforementioned indications. The appropriate dosage amounts for an
animal can be determined by methods known in the art. Generally, a
therapeutic effective amount for the desired purpose is
administered. The dosage of the crystalline polymorph of
venlafaxine hydrochloride disclosed herein is generally from about
75 to about 300 mg per day.
[0027] The crystalline polymorph can be formulated into a
pharmaceutical composition. Preferably, the pharmaceutical
composition comprises an amount of the crystalline polymorph of
venlafaxine hydrochloride effective to treat the desired indication
in an animal, such as a human. According to one preferred
embodiment, the pharmaceutical composition comprises at least about
20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2,
99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of the
crystalline polymorph of venlafaxine hydrochloride, based upon 100%
total weight of venlafaxine hydrochloride in the pharmaceutical
composition. According to another embodiment, the pharmaceutical
composition comprises at least about 20, 30, 40, 50, 60, 70, 80,
90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7,
99.8, or 99.9% by weight of the crystalline polymorph of
venlafaxine hydrochloride, based upon 100% total weight of
crystalline venlafaxine hydrochloride in the pharmaceutical
composition.
[0028] The pharmaceutical composition can also be substantially
free or completely free of other crystalline polymorphs of
venlafaxine hydrochloride, such as Forms I and II. The terms
"substantially free" and "substantially pure" include those
pharmaceutical compositions that contain less than 0.01, 0.1, 0.2,
0.3, 0.4, 0.5, 1 or 2% by weight of other crystalline polymorphs,
such as Form I or II or both, based upon the total weight of
pharmaceutical composition (or alternatively based upon on the
total weight of venlafaxine hydrochloride in the pharmaceutical
composition).
[0029] According to one embodiment, the pharmaceutical composition
contains from about 25 to about 350 mg of the crystalline polymorph
of venlafaxine hydrochloride. More preferably, pharmaceutical
compositions of the present invention contain 75 mg, 150 mg or 225
mg of the crystalline polymorph of venlafaxine hydrochloride.
[0030] The pharmaceutical composition may also include one or more
pharmaceutically acceptable carriers or diluents and excipients.
The term "excipient" includes, but is not limited to, those
materials that are acceptable for use in pharmaceutical
formulations, and are added to the formulation to promote the
stability and viability of the formulation, such as binders,
bulking agents, clarifying agents, buffering agents, wetting
agents, lubricants, sweeteners, and flavoring agents. Suitable
excipients include, but are not limited to, cellulose, ethyl
cellulose, gelatin, hydroxypropyl methylcellulose, iron oxide,
titanium dioxide, lactose, magnesium stearate, and sodium starch
glycolate. Suitable pharmaceutically acceptable carriers, diluents,
and excipients also include those described in Remington's, The
Science and Practice of Pharmacy, (Gennaro, A. R., ed., 19.sup.th
edition, 1995, Mack Pub. Co.) which is herein incorporated by
reference. The phrase "pharmaceutically acceptable" refers to
additives or compositions that are physiologically tolerable and do
not typically produce an allergic or similar untoward reaction,
such as gastric upset, dizziness and the like, when administered to
an animal, such as a mammal (e.g. a human).
[0031] According to one preferred embodiment, the pharmaceutical
composition is an extended release formulation, such as that
described in U.S. Pat. No. 6,274,171, which is herein incorporated
by reference. For example, an extended release formulation may
comprise spheroids comprised of the crystalline polymorph of the
present invention, microcrystalline cellulose, and, optionally,
hydroxypropyl-methylcellulose. The spheroids are preferably coated
with a film coating composition comprised of ethyl cellulose and
hydroxypropylmethylcellulose.
[0032] The pharmaceutical composition may be a dosage form, such as
a liquid (e.g., elixirs and suspensions), capsule, pill, or tablet.
The pharmaceutical compositions and the crystalline polymorph of
venlafaxine hydrochloride may be administered to animals,
including, but not limited to, mammals (e.g. humans), orally,
intravenously, intramuscularly, parenterally intraperitoneally,
subdermally, buccally, subcutaneously, transdermally, topically,
rectally, vaginally, or intranasally. Preferably, the composition
is administered orally.
[0033] The crystalline polymorph of the present invention can be
prepared by heating venlafaxine hydrochloride of form I or II or
mixtures thereof to at least about 197.degree. C. and more
preferably at least about 200.degree. C. According to one
embodiment, the venlafaxine hydrochloride is heated to about
200.degree. C. Generally, the venlafaxine hydrochloride is heated
for a time sufficient to form the crystalline polymorph of the
present invention. Preferably, the venlafaxine hydrochloride
precursor is heated for at least about 60 minutes and more
preferably for at least about 150 minutes. The crystalline
polymorph may be prepared in substantially pure form by heating the
venlafaxine hydrochloride precursor for a sufficient amount of
time.
[0034] Venlafaxine hydrochloride may be prepared by any method
known in the art including, but not limited to, the methods
described in U.S. Pat. Nos. 4,535,186 and 4,761,501 and
International Patent Publication Nos. WO 00/32555, WO 00/32556, and
WO 01/07397, all of which are hereby incorporated by reference.
[0035] The crystals formed may be recovered by any method known in
the art, such as filtration, centrifugation, or with a Buchner
style filter, Rosenmund filter, or plates and frame press.
Typically, the crystals are recovered as solids.
[0036] The crystalline polymorph can be converted into Form I by
recrystallizing it in ethyl acetate in ethanol (e.g., 80% ethyl
acetate in ethanol).
[0037] As discussed above, substantially pure forms of the
crystalline polymorph can be prepared such as by heating one or
more forms of venlafaxine hydrochloride to about 200.degree. C. for
a sufficient time. The substantially pure crystalline polymorph can
be used to prepare other substantially pure crystalline polymorphic
forms of venlafaxine hydrochloride, such as form I, by the methods
described above. The substantially pure venlafaxine hydrochloride
product can be incorporated into pharmaceutical compositions and
dosage forms as known in the art.
EXAMPLES
[0038] The following examples are illustrative and are not meant to
limit the scope of the claimed invention. The venlafaxine
hydrochloride which is used as a raw material in the example below
can be prepared by any method known in the art.
Example 1
Preparation of Anhydrous Venlafaxine Hydrochloride
[0039] About 100 mg of venlafaxine hydrochloride of Form II was put
in a glass vial, flushed with nitrogen gas and then sealed by heat.
The sealed vial was put in an oil bath at about 200.degree. C.
(197.degree. C. to 200.degree. C.) for 1 hour or until the shape of
the crystals changed to form cream-white crystals.
Example 2
Preparation of Anhydrous Venlafaxine Hydrochloride
[0040] The procedure in Example 1 was repeated with 500 mg of
venlafaxine hydrochloride of Form II, except the vial was left in
the oil bath for 2.5 hours instead of 1 hour.
Example 3
Preparation of Anhydrous Venlafaxine Hydrochloride
[0041] The procedure in Example 1 was repeated, except an aluminum
vial was used instead of a glass vial.
Example 4
X-ray Powder Diffraction (XRPD)
[0042] XRPD was performed on the crystalline polymorph of
venlafaxine hydrochloride of the present invention under dry
conditions with a Scintag X2 X-Ray Diffraction System Model 00-A02,
available from Thermo ARL of Ecublens, Switzerland. The XRPD
instrument had the following parameters: TABLE-US-00002 Scan Type:
Normal Start Angle: 3 degrees Stop Angle: 40 degrees Number of
Points: 1851 points Step Size: 0.02 degrees Datafile Resolution:
1600 Scan Rate: 0.04 Scan Mode: Step Wavelength: 1.540562
Diffraction Optics: Detector: Type: Fixed Slits X2 Configuration:
No Tube: Type: Fixed Slits X2 Configuration: No
The results are shown in FIG. 1.
[0043] This procedure was repeated for Forms I and II of
venlafaxine hydrochloride. The results for Forms I and II are shown
in FIGS. 2 and 3, respectively.
Example 5
Intrinsic Dissolution Rate
[0044] The intrinsic dissolution rates of Form II and the
crystalline polymorph of the present invention were determined as
follows. Pellets of venlafaxine hydrochloride were prepared by
compressing 100 mg of each material in a die (Wood's apparatus) at
1000 psi for 1 minute with a Carver press. The pellets produced
were then fitted into a dissolution apparatus (Vankel 7010 equipped
with a Cary 300 Ultraviolet/Visible Spectrophotometer) which
resulted in a single exposed surface area of 0.5 cm.sup.2. The
dissolution rate in 900 mL of water was determined by USP 23
(1995), section 711, page 1791 (Dissolution, apparatus 2), with a
rotation speed of 100 rpm at 37.degree. C. The dissolution media
was circulated through a 1.0 cm path microflow cell at a flow rate
of 10 mL/minute. Ultraviolet absorbance was recorded at 220 nm.
[0045] Both Form II and the crystalline polymorph of the present
invention exhibited dissolution rates of 24.7
mg/cm.sup.2-minute.
Example 6
Differential Scanning Calorimetry (DSC)
[0046] DSC measurements on the anhydrous venlafaxine hydrochloride
crystalline polymorph of the present invention were carried out in
a sealed pan at a scan rate of 10.degree. C./minute from 25.degree.
C. to 240.degree. C. under a nitrogen purge with a Pyris I DSC
available from Perkin-Elmer of Shelton, Conn. The DSC scan is shown
in FIG. 4.
[0047] FIG. 4 shows one endotherm at 221.degree. C. (heat of fusion
is 116 J/g), which was the melting of the anhydrous venlafaxine
hydrochloride. The onset melting temperature for the venlafaxine
hydrochloride was 219.degree. C.
Example 7
Thermogravimetric Analysis (TGA)
[0048] A sample of the venlafaxine hydrochloride crystalline
polymorph of the present invention was heated from 28 to
238.degree. C. at a scan rate of 10.degree. C./minute in a Pyris I
TGA, available from Perkin-Elmer of Shelton, Conn., under a
nitrogen purge. The results are shown in FIG. 5. The sample lost
little weight until it was heated near the melting point of
venlafaxine hydrochloride.
[0049] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims. It is further to be understood that values are approximate,
and are provided for description.
[0050] Patents, patent applications, publications, procedures, and
the like are cited throughout this application, the disclosures of
which are incorporated herein by reference in their entireties. To
the extent that a conflict may exist between the specification and
a reference, the language of the disclosure made herein
controls.
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