U.S. patent application number 14/605334 was filed with the patent office on 2015-07-16 for formulations, salts and polymorphs of transnorsertraline and uses thereof.
The applicant listed for this patent is SUNOVION PHARMACEUTICALS INC.. Invention is credited to Philip James Bonasia, Susan S. D'souza, Cai Gu Huang, Sharon M. LAUGHLIN, Surendra P. Singh, Michael J. Sizensky, Harold Scott Wilkinson.
Application Number | 20150196502 14/605334 |
Document ID | / |
Family ID | 44115510 |
Filed Date | 2015-07-16 |
United States Patent
Application |
20150196502 |
Kind Code |
A1 |
LAUGHLIN; Sharon M. ; et
al. |
July 16, 2015 |
FORMULATIONS, SALTS AND POLYMORPHS OF TRANSNORSERTRALINE AND USES
THEREOF
Abstract
Provided herein are pharmaceutical compositions comprising
transnorsertraline, salts and polymorphic forms of
transnorsertraline, methods of making the compositions, and methods
for their use for the treatment of CNS diseases, including
depression.
Inventors: |
LAUGHLIN; Sharon M.;
(Hudson, MA) ; Sizensky; Michael J.; (South
Grafton, MA) ; Singh; Surendra P.; (Shrewsbury,
MA) ; Wilkinson; Harold Scott; (Westborough, MA)
; Huang; Cai Gu; (Sudbury, MA) ; Bonasia; Philip
James; (Needham, MA) ; D'souza; Susan S.;
(Marlborough, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUNOVION PHARMACEUTICALS INC. |
Marborough |
MA |
US |
|
|
Family ID: |
44115510 |
Appl. No.: |
14/605334 |
Filed: |
January 26, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13513170 |
Jan 9, 2013 |
8957114 |
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PCT/US2010/058831 |
Dec 3, 2010 |
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14605334 |
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61266864 |
Dec 4, 2009 |
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Current U.S.
Class: |
514/647 ;
564/308 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 25/18 20180101; A61P 25/14 20180101; A61K 31/135 20130101;
A61P 25/04 20180101; A61P 25/30 20180101; A61P 15/08 20180101; A61P
25/22 20180101; C07C 211/42 20130101; A61P 25/00 20180101; A61P
25/24 20180101; A61K 9/2018 20130101; A61P 25/28 20180101; A61P
25/20 20180101; A61P 15/12 20180101; A61K 9/4858 20130101; A61P
9/00 20180101; A61P 3/04 20180101 |
International
Class: |
A61K 31/135 20060101
A61K031/135 |
Claims
1.-7. (canceled)
8. A crystalline hydrochloride salt of transnorsertraline or a
hydrate thereof, which has an X-ray powder diffraction pattern
comprising peaks at about 14.9, 17.8, 19.2, 23.3, 24.6 and 25.2
degrees 2.theta..
9. The salt of claim 8 which has an X-ray powder diffraction
pattern further comprising peaks at about 5.0 and 21.8 degrees
2.theta..
10. The salt of claim 9 which has a calculated X-ray powder
diffraction pattern comprising peaks at about 5.1, 15.0, 18.0,
19.5, 22.0 23.5, 24.8 and 25.4 degrees 2.theta., based on data
collected at about 173 K on a single crystal.
11. The salt of claim 9 which has the following approximate unit
cell dimensions: a=16.8 .ANG., b=5.2 .ANG., c=19.1 .ANG.,
.alpha.=90.0 .degree., .beta.=113.1.degree. and
.gamma.=90.0.degree..
12. The salt of claim 9 which has the following approximate unit
cell dimensions when measured at about 173 K: a=16.83 .ANG., b=5.23
.ANG., c=19.06 .ANG., .alpha.=90.00.degree., .beta.=113.10.degree.
and .gamma.=90.00.degree..
13. The salt of claim 12 wherein the approximate unit cell
dimensions are: a=16.834 .ANG., b=5.226 .ANG., c=19.059 .ANG.,
.alpha.=90.00.degree., .beta.=113.10.degree. and
.gamma.=90.00.degree..
14. The salt of claim 11 which has the space group C2 (no. 5).
15. The salt of claim 11 wherein the unit cell contains four
transnorsertraline hydrochlorides (Z=4).
16. The salt of claim 8 which has a density of about 1.4 g
cm.sup.-3.
17-18. (canceled)
19. A method of treating, preventing, or managing a neurological
disorder comprising administering to a patient a therapeutically or
prophylactically effective amount of a compound according to claim
8.
20. The method of claim 19, wherein the neurological disorder is
depression, cognitive deficits, fibromyalgia, pain, a sleep related
disorder, chronic fatigue syndrome, attention deficit disorder
(ADD), attention deficit hyperactivity disorder (ADHD), restless
leg syndrome, schizophrenia, anxiety, obsessive compulsive
disorder, posttraumatic stress disorder, seasonal affective
disorder (SAD), premenstrual dysphoria, post-menopausal vasomotor
symptoms, a neurodegenerative disease, manic conditions, dysthymic
disorder, cyclothymic disorder, obesity, or substance abuse or
dependency.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/266,864, filed Dec. 4, 2009, the entirety
of which is incorporated herein by reference.
1. FIELD
[0002] Provided herein are pharmaceutical compositions comprising
transnorsertraline, salts and polymorphic forms of
transnorsertraline, methods of making the compositions, and methods
for their use for the treatment of CNS diseases, including
depression.
2. BACKGROUND
[0003] 2.1 Transnorsertraline
[0004] Transnorsertraline, i.e.,
(1R,4S)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
and
(1S,4R)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalena-
mine are described in, for example, U.S. Pat. No. 7,087,785 B2
("the '785 patent"; incorporated herein by reference in its
entirety), have the following chemical structures,
respectively:
##STR00001##
[0005] Uses of transnorsertraline in the treatment, prevention, or
management of affective disorders and other various CNS disorders
are also disclosed in the '785 patent. Such disorders include, but
are not limited to, depression, mood disorders, anxiety disorders,
behavioral disorders, eating disorders, substance abuse disorders,
and sexual function disorders.
[0006] 2.2 Salts and Polymorphic Forms
[0007] Whether crystalline or amorphous, potential solid forms of a
pharmaceutical compound include single-component and
multiple-component solids. Single-component solids consist
essentially of the pharmaceutical compound in the absence of other
compounds. Variety among single-component crystalline materials may
potentially arise, e.g., from the phenomenon of polymorphism,
wherein multiple three-dimensional arrangements exist for a
particular pharmaceutical compound (see, e.g., S. R. Byrn et al.,
Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).
[0008] Solid forms such as salts, crystal forms, e.g., polymorphic
forms of a compound are known in the pharmaceutical art to affect,
for example, the solubility, stability, flowability, fractability,
and compressibility of the compound as well as the safety and
efficacy of drug products based on the compound, (see, e.g.,
Knapman, K. Modern Drug Discoveries, 2000: 53).
[0009] The importance of studying polymorphs was underscored by the
case of ritonavir, an HIV protease inhibitor that was formulated as
soft gelatin capsules. About two years after the product was
launched, the unanticipated precipitation of a new, less soluble
polymorph in the formulation necessitated the withdrawal of the
product from the market until a more consistent formulation could
be developed (see S. R. Chemburkar et al., Org. Process Res. Dev.,
(2000) 4:413-417). Thus, the preparation of solid forms is of great
importance in the development of a safe, effective, stable and
marketable pharmaceutical compound.
[0010] New salts and polymorphic forms of transnorsertraline can
further the development of formulations for the treatment,
prevention or management of CNS diseases.
[0011] 2.3 Treatment of Neurological Disorders
[0012] Serotonin, i.e., 5-HT, is known to play an important role in
the treatment of various CNS disorders. Among others, 5-HT1A
(serotonin 1A) receptors provide an important mechanism for
controlling 5-HT release in the brain. These receptors are located
presynaptically in the raphe nuclei where they function as
autoreceptors to inhibit the firing rate of 5-HT neurons.
5-HT.sub.1A receptors are also located postsynaptically in
corticolimbic regions where they also reduce firing activity of
5-HT neurons. At the initiation of treatment with selective
serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine
reuptake inhibitors (SNRIs), the 5-HT.sub.1A autoreceptors are
activated by 5-HT, leading to a reduction in 5-HT neuronal firing.
As SSRI or SNRI treatment continues, however, 5-HT.sub.1A
autoreceptors become desensitized, and the firing activity is
restored. This adaptive change is believed to contribute, at least
in part, to the delay in efficacy of SSRIs and SNRIs in treating
various neurological disorders.
[0013] Therefore, a need exists for the treatment, prevention, or
management of various neurological disorders, wherein the
desensitization of 5-HT receptors may be minimized and the increase
in 5-HT neuronal firing may be maintained.
3. SUMMARY
[0014] Provided herein are pharmaceutical compositions comprising
transnorsertraline, salts and polymorphic forms of
transnorsertraline, methods of making compositions with the salts
and polymorphic forms, and methods for their use for the treatment
of CNS diseases, including depression.
[0015] In one embodiment, provided herein are stable pharmaceutical
compositions and/or formulations of transnorsertraline, or a
pharmaceutically acceptable salt or solvate thereof.
[0016] In another embodiment, provided herein is a salt of
transnorsertraline selected from the group consisting of
hydrochloride, acetate, L-malate, besylate, benzoate, tosylate,
fumarate, hydrobromide, maleate, citrate, phosphate, succinate,
L-tartrate, D-tartrate, S-mandelate and pyroglutamate.
[0017] In one embodiment, the salt is the hydrochloride salt. In
one embodiment, the hydrochloride salt of transnorsertraline is an
anhydrous solid. In another embodiment, the hydrochloride salt of
transnorsertraline exists as a monohydrate.
[0018] In one embodiment, the transnorsertraline hydrochloride is
(1R,4S)-transnorsertraline hydrochloride, i.e.,
(1R,4S)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
hydrochloride. In another embodiment, the transnorsertraline
hydrochloride is (1S,4R)-transnorsertraline hydrochloride, i.e. ,
(1S,4R)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
hydrochloride.
[0019] Also provided herein are methods of treating, preventing or
managing neurological disorders comprising administering to a
subject (e.g., patient) a formulation, salt or polymorph of
transnorsertraline as disclosed herein. Neurological disorders that
may be treated, prevented, or managed by the methods provided
herein are described in detail herein elsewhere.
[0020] In some embodiments, the formulation, salt or polymorph of
transnorsertraline is administered in combination with one or more
additional therapeutic agents, or pharmaceutically acceptable
salts, solvates, or stereoisomers thereof.
4. BRIEF DESCRIPTION OF FIGURES
[0021] FIG. 1A illustrates the crystal habit of anhydrous
transnorsertraline hydrochloride.
[0022] FIG. 1B illustrates the crystal habit of transnorsertraline
hydrochloride monohydrate.
[0023] FIG. 2 illustrates the calculated XRPD pattern of anhydrous
transnorstertraline hydrochloride.
[0024] FIG. 3 illustrates the experimental XRPD pattern of
anhydrous transnorstertraline hydrochloride.
[0025] FIG. 4 illustrates the ORTEP diagram of anhydrous
transnorstertraline hydrochloride.
[0026] FIG. 5 illustrates the calculated XRPD pattern of
transnorstertraline hydrochloride monohydrate.
[0027] FIG. 6 illustrates the experimental XRPD pattern of
transnorstertraline hydrochloride monohydrate.
[0028] FIG. 7 illustrates the ORTEP diagram of transnorstertraline
hydrochloride monohydrate.
[0029] FIG. 8 is a typical HPLC chromatogram of transnorsertraline
hydrochloride 1 mg Tablets of example 6.27.
[0030] FIG. 9 is an overlay of HPLC chromatograms from the
stability studies of example 6.31.
5. DETAILED DESCRIPTION
[0031] Provided herein are pharmaceutical compositions comprising
transnorsertraline, salts and polymorphic forms of
transnorsertraline, methods of making compositions with the salts
and polymorphic forms, and methods for their use for the treatment
of CNS diseases, including depression.
[0032] In one embodiment, provided herein are stable pharmaceutical
compositions and/or formulations of transnorsertraline, or a
pharmaceutically acceptable salt or solvate thereof.
[0033] In one embodiment, the stable pharmaceutical compositions
and/or formulations of transnorsertraline comprise less than about
3% by weight of a compound of formula (II):
##STR00002##
[0034] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than about 1.5% or less than about 1% by weight of a compound
of formula (II).
[0035] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than about 4% by weight of compounds of formula (III):
##STR00003##
[0036] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than about 2% or less than about 1% by weight of compounds of
formula (III)
[0037] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than about 3% by weight of a compound of formula (II) and less
than about 4% by weight of compounds of formula (III).
[0038] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than about 1.5% by weight of a compound of formula (II) and
less than about 2% by weight of compounds of formula (III).
[0039] In another embodiment, the stable pharmaceutical
compositions and/or formulations of transnorsertraline comprise
less than less than about 1% by weight each of the compounds of
formulae (II) and (III).
[0040] In certain embodiments, without being bound to any
particular theory, it is believed that the compound of formula (II)
are adducts of transnorsertraline formed by the decomposition of
transnorsertaline in a pharmaceutical dosage form, e.g., a tablet,
in the presence of mannose.
[0041] In certain embodiments, without being bound to any
particular theory, it is believed that the compounds of formula
(III) are oxidative decomposition products of transnorsertraline
formed by the decomposition of transnorsertaline in a
pharmaceutical dosage form, e.g., a tablet, in the presence of
dicalcium phosphate (e.g., A-TAB).
[0042] In one embodiment, the stable pharmaceutical compositions
provided herein are in an immediate-release dosage form.
[0043] In another embodiment, the stable pharmaceutical
compositions provided herein are in a controlled-release dosage
form.
[0044] In one embodiment, the pharmaceutical composition comprises
transnorsertraline, or a pharmaceutically acceptable salt or
solvate thereof, and mannitol, xylitol or a combination thereof. In
one embodiment, the pharmaceutical composition comprises
transnorsertraline, or a pharmaceutically acceptable salt or
solvate thereof, and at least about 5%, 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98%
by weight of mannitol or xylitol.
[0045] In another embodiment, the pharmaceutical composition
comprises transnorsertraline, or a pharmaceutically acceptable salt
or solvate thereof, and mannitol. In one embodiment, the
pharmaceutical composition comprises transnorsertraline, or a
pharmaceutically acceptable salt or solvate thereof, and at least
about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97% or 98% by weight of mannitol.
[0046] In one embodiment, provided herein is a stable
pharmaceutical composition which comprises transnorsertraline, or a
pharmaceutically acceptable salt or solvate thereof, and mannitol,
wherein the stable pharmaceutical composition contains less than
about 1 .mu.g to about 100 .mu.g of mannose per 100 mg of mannitol.
In another embodiment, the stable pharmaceutical composition
contains less than about 10 .mu.g to about 100 .mu.g of mannose per
100 mg of mannitol. In another embodiment, the stable
pharmaceutical composition contains less than about 1 .mu.g to
about 50 .mu.g of mannose per 100 mg of mannitol. In another
embodiment, the stable pharmaceutical composition contains less
than about 1 .mu.g to about 20 .mu.g of mannose per 100 mg of
mannitol. In another embodiment, the stable pharmaceutical
composition contains less than about 10 .mu.g or less than about 5
.mu.g of mannose per 100 mg of mannitol.
[0047] In one embodiment, provided herein are pharmaceutical
compositions which are stable for at least about 5 to about 30
weeks. In another embodiment, the compositions are stable at a
temperature of between about 20.degree. C. to about 50.degree. C.
for at least about 5 to about 30 weeks. In another embodiment, the
compositions are stable at a temperature of between about
20.degree. C. to about 50.degree. C. for at least about 5 to about
30 weeks at a relative humidity of between about 35% and about
85%.
[0048] In another embodiment, when the pharmaceutical composition
comprises mannitol, the combination of excipients in the
composition, absent the active ingredient, contains, or generates
upon storage for from about 5 to about 30 weeks, at a temperature
of between about 20.degree. C. to about 50.degree. C., and at a
relative humidity of between about 35% and about 85% in a sealed
package, less than about 0.05% mannose relative to the weight of
mannitol. In another embodiment, said storage is for about 24
weeks. In another embodiment, said temperature is about 30.degree.
C. In another embodiment, said temperature is about 40.degree. C.
In another embodiment, said relative humidity is about 65%. In
another embodiment, said relative humidity is about 75%. In another
embodiment, the pharmaceutical composition contains or generates
less than about 0.02% of mannose; or less than about 0.01% of
mannose relative to the weight of mannitol.
[0049] In one embodiment, the pharmaceutical composition further
comprises magnesium stearate, calcium stearate, zinc stearate or
stearic acid. In one embodiment, the pharmaceutical composition
further comprises at least 0.1%, 0.2%, 0.5%, 0.75%, 1%, 1.5%, 2%,
3%, or 5% by weight of magnesium stearate, calcium stearate, zinc
stearate or stearic acid.
[0050] In one embodiment, the pharmaceutical composition further
comprises talc, kaolin or bentonite. In one embodiment, the
pharmaceutical composition further comprises at least 0.5%, 1%, 2%,
3%, 5%, 10%, 15%, 20%, 30%, or 40% by weight of talc, kaolin or
bentonite.
[0051] In another embodiment, provided herein is a pharmaceutical
composition comprising transnorsertraline, or a pharmaceutically
acceptable salt or solvate thereof, mannitol, magnesium stearate,
talc and sodium starch glycolate.
[0052] In another embodiment, provided herein is a pharmaceutical
composition comprising transnorsertraline, or a pharmaceutically
acceptable salt or solvate thereof, 10 to 98% by weight of
mannitol, magnesium stearate, talc and sodium starch glycolate.
[0053] In another embodiment, the pharmaceutical composition
comprises 50 to 98% by weight of mannitol.
[0054] In another embodiment, the pharmaceutical composition
comprises 80 to 98% by weight of mannitol.
[0055] In another embodiment, the pharmaceutical composition
comprises 85 to 98% by weight of mannitol.
[0056] In another embodiment, the pharmaceutical composition
comprises 86 to 98% by weight of mannitol.
[0057] In one embodiment, the pharmaceutical composition is a
capsule comprising transnorsertraline, or a pharmaceutically
acceptable salt or solvate thereof, mannitol, talc, sodium starch
glycolate and magnesium stearate in a capsule shell. The capsule
may be prepared at a 0.5, 1.0 or 2.0 mg strength of
transnorsertraline. The capsule may be prepared in a 100, 150, 200
or 300 mg fill weight capsule.
[0058] In another embodiment, the pharmaceutical composition is a
tablet comprising transnorsertraline, or a pharmaceutically
acceptable salt or solvate thereof, mannitol, talc, sodium starch
glycolate and magnesium stearate. The tablet may be coated or
uncoated. The tablet may be prepared at a 0.5, 1.0 or 2.0 mg
strength of transnorsertraline. The tablet may be prepared as a
100, 150, 200 or 300 mg weight tablet.
[0059] In certain embodiments, the mannitol used in the preparation
of the compositions provided herein is Pearlitol 160C.
[0060] In certain embodiments, the sodium starch glycolate used in
the preparation of the compositions provided herein is
Primojel.
[0061] Also provided herein is a method of determining the
suitability of an excipient or combination of excipients for use in
a transnorsertraline formulation provided herein. In one
embodiment, the method comprises the determination of the level of
mannose in a sample of mannitol or a mannitol-containing
formulation provided herein, wherein a level of mannose in mannitol
of less than or equal to about 0.1% by weight indicates suitability
for use in a stable transnorsertraline formulation.
[0062] In another embodiment, a level of mannose in mannitol of
less than or equal to about 0.05% by weight indicates suitability
for use in a stable transnorsertraline formulation.
[0063] In another embodiment, a level of mannose in mannitol of
less than or equal to about 0.02% by weight indicates suitability
for use in a stable transnorsertraline formulation.
[0064] In another embodiment, a level of a level of mannose in
mannitol of less than or equal to about 0.01% by weight indicates
suitability for use in a stable transnorsertraline formulation.
[0065] In one embodiment, the method of determining the level of
mannose in mannitol or a mannitol-containing formulation provided
herein comprises the use of a HPLC (high pressure liquid
chromatography) instrument. In another embodiment, the HPLC
instrument comprises a corona charged aerosol detector.
[0066] In another embodiment, the method of determining the level
of mannose in mannitol or a mannitol-containing formulation
provided herein comprises the use of ion chromatography (IC).
[0067] Also provided herein is a salt of transnorsertraline
selected from the group consisting of hydrochloride, acetate,
L-malate, besylate, benzoate, tosylate, fumarate, hydrobromide,
maleate, citrate, phosphate, succinate, L-tartrate, D-tartrate,
S-mandelate and pyroglutamate.
[0068] In one embodiment, the salt is the hydrochloride salt. In
one embodiment, the hydrochloride salt of transnorsertraline is an
anhydrous solid. In another embodiment, the hydrochloride salt of
transnorsertraline exists as a monohydrate.
[0069] In one embodiment, the transnorsertraline hydrochloride is
(1R,4S)-transnorsertraline hydrochloride, i.e.,
(1R,4S)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
hydrochloride. In another embodiment, the transnorsertraline
hydrochloride is (1S,4R)-transnorsertraline hydrochloride, i.e.,
(1S,4R)-trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine
hydrochloride.
[0070] In one embodiment, the hydrochloride salt of
transnorsertraline is essentially free of water.
[0071] In one embodiment, the hydrochloride salt of
transnorsertraline is the crystalline anhydrate.
[0072] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has an X-ray powder diffraction
pattern comprising peaks at about 14.9, 17.8, 19.2, 23.3, 24.6 and
25.2 degrees 2.theta.. In another embodiment, the hydrochloride
salt of transnorsertraline anhydrate has an X-ray powder
diffraction pattern further comprising peaks at about 5.0 and 21.8
degrees 2.theta..
[0073] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has a calculated X-ray powder
diffraction pattern comprising peaks at about 5.0, 15.0, 18.0,
19.5, 22.0 23.5, 24.8 and 25.4 degrees 2.theta., based on data
collected at about 173 K on a single crystal.
[0074] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has the following approximate unit
cell dimensions:
[0075] a=16.8 .ANG., b=5.2 .ANG., c=19.1 .ANG.,
.alpha.=90.0.degree., .beta.=113.1.degree. and
.gamma.=90.0.degree..
[0076] In another embodiment, the hydrochloride salt of
transnorsertraline anhydrate has the following approximate unit
cell dimensions when measured at about 173 K:
[0077] a=16.83 .ANG., b=5.23 .ANG., c=19.06 .ANG.,
.alpha.=90.00.degree., .beta.=113.10.degree. and
.gamma.=90.00.degree..
[0078] In another embodiment, the approximate unit cell dimensions
are:
[0079] a=16.834 .ANG., b=5.226 .ANG., c=19.059 .ANG.,
.alpha.=90.00.degree., .beta.=113.10.degree. and
.gamma.=90.00.degree..
[0080] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has the space group C2 (no. 5).
[0081] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has a unit cell which contains four
transnorsertraline hydrochlorides (Z=4).
[0082] In one embodiment, the hydrochloride salt of
transnorsertraline anhydrate has a density of about 1.4 g
cm.sup.-3.
[0083] In one embodiment, the hydrochloride salt of
transnorsertraline is a monohydrate.
[0084] In another embodiment, the hydrochloride salt of
transnorsertraline monohydrate is crystalline.
[0085] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has an X-ray powder diffraction
pattern comprising peaks at about 12.1, 13.0, 16.8, 17.8, 20.4,
23.4, 24.2 and 27.1 degrees 2.theta.. In another embodiment, the
hydrochloride salt of transnorsertraline monohydrate has an X-ray
powder diffraction pattern which further comprising peaks at about
20.9, 21.1 and 26.2 degrees 2.theta..
[0086] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has a calculated X-ray powder
diffraction pattern comprising peaks at about 12.1, 13.1, 16.9,
17.9, 20.5, 21.0, 21.3, 23.6, 24.3, 26.3 and 27.2 degrees 2.theta.,
based on data collected at about 150 K on a single crystal.
[0087] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has the following approximate unit
cell dimensions:
[0088] a=7.3 .ANG., b=7.6 .ANG., c=15.3 .ANG.,
.alpha.=90.0.degree., .beta.=90.1.degree. and
.gamma.=90.0.degree..
[0089] In another embodiment, the hydrochloride salt of
transnorsertraline monohydrate has the following approximate unit
cell dimensions when measured at about 150 K:
[0090] a=7.30 .ANG., b=7.56 .ANG., c=15.29 .ANG.,
.alpha.=90.00.degree., .beta.=90.09.degree. and
.gamma.=90.00.degree..
[0091] In another embodiment, the approximate unit cell dimensions
are:
[0092] a=7.296 .ANG., b=7.557 .ANG., c=15.287 .ANG.,
.alpha.=90.00.degree., .beta.=90.09.degree. and
.gamma.=90.00.degree..
[0093] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has the space group P2.sub.1 (no.
4).
[0094] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has a unit cell which contains two
transnorsertraline hydrochlorides (Z=2).
[0095] In one embodiment, the hydrochloride salt of
transnorsertraline monohydrate has a density of about 1.4 g
cm.sup.-3.
[0096] Also provided herein is a method of treating, preventing, or
managing a neurological disorder comprising administering to a
patient a therapeutically or prophylactically effective amount of a
transnorsertraline hydrochloride, or a pharmaceutically acceptable
solvate or stereoisomer thereof.
[0097] In one embodiment, provided herein is a method of treating,
preventing, or managing a neurological disorder comprising
administering to a patient a composition provided herein which
comprises a therapeutically or prophylactically effective amount of
a transnorsertraline or a pharmaceutically acceptable salt, solvate
or stereoisomer thereof.
[0098] In one embodiment, the neurological disorder is depression,
cognitive deficits, fibromyalgia, pain, a sleep related disorder,
chronic fatigue syndrome, attention deficit disorder (ADD),
attention deficit hyperactivity disorder (ADHD), restless leg
syndrome, schizophrenia, anxiety, obsessive compulsive disorder,
posttraumatic stress disorder, seasonal affective disorder (SAD),
premenstrual dysphoria, post-menopausal vasomotor symptoms, a
neurodegenerative disease, manic conditions, dysthymic disorder,
cyclothymic disorder, obesity, or substance abuse or
dependency.
[0099] In one embodiment, the method comprises administering to the
patient a therapeutically or prophylactically effective amount of a
transnorsertraline composition provided herein as an adjunctive
therapy.
[0100] In one embodiment, the method further comprises
administering to the patient a therapeutically or prophylactically
effective amount of one or more additional active agents.
[0101] 5.1 Definitions
[0102] As used herein, and unless otherwise indicated, the terms
"treat," "treating" and "treatment" refer to the eradication or
amelioration of a disease or disorder, or of one or more symptoms
associated with the disease or disorder. In certain embodiments,
the terms refer to minimizing the spread or worsening of the
disease or disorder resulting from the administration of one or
more prophylactic or therapeutic agents to a subject with such a
disease or disorder. In some embodiments, the terms refer to the
administration of a compound provided herein, with or without other
additional active agent, after the onset of symptoms of the
particular disease.
[0103] As used herein, and unless otherwise indicated, the terms
"prevent," "preventing" and "prevention" refer to the prevention of
the onset, recurrence or spread of a disease or disorder, or of one
or more symptoms thereof. In certain embodiments, the terms refer
to the treatment with or administration of a compound provided
herein, with or without other additional active compound, prior to
the onset of symptoms, particularly to patients at risk of disease
or disorders provided herein. The terms encompass the inhibition or
reduction of a symptom of the particular disease. Patients with
familial history of a disease in particular are candidates for
preventive regimens in certain embodiments. In addition, patients
who have a history of recurring symptoms are also potential
candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term
"prophylactic treatment."
[0104] As used herein, and unless otherwise specified, the terms
"manage," "managing," and "management" refer to preventing or
slowing the progression, spread or worsening of a disease or
disorder, or of one or more symptoms thereof. Often, the beneficial
effects that a subject derives from a prophylactic and/or
therapeutic agent do not result in a cure of the disease or
disorder. In this regard, the term "managing" encompasses treating
a patient who had suffered from the particular disease in an
attempt to prevent or minimize the recurrence of the disease.
[0105] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment or
management of a disease or disorder, or to delay or minimize one or
more symptoms associated with the disease or disorder. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment or management
of the disease or disorder. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or
enhances the therapeutic efficacy of another therapeutic agent.
[0106] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease or disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of therapeutic agent, alone or in combination with other
agents, which provides a prophylactic benefit in the prevention of
the disease. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0107] As used herein, and unless otherwise specified, the term
"subject" is defined herein to include animals such as mammals,
including, but not limited to, primates (e.g., humans), cows,
sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
In specific embodiments, the subject is a human.
[0108] As used herein, and unless otherwise specified, the term
"stable" refers to a compound or composition that does not readily
decompose or change in chemical makeup or physical state. A stable
composition or formulation provided herein does not significantly
decompose under normal manufacturing or storage conditions.
[0109] As used herein, and unless otherwise indicated, the term
"pharmaceutically acceptable salt" refers to salts prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
acids and organic acids. Suitable non-toxic acids include inorganic
and organic acids such as, but not limited to, acetic, alginic,
anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic,
glucorenic, galacturonic, glycidic, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic (e.g., L-malic), mandelic (e.g.,
S-mandelic), methanesulfonic, mucic, nitric, pamoic, pantothenic,
phenylacetic, propionic, phosphoric, pyroglutamic, salicylic,
stearic, succinic, sulfanilic, sulfuric, tartaric acid (e.g.,
L-tartaric acid and D-tartaric acid), p-toluenesulfonic and the
like.
[0110] As used herein, and unless otherwise indicated, the term
"solvate" means a compound provided herein or a salt thereof, that
further includes a stoichiometric or non-stoichiometric amount of
solvent bound by non-covalent intermolecular forces. Where the
solvent is water, the solvate is a hydrate.
[0111] The terms "solid form," "solid forms" and related terms,
when used herein refer to a physical form comprising
transnorsertraline or a salt thereof, which is not in a liquid or a
gaseous state. Solid forms may be crystalline, amorphous, partially
crystalline and/or partially amorphous.
[0112] The term "crystalline" and related terms used herein, when
used to describe a substance, component or product, means that the
substance, component or product is substantially crystalline as
determined by X-ray diffraction. See, e.g., Remington's
Pharmaceutical Sciences, 18.sup.th ed., Mack Publishing, Easton
Pa., 173 (1990); The United States Pharmacopeia, 23.sup.rd ed.,
1843-1844 (1995).
[0113] The term "crystal forms" and related terms herein refers to
the various crystalline modifications comprising a given substance,
including single-component crystal forms and multiple-component
crystal forms, and including, but not limited to, polymorphs,
solvates, hydrates, co-crystals and other molecular complexes, as
well as salts, solvates of salts, hydrates of salts, other
molecular complexes of salts, and polymorphs thereof. In certain
embodiments, a crystal form of a substance may be substantially
free of amorphous forms and/or other crystal forms. In other
embodiments, a crystal form of a substance may contain about 1%,
about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about
20%, about 25%, about 30%, about 35%, about 40%, about 45% or about
50% of one or more amorphous forms and/or other crystal forms on a
weight and/or molar basis.
[0114] Different crystal forms may have different physical
properties such as, for example, melting temperatures, heats of
fusion, solubilities, dissolution rates and/or vibrational spectra
as a result of the arrangement or conformation of the molecules or
ions in the crystal lattice. The differences in physical properties
exhibited by crystal forms affect pharmaceutical parameters such as
storage stability, compressibility and density (important in
formulation and product manufacturing), and dissolution rate (an
important factor in bioavailability). Differences in stability can
result from changes in chemical reactivity (e.g., differential
oxidation, such that a dosage form discolors more rapidly when
comprised of one crystal form than when comprised of another
crystal form) or mechanical changes (e.g., tablets crumble on
storage as one crystal form converts into another) or both (e.g.,
tablets of one crystal form are more susceptible to breakdown at
high humidity). As a result of solubility/dissolution differences,
in the extreme case, some crystal form transitions may result in
lack of potency or, at the other extreme, toxicity. In addition,
the physical properties of the crystal form may be important in
processing; for example, one crystal form might be more likely to
form solvates or might be difficult to filter and wash free of
impurities (e.g., particle shape and size distribution might be
different between crystal forms).
[0115] Crystal forms of a substance can be obtained by a number of
methods, as known in the art. Such methods include, but are not
limited to, melt recrystallization, melt cooling, solvent
recrystallization, recrystallization in confined spaces such as,
e.g., in nanopores or capillaries, recrystallization on surfaces or
templates such as, e.g., on polymers, recrystallization in the
presence of additives, such as, e.g., co-crystal counter-molecules,
desolvation, dehydration, rapid evaporation, rapid cooling, slow
cooling, vapor diffusion, sublimation, grinding, solvent-drop
grinding, microwave-induced precipitation, sonication-induced
precipitation, laser-induced precipitation and precipitation from a
supercritical fluid.
[0116] Techniques for characterizing crystal forms and amorphous
forms include, but are not limited to, thermal gravimetric analysis
(TGA), differential scanning calorimetry (DSC), X-ray powder
diffractometry (XRPD), single crystal X-ray diffractometry,
vibrational spectroscopy, e.g., infrared (IR) and Raman
spectroscopy, solid-state nuclear magnetic resonance (NMR)
spectroscopy, optical microscopy, hot stage optical microscopy,
scanning electron microscopy (SEM), electron crystallography and
quantitative analysis, particle size analysis (PSA), surface area
analysis, solubility studies and dissolution studies.
[0117] The terms "polymorph," "polymorphic form" and related terms
herein refer to a crystal form consisting of the same molecule,
molecules and/or ions as another crystal form. The term
"amorphous," "amorphous form," and related terms used herein mean
that the substance, component or product in question is not
substantially crystalline as determined by X-ray diffraction. In
certain embodiments, an amorphous form of a substance may be
substantially free of other amorphous forms and/or crystal forms.
In other embodiments, an amorphous form of a substance may contain
about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about
15%, about 20%, about 25%, about 30%, about 35%, about 40%, about
45% or about 50% of one or more other amorphous forms and/or
crystal forms on a weight and/or molar basis. Amorphous forms of a
substance can be obtained by a number of methods, as known in the
art. Such methods include, but are not limited to, heating, melt
cooling, rapid melt cooling, solvent evaporation, rapid solvent
evaporation, desolvation, sublimation, grinding, cryo-grinding and
freeze drying.
[0118] As used herein, and unless otherwise specified, the terms
"about" and "approximately," when used in connection with doses,
amounts, or weight percent of ingredients of a composition or a
dosage form, mean a dose, amount, or weight percent that is
recognized by those of ordinary skill in the art to provide a
pharmacological effect equivalent to that obtained from the
specified dose, amount, or weight percent. Specifically, the terms
"about" and "approximately," when used in this context, contemplate
a dose, amount, or weight percent within 15%, more specifically
within 10%, more specifically within 5%, of the specified dose,
amount, or weight percent.
[0119] As used herein, a crystal form that is "essentially free" of
water and/or solvent in the crystal lattice has a quantity of water
and/or solvent in the crystal lattice which is, in certain
embodiments approximately near the limit of detection, in other
embodiments approximately at the limit of detection, and in other
embodiments approximately below the limit of detection for solvent
and/or water in the crystal lattice when measured using a
conventional solid-state analytical technique, e.g., a technique
described herein. In certain embodiments, the solid-state
analytical technique used to determine the quantity of water and/or
solvent in the crystal lattice is thermogravimetric analysis. In
other embodiments, the solid-state analytical technique used to
determine the quantity of water and/or solvent in the crystal
lattice is Karl Fischer analysis. In other embodiments, a crystal
form which is "essentially free" of water and/or solvent in the
crystal lattice has a quantity of water and/or solvent which is
less than about 5%, less than about 4%, less than about 3%, less
than about 2%, less than about 1%, less than about 0.9%, less than
about 0.8%, less than about 0.7%, less than about 0.6%, less than
about 0.5%, less than about 0.4%, less than about 0.3%, less than
about 0.2%, less than about 0.1%, or less than about 0.01% of the
total weight of the crystal form.
[0120] As used herein, a crystalline or amorphous form that is
"pure," i.e., substantially free of other crystalline or amorphous
forms, contains less than about 10 percent by weight of one or more
other crystalline or amorphous form, preferably less than about 5
percent by weight of one or more other crystalline or amorphous
form, more preferably less than about 3 percent by weight of one or
more other crystalline or amorphous form, most preferably less than
about 1 percent by weight of one or more other crystalline or
amorphous form.
[0121] As used herein and unless otherwise indicated, a composition
that is "substantially free" of a compound means that the
composition contains less than about 20 percent by weight, more
preferably less than about 10 percent by weight, even more
preferably less than about 5 percent by weight, and most preferably
less than about 3 percent by weight of the compound.
[0122] As used herein, and unless otherwise specified, the term
"neurological disorder" refers to any condition of the central or
peripheral nervous system of a mammal. The term "neurological
disorder" includes, but is not limited to, neurodegenerative
diseases (e.g., Alzheimer's disease, Parkinson's disease and
amyotrophic lateral sclerosis), neuropsychiatric diseases (e.g.,
schizophrenia and anxieties, such as general anxiety disorder), and
affective disorders (e.g., depression and attention deficit
disorder). Exemplary neurological disorders include, but are not
limited to, MLS (cerebellar ataxia), Huntington's disease, Down
syndrome, multi-infarct dementia, status epilecticus, contusive
injuries (e.g., spinal cord injury and head injury), viral
infection induced neurodegeneration, (e.g., AIDS,
encephalopathies), epilepsy, benign forgetfulness, closed head
injury, sleep disorders, depression, dementias, movement disorders,
psychoses, alcoholism, post-traumatic stress disorder and the like.
"Neurological disorder" also includes any condition associated with
the disorder. For instance, a method of treating a
neurodegenerative disorder includes methods of treating loss of
memory and/or loss of cognition associated with a neurodegenerative
disorder. An exemplary method would also include treating or
preventing loss of neuronal function characteristic of
neurodegenerative disorder. "Neurological disorder" also includes
any disease or condition that is implicated, at least in part, in
monoamine (e.g., norepinephrine) signaling pathways (e.g.,
cardiovascular disease).
[0123] As used herein, and unless otherwise specified, the term
"affective disorder" includes depression, attention deficit
disorder, attention deficit disorder with hyperactivity, bipolar
and manic conditions (e.g., bipolar disorder), and the like. The
terms "attention deficit disorder" (ADD) and "attention deficit
disorder with hyperactivity" (ADDH), or attention
deficit/hyperactivity disorder (ADHD), are used herein in
accordance with the accepted meanings as found in Diagnostic and
Statistical Manual of Mental Disorders, 4.sup.th Ed., American
Psychiatric Association (1997) (DSM-IV.TM.).
[0124] As used herein, and unless otherwise specified, the term
"depression" includes all forms of depression including, but not
limited to, major depressive disorder (MDD), seasonal affective
disorder (SAD) and dysthymia. "Major depressive disorder" is used
herein interchangeably with "unipolar depression" and "major
depression." "Depression" may also includes any condition commonly
associated with depression, such as all forms of fatigue (e.g.,
chronic fatigue syndrome) and cognitive deficits.
[0125] As used herein, and unless otherwise specified, the terms
"obsessive-compulsive disorder," "substance abuse," "pre-menstrual
syndrome," "anxiety," "eating disorders" and "migraine" are used
herein in a mariner consistent with their accepted meanings in the
art. See, e.g., DSM-IV.TM.. For example, the term "eating
disorder," as used herein, refers to abnormal compulsions to avoid
eating or uncontrollable impulses to consume abnormally large
amounts of food. These disorders may affect not only the social
well-being, but also the physical well-being of sufferers. Examples
of eating disorders include, but are not limited to, anorexia
nervosa, bulimia, and binge eating.
[0126] As used herein, and unless otherwise specified, the term
"pain" refers to an unpleasant sensory and emotional experience.
The term "pain," as used herein, refers to all categories of pain,
including pain that is described in terms of stimulus or nerve
response, e.g., somatic pain (normal nerve response to a noxious
stimulus) and neuropathic pain (abnormal response of a injured or
altered sensory pathway, often without clear noxious input); pain
that is categorized temporally, e.g., chronic pain and acute pain;
pain that is categorized in terms of its severity, e.g., mild,
moderate, or severe; and pain that is a symptom or a result of a
disease state or syndrome, e.g., inflammatory pain, cancer pain,
AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac
ischaemia, and diabetic peripheral neuropathic pain. See, e.g.,
Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et
al., eds., 12th ed. 1991); Williams et al., J. Med. Chem. 42:
1481-1485 (1999), herein each incorporated by reference in their
entirety. "Pain" is also meant to include mixed etiology pain, dual
mechanism pain, allodynia, causalgia, central pain, hyperesthesia,
hyperpathia, dysesthesia, and hyperalgesia. In addition, the term
"pain" includes pain resulting from dysfunction of the nervous
system: organic pain states that share clinical features of
neuropathic pain and possible common pathophysiology mechanisms,
but are not initiated by an identifiable lesion in any part of the
nervous system.
[0127] The term "somatic pain," as used herein, refers to a normal
nerve response to a noxious stimulus such as injury or illness,
e.g., trauma, burn, infection, inflammation, or disease process
such as cancer, and includes both cutaneous pain (e.g., skin,
muscle or joint derived) and visceral pain (e.g., organ
derived).
[0128] The term "neuropathic pain," as used herein, refers to a
heterogeneous group of neurological conditions that result from
damage to the nervous system. The term also refers to pain
resulting from injury to or dysfunctions of peripheral and/or
central sensory pathways, and from dysfunctions of the nervous
system, where the pain often occurs or persists without an obvious
noxious input. This includes pain related to peripheral
neuropathies as well as central neuropathic pain. Common types of
peripheral neuropathic pain include diabetic neuropathy (also
called diabetic peripheral neuropathic pain, or DN, DPN, or DPNP),
post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN).
Central neuropathic pain, involving damage to the brain or spinal
cord, can occur following stroke, spinal cord injury, and as a
result of multiple sclerosis, and is also encompassed by the term.
Other types of pain that are meant to be included in the definition
of neuropathic pain include, but are not limited to, pain from
neuropathic cancer pain, HIV/AIDS induced pain, phantom limb pain,
and complex regional pain syndrome.
[0129] The term also encompasses the common clinical features of
neuropathic pain including, but not limited to, sensory loss,
allodynia (non-noxious stimuli produce pain), hyperalgesia and
hyperpathia (delayed perception, summation, and painful
aftersensation). Pain is often a combination of nociceptive and
neuropathic types, for example, mechanical spinal pain and
radiculopathy or myelopathy.
[0130] As used herein, and unless otherwise specified, the term
"acute pain" refers to the normal, predicted physiological response
to a noxious chemical, thermal or mechanical stimulus typically
associated with invasive procedures, trauma and disease. It is
generally time-limited, and may be viewed as an appropriate
response to a stimulus that threatens and/or produces tissue
injury. The term also refers to pain which is marked by short
duration or sudden onset.
[0131] As used herein, and unless otherwise specified, the term
"chronic pain" encompasses the pain occurring in a wide range of
disorders, for example, trauma, malignancies and chronic
inflammatory diseases such as rheumatoid arthritis. Chronic pain
may last more than about six months. In addition, the intensity of
chronic pain may be disproportionate to the intensity of the
noxious stimulus or underlying process. The term also refers to
pain associated with a chronic disorder, or pain that persists
beyond resolution of an underlying disorder or healing of an
injury, and that is often more intense than the underlying process
would predict. It may be subject to frequent recurrence.
[0132] As used herein, and unless otherwise specified, the term
"inflammatory pain" is pain in response to tissue injury and the
resulting inflammatory process. Inflammatory pain is adaptive in
that it elicits physiologic responses that promote healing.
However, inflammation may also affect neuronal function.
Inflammatory mediators, including PGE.sub.2 induced by the COX2
enzyme, bradykinins, and other substances, bind to receptors on
pain-transmitting neurons and alter their function, increasing
their excitability and thus increasing pain sensation. Much chronic
pain has an inflammatory component. The term also refers to pain
which is produced as a symptom or a result of inflammation or an
immune system disorder.
[0133] As used herein, and unless otherwise specified, the term
"visceral pain" refers to pain which is located in an internal
organ.
[0134] As used herein, and unless otherwise specified, the term
"mixed etiology pain" refers to pain that contains both
inflammatory and neuropathic components.
[0135] As used herein, and unless otherwise specified, the term
"dual mechanism pain" refers to pain that is amplified and
maintained by both peripheral and central sensitization.
[0136] As used herein, and unless otherwise specified, the term
"causalgia" refers to a syndrome of sustained burning, allodynia,
and hyperpathia after a traumatic nerve lesion, often combined with
vasomotor and sudomotor dysfunction and later trophic changes.
[0137] As used herein, and unless otherwise specified, the term
"central pain" refers to pain initiated by a primary lesion or
dysfunction in the central nervous system.
[0138] As used herein, and unless otherwise specified, the term
"hyperesthesia" refers to increased sensitivity to stimulation,
excluding the special senses.
[0139] As used herein, and unless otherwise specified, the term
"hyperpathia" refers to a painful syndrome characterized by an
abnormally painful reaction to a stimulus, especially a repetitive
stimulus, as well as an increased threshold. It may occur with
allodynia, hyperesthesia, hyperalgesia, or dysesthesia.
[0140] As used herein, and unless otherwise specified, the term
"dysesthesia" refers to an unpleasant abnormal sensation, whether
spontaneous or evoked. In certain embodiments, dysesthesia include
hyperalgesia and allodynia.
[0141] As used herein, and unless otherwise specified, the term
"hyperalgesia" refers to an increased response to a stimulus that
is normally painful. It reflects increased pain on suprathreshold
stimulation.
[0142] As used herein, and unless otherwise specified, the term
"allodynia" refers to pain due to a stimulus that does not normally
provoke pain.
[0143] As used herein, and unless otherwise specified, the term
"Diabetic Peripheral Neuropathic Pain" (DPNP), also called diabetic
neuropathy, DN or diabetic peripheral neuropathy), refers to
chronic pain caused by neuropathy associated with diabetes
mellitus. The classic presentation of DPNP is pain or tingling in
the feet that can be described not only as "burning" or "shooting"
but also as severe aching pain. Less commonly, patients may
describe the pain as itching, tearing, or like a toothache. The
pain may be accompanied by allodynia and hyperalgesia and an
absence of symptoms, such as numbness.
[0144] As used herein, and unless otherwise specified, the term
"Post-Herpetic Neuralgia", also called "Postherpetic Neuralgia
(PHN)", refers to a painful condition affecting nerve fibers and
skin. Without being limited by a particular theory, it is a
complication of shingles, a second outbreak of the varicella zoster
virus (VZV), which initially causes chickenpox.
[0145] As used herein, and unless otherwise specified, the term
"neuropathic cancer pain" refers to peripheral neuropathic pain as
a result of cancer, and can be caused directly by infiltration or
compression of a nerve by a tumor, or indirectly by cancer
treatments such as radiation therapy and chemotherapy
(chemotherapy-induced neuropathy).
[0146] As used herein, and unless otherwise specified, the term
"HIV/AIDS peripheral neuropathy" or "HIV/AIDS related neuropathy"
refers to peripheral neuropathy caused by HIV/AIDS, such as acute
or chronic inflammatory demyelinating neuropathy (AIDP and CIDP,
respectively), as well as peripheral neuropathy resulting as a side
effect of drugs used to treat HIV/AIDS.
[0147] As used herein, and unless otherwise specified, the term
"Phantom Limb Pain" refers to pain appearing to come from where an
amputated limb used to be. Phantom limb pain can also occur in
limbs following paralysis (e.g., following spinal cord injury).
"Phantom Limb Pain" is usually chronic in nature.
[0148] As used herein, and unless otherwise specified, the term
"Trigeminal Neuralgia (TN)" refers to a disorder of the fifth
cranial (trigeminal) nerve that causes episodes of intense,
stabbing, electric-shock-like pain in the areas of the face where
the branches of the nerve are distributed (lips, eyes, nose, scalp,
forehead, upper jaw, and lower jaw). It is also known as the
"suicide disease".
[0149] As used herein, and unless otherwise specified, the term
"Complex Regional Pain Syndrome (CRPS)," formerly known as Reflex
Sympathetic Dystrophy (RSD), refers to a chronic pain condition
whose key symptom is continuous, intense pain out of proportion to
the severity of the injury, which gets worse rather than better
over time. The term encompasses type 1 CRPS, which includes
conditions caused by tissue injury other than peripheral nerve, and
type 2 CRPS, in which the syndrome is provoked by major nerve
injury, and is sometimes called causalgia.
[0150] As used herein, and unless otherwise specified, the term
"fibromyalgia" refers to a chronic condition characterized by
diffuse or specific muscle, joint, or bone pain, along with fatigue
and a range of other symptoms. Previously, fibromyalgia was known
by other names such as fibrositis, chronic muscle pain syndrome,
psychogenic rheumatism and tension myalgias.
[0151] As used herein, and unless otherwise specified, the term
"convulsion" refers to a neurological disorder and is used
interchangeably with "seizure," although there are many types of
seizure, some of which have subtle or mild symptoms instead of
convulsions. Seizures of all types may be caused by disorganized
and sudden electrical activity in the brain. In some embodiments,
convulsions are a rapid and uncontrollable shaking during which the
muscles contract and relax repeatedly.
[0152] The embodiments provided herein can be understood more fully
by reference to the following detailed description and illustrative
examples, which are intended to exemplify non-limiting
embodiments.
[0153] 5.2 Pharmaceutical Compositions
[0154] In one embodiment, provided herein are pharmaceutical
compositions comprising: transnorsertraline, or a pharmaceutically
acceptable salt or solvate thereof; and a pharmaceutically
acceptable carrier or excipient.
[0155] Solid dosage forms of transnorsertraline, or
pharmaceutically acceptable salts or solvates thereof, are desired
for ease of dosing to subjects and patients as well as providing
easy to administer formulations for out-of-clinic dosing. These
dosage forms should be manufacturable on automated equipment and
have acceptable chemical and physical stability that can exceed 1
year. These solid dosage forms of transnorsertraline, or
pharmaceutically acceptable salts or solvates thereof are desired
for development, clinical, and commercial uses.
[0156] Many excipient mixtures with transnorsertraline or a
pharmaceutically acceptable salt or solvate thereof are not
chemically stable. For example, hard gelatin capsules containing
transnorsertraline hydrochloride in combination with the excipients
found in Zoloft.RTM. (sertraline) tablets resulted in a formulation
with poor chemical stability, and in particular with multiple
oxidation products. These excipients are dibasic calcium phosphate
dihydrate, microcrystalline cellulose, sodium starch glycolate,
magnesium stearate, as well as other excipients that are likely in
the coating of these tablets. See Physician's Desk Reference entry
for Zoloft.RTM. (sertraline).
[0157] Therefore, in certain embodiments, the excipients mannitol
or xylitol may be used rather than other common saccharide
excipients (e.g., lactose or cellulose) in order to improve the
stability of the transnorsertraline compositions provided herein.
The use of saccharides other than mannitol or xylitol promotes
degradation of pharmaceutical compositions comprising
transnorsertraline or a pharmaceutically acceptable salt or solvate
thereof.
[0158] In some embodiments, the pharmaceutical compositions
provided herein comprise 10 to 98% by weight of mannitol or
xylitol. In other embodiments, additional excipients used in the
pharmaceutical compositions provided herein may include magnesium
stearate, talc and sodium starch glycolate. Magnesium stearate,
talc and sodium starch glycolate have been found to be compatible
with transnorsertraline, or a pharmaceutically acceptable salts or
solvates thereof, such that these excipients, in addition to
mannitol and xylitol, are preferred.
[0159] Formulations comprising transnorsertraline, or a
pharmaceutically acceptable salts or solvates thereof, and the
excipients described above may be prepared according to the
following processes.
[0160] Blends for capsules formulations containing
transnorsertraline or a pharmaceutically acceptable salt or solvate
thereof may be manufactured using a process in which
transnorsertraline hydrochloride is first blended with talc; this
mixture is then blended with mannitol in geometric dilution. The
remaining mannitol and sodium starch glycolate are blended with the
mixture; lastly, magnesium stearate is blended with the previous
mixture. The blend may be encapsulated on a manual, semi-automatic
or fully automatic capsule filling machine or device.
[0161] The process may be modified such that transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof is first
blended with a portion of talc plus mannitol; this mixture is then
blended with additional mannitol. Then the remaining mannitol and
sodium starch glycolate are blended with the mixture; lastly,
magnesium stearate is blended with the previous mixture. The blend
may be encapsulated on a manual, semi-automatic or fully automatic
capsule filling machine or device.
[0162] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a portion of talc plus mannitol; this
mixture is then blended with a mixture of mannitol plus sodium
starch glycolate; lastly, magnesium stearate is blended with the
previous mixture. The blend may be encapsulated on a manual,
semi-automatic or fully automatic capsule filling machine or
device.
[0163] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol plus sodium
starch glycolate; this mixture is then blended with the remaining
excipients (minus the magnesium stearate). Lastly, magnesium
stearate is blended with the previous mixture. The blend may be
encapsulated on a manual, semi-automatic or fully automatic capsule
filling machine or device.
[0164] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus sodium starch
glycolate; this mixture is then blended with the mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be encapsulated on a manual, semi-automatic or fully automatic
capsule filling machine or device.
[0165] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with talc; this mixture is then blended with the
mannitol. Lastly, magnesium stearate is blended with the previous
mixture. The blend may be encapsulated on a manual, semi-automatic
or fully automatic capsule filling machine or device.
[0166] Another modification of the process may be performed by
transnorsertraline or a pharmaceutically acceptable salt or solvate
thereof with a mixture of talc plus mannitol; this mixture is then
blended with the remaining mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0167] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with mannitol; this mixture is then blended with
a mixture of talc plus mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0168] Another modification of the process may be performed by
blending a portion of magnesium stearate with transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof in each of
the above processes. Lastly, the rest of the magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0169] Blends for tablet formulations containing transnorsertraline
or a pharmaceutically acceptable salt or solvate thereof may be
manufactured using a process in which transnorsertraline or a
pharmaceutically acceptable salt or solvate thereof is first
blended with talc; this mixture is then blended with mannitol in
geometric dilution. Then the remaining mannitol and sodium starch
glycolate are blended with the mixture; lastly, magnesium stearate
is blended with the previous mixture. The blend may be compressed
on a tablet press or machine.
[0170] The process for manufacturing uncoated tablets may be
modified such that transnorsertraline or a pharmaceutically
acceptable salt or solvate thereof is first blended with a portion
of talc plus mannitol; this mixture is then blended with additional
mannitol. Then the remaining mannitol and sodium starch glycolate
are blended with the mixture; lastly, magnesium stearate is blended
with the previous mixture. The blend may be compressed on a tablet
press or machine.
[0171] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a portion of talc plus mannitol; this
mixture is then blended with a mixture of mannitol plus sodium
starch glycolate; magnesium stearate is blended with the previous
mixture. The blend may be compressed on a tablet press or
machine.
[0172] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol plus sodium
starch glycolate; this mixture is then blended with the remaining
excipients (minus the magnesium stearate). Lastly, magnesium
stearate is blended with the previous mixture. The blend may be
compressed on a tablet press or machine.
[0173] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus sodium starch
glycolate; this mixture is then blended with the mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be compressed on a tablet press or machine.
[0174] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with talc; this mixture is then blended with the
mannitol. Lastly, magnesium stearate is blended with the previous
mixture. The blend may be compressed on a tablet press or
machine.
[0175] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol; this
mixture is then blended with the remaining mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be compressed on a tablet press or machine.
[0176] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with mannitol; this mixture is then blended with
a mixture of talc plus mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be compressed on a
tablet press or machine.
[0177] Another modification of the process may be performed by
blending a portion of magnesium stearate with transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof in each of
the above processes. Lastly, the rest of the magnesium stearate may
be blended with the previous mixture. The blend may be compressed
on a tablet press or machine.
[0178] Each of the tablets described above may also be manufactured
as a coated tablet. The coating may be one of three types; these
include compression coating, film-coating, or gelatin coating. The
coatings each may or may not contain a coloring agent; these
coloring agents may be titanium dioxide, and/or soluble colorants,
such as dyes, and/or insoluble colorants such as lakes and/or
colored iron oxides.
[0179] Specific formulations of transnorsertraline or a
pharmaceutically acceptable salt or solvate thereof in capsule or
tablet form are provided below. Formulations of other weights for
capsules or tablets may also be prepared using similar or varied
percentages of excipients.
[0180] A 300.0 mg capsule may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 2.875 mg of talc, 275.0
mg of Pearlitol 160C (mannitol), 18.0 mg of Primojel (sodium starch
glycolate), 3.0 mg of magnesium stearate and a size #1 Swedish
Orange capsule shell #4188.
[0181] Alternatively, a 300.0 mg capsule may be prepared without
Primojel, using 1.125 mg of transnorsertraline hydrochloride
anhydrate, 2.875 mg of talc, 293.0 mg of Pearlitol 160C (mannitol),
3.0 mg of magnesium stearate and a size #1 Swedish Orange capsule
shell #4188.
[0182] A 150.0 mg capsule may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
137.5 mg of Pearlitol 160C (mannitol), 9.0 mg of Primojel (sodium
starch glycolate), 1.5 mg of magnesium stearate and a size 1
Swedish Orange capsule shell #4188.
[0183] Alternatively, a 150.0 mg capsule may be prepared without
Primojel, using 0.5625 mg of transnorsertraline hydrochloride
anhydrate, 1.4375 mg of talc, 146.5 mg of Pearlitol 160C
(mannitol), 1.5 mg of magnesium stearate and a size #1 Swedish
Orange capsule shell #4188.
[0184] A 300.0 mg capsule may also be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 272.0
mg of Pearlitol 160C (mannitol), 18.0 mg of Primojel (sodium starch
glycolate), 3.0 mg of magnesium stearate and a size #1 Swedish
Orange capsule shell #4188.
[0185] Alternatively, the 300.0 mg capsule may be prepared without
Primojel, using 2.25 mg of transnorsertraline hydrochloride
anhydrate, 4.75 mg of talc, 290.0 mg of Pearlitol 160C (mannitol),
3.0 mg of magnesium stearate and a size #1 Swedish Orange capsule
shell #4188.
[0186] Capsules of 100.0, 150.0 and 200.0 mg fill weights having
0.5 mg strength of transnorsertraline in various capsule shell
sizes may be prepared as follows.
[0187] A 100.0 mg capsule may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc, 91.0
mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate), 1.0
mg of magnesium stearate and a size #4 hard gelatin capsule
shell.
[0188] A 150.0 mg capsule may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
137.5 mg of mannitol, 9.0 mg of Primojel (sodium starch glycolate),
1.5 mg of magnesium stearate and a size #3 hard gelatin capsule
shell.
[0189] A 200.0 mg capsule may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
184.0 mg of mannitol, 12.0 mg of Primojel (sodium starch
glycolate), 2.0 mg of magnesium stearate and a size #2 hard gelatin
capsule shell.
[0190] Capsules of 100.0, 150.0 and 200.0 mg fill weights having
1.0 mg strength of transnorsertraline in various capsule shell
sizes are prepared as follows.
[0191] A 100.0 mg capsule may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
90.44 mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate),
1.0 mg of magnesium stearate and a size #4 hard gelatin capsule
shell.
[0192] A 150.0 mg capsule may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
136.94 mg of mannitol, 9.0 mg of Primojel (sodium starch
glycolate), 1.5 mg of magnesium stearate and a size #3 hard gelatin
capsule shell.
[0193] A 200.0 mg capsule may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
183.44 mg of mannitol, 12.0 mg of Primojel (sodium starch
glycolate), 2.0 mg of magnesium stearate and a size #2 hard gelatin
capsule shell.
[0194] Capsules of 100.0, 150.0 and 200.0 mg fill weights having
2.0 mg strength of transnorsertraline in various capsule shell
sizes may be prepared as follows.
[0195] A 100.0 mg capsule may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 86.0
mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate), 1.0
mg of magnesium stearate and a size #4 hard gelatin capsule
shell.
[0196] A 150.0 mg capsule may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 132.5
mg of mannitol, 9.0 mg of Primojel (sodium starch glycolate), 1.5
mg of magnesium stearate and a size #3 hard gelatin capsule
shell.
[0197] A 200.0 mg capsule may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 179.0
mg of mannitol, 12.0 mg of Primojel (sodium starch glycolate), 2.0
mg of magnesium stearate and a size #2 hard gelatin capsule
shell.
[0198] Tablets of 100.0, 150.0 and 200.0 mg weights having 0.5 mg
strength of transnorsertraline may be prepared as follows.
[0199] A 100.0 mg tablet is prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc, 91.0
mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate) and
1.0 mg of magnesium stearate.
[0200] A 100.0 mg tablet may also be prepared without Primojel,
using 0.5625 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 97.0 mg of mannitol and 1.0 mg of magnesium
stearate.
[0201] A 150.0 mg tablet may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
137.5 mg of mannitol, 9.0 mg of Primojel (sodium starch glycolate)
and 1.5 mg of magnesium stearate.
[0202] A 150.0 mg tablet may also be prepared without Primojel,
using 0.5625 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 146.5 mg of mannitol and 1.5 mg of magnesium
stearate.
[0203] A 200.0 mg tablet may be prepared using 0.5625 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
184.0 mg of mannitol, 12.0 mg of Primojel (sodium starch glycolate)
and 2.0 mg of magnesium stearate.
[0204] A 200.0 mg tablet may also be prepared without Primojel,
using 0.5625 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 196.0 mg of mannitol and 2.0 mg of magnesium
stearate.
[0205] Tablets of 100.0, 150.0 and 200.0 mg weights having 1.0 mg
strength of transnorsertraline may be prepared as follows.
[0206] A 100.0 mg tablet may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
90.44 mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate)
and 1.0 mg of magnesium stearate.
[0207] A 100.0 mg tablet may also be prepared without Primojel,
using 1.125 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 96.44 mg of mannitol and 1.0 mg of magnesium
stearate.
[0208] A 150.0 mg tablet may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
136.94 mg of mannitol, 9.0 mg of Primojel (sodium starch glycolate)
and 1.5 mg of magnesium stearate.
[0209] A 150.0 mg tablet may also be prepared without Primojel,
using 1.125 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 145.94 mg of mannitol and 1.5 mg of magnesium
stearate.
[0210] A 200.0 mg tablet may be prepared using 1.125 mg of
transnorsertraline hydrochloride anhydrate, 1.4375 mg of talc,
183.44 mg of mannitol, 12.0 mg of Primojel (sodium starch
glycolate) and 2.0 mg of magnesium stearate.
[0211] A 200.0 mg tablet may also be prepared without Primojel,
using 1.125 mg of transnorsertraline hydrochloride anhydrate,
1.4375 mg of talc, 195.44 mg of mannitol and 2.0 mg of magnesium
stearate.
[0212] Tablets of 100.0, 150.0 and 200.0 mg weights having 2.0 mg
strength of transnorsertraline may be prepared as follows.
[0213] A 100.0 mg tablet may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 86.0
mg of mannitol, 6.0 mg of Primojel (sodium starch glycolate) and
1.0 mg of magnesium stearate.
[0214] A 100.0 mg tablet may also be prepared without Primojel,
using 2.25 mg of transnorsertraline hydrochloride anhydrate, 4.75
mg of talc, 92.0 mg of mannitol and 1.0 mg of magnesium
stearate.
[0215] A 150.0 mg tablet may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 132.5
mg of mannitol, 9.0 mg of Primojel (sodium starch glycolate) and
1.5 mg of magnesium stearate.
[0216] A 150.0 mg tablet may also be prepared without Primojel,
using 2.25 mg of transnorsertraline hydrochloride anhydrate, 4.75
mg of talc, 141.5 mg of mannitol and 1.5 mg of magnesium
stearate.
[0217] A 200.0 mg tablet may be prepared using 2.25 mg of
transnorsertraline hydrochloride anhydrate, 4.75 mg of talc, 179.0
mg of mannitol, 12.0 mg of Primojel (sodium starch glycolate) and
2.0 mg of magnesium stearate.
[0218] A 200.0 mg tablet may also be prepared without Primojel,
using 2.25 mg of transnorsertraline hydrochloride anhydrate, 4.75
mg of talc, 191.0 mg of mannitol and 2.0 mg of magnesium
stearate.
[0219] Capsules and tablets of other weights may be prepared using
10%-98% mannitol, 0.1%-5% magnesium stearate, 0.5%-40% talc, and
0%-10% sodium starch glycolate.
[0220] Capsules and tablets of other weights may also be prepared
using 5%-99% mannitol, 0.05%-15% magnesium stearate, 0%-50% talc,
and 0%-40% sodium starch glycolate.
[0221] Capsules and tablets of other weights may also be prepared
using 5%-99% mannitol, 0%-15% magnesium stearate, 0.5%-50% talc,
and 0%-40% sodium starch glycolate.
[0222] In some embodiments, the pharmaceutical compositions
provided herein may optionally comprise one or more other active
agents. Examples of suitable agents are provided herein
elsewhere.
[0223] Certain pharmaceutical compositions are single unit dosage
forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal,
buccal, trachea, bronchial, or rectal), parenteral (e.g.,
subcutaneous, intravenous, bolus injection, intramuscular, or
intraarterial), or transdermal administration to a patient.
Examples of dosage forms include, but are not limited to: tablets;
caplets; capsules, such as soft elastic or hard gelatin capsules;
cachets; troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; Unit Dose Vial (UDV)
nebulized solutions; dressings; creams; plasters; solutions;
patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid
dosage forms suitable for oral or mucosal administration to a
patient, including suspensions (e.g., aqueous or non-aqueous liquid
suspensions, oil-in-water emulsions, or a water-in-oil liquid
emulsions), solutions, and elixirs; liquid dosage forms suitable
for parenteral administration to a patient; and sterile solids
(e.g., crystalline or amorphous solids) that can be reconstituted
to provide liquid dosage forms suitable for parenteral
administration to a patient.
[0224] In one embodiment, the dosage form is an oral dosage form.
In another embodiment, the oral dosage form is a capsule, tablet,
or syrup. In another embodiment, the dosage form is a parenteral
dosage form.
[0225] The formulation should suit the mode of administration. For
example, oral administration may require enteric coatings to
protect the compounds administered from degradation within the
gastrointestinal tract. In another example, the compounds may be
administered in a liposomal formulation to shield the compounds
from degradative enzymes, facilitate transport in circulatory
system, and effect delivery across cell membranes to intracellular
sites.
[0226] The composition, shape, and type of dosage forms will
typically vary depending on their use. For example, a dosage form
used in the acute treatment of a disease may contain larger amounts
of one or more of the active ingredients it comprises than a dosage
form used in the chronic treatment of the same disease. Similarly,
a parenteral dosage form may contain smaller amounts of one or more
of the active ingredients it comprises than an oral dosage form
used to treat the same disease. These and other ways in which
specific dosage forms will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0227] The selected dosage level and frequency of administration of
the pharmaceutical compositions provided herein will depend upon a
variety of factors including the route of administration, the time
of administration, the rate of excretion of the therapeutic agents,
the duration of the treatment, other drugs, compounds and/or
materials used in the patient, the age, sex, weight, condition,
general health and prior medical history of the patient being
treated, and like factors well known in the medical arts. For
example, the dosage regimen is likely to vary with pregnant women,
nursing mothers and children relative to healthy adults. A
physician having ordinary skill in the art can readily determine
and prescribe the therapeutically effective amount of the
pharmaceutical composition required.
[0228] The pharmaceutical compositions provided herein may further
comprise a pharmaceutically acceptable carrier. The term
"pharmaceutically acceptable carrier" means one or more
pharmaceutically acceptable excipients. Examples of such excipients
are well known in the art and are listed in the USP (XXI)/NF (XVI),
incorporated herein in its entirety by reference thereto, and
include without limitation, binders, diluents, fillers,
disintegrants, super disintegrants, lubricants, surfactants,
antiadherents, stabilizers, and the like. The term "additives" is
synonymous with the term "excipients," as used herein.
[0229] The term "pharmaceutically acceptable" is used herein to
refer to those compounds, materials, compositions and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for administration to and for use in contact with the
tissues and fluids of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable medically sound
benefit/risk ratio. Further, the term "pharmaceutically acceptable
excipient" is employed to mean that there are no untoward chemical
or physical incompatibilities between the active ingredients and
any of the excipient components of a given dosage form. For
example, an untoward chemical reaction is one wherein the potency
of compounds used in methods and compositions provided herein is
detrimentally reduced or increased due to the addition of one or
more excipients. Another example of an untoward chemical reaction
is one wherein the taste of the dosage form becomes excessively
sweet, sour or the like to the extent that the dosage form becomes
unpalatable. Each excipient must be "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not injurious to the patient.
[0230] Physical incompatibility refers to incompatibility among the
various components of the dosage form and any excipient(s) thereof.
For example, the combination of the excipient(s) and the active
ingredient(s) may form an excessively hygroscopic mixture or an
excessively segregated mixture to the degree that the desired shape
of the dosage form (e.g., tablet, troche etc.), its stability or
the like cannot be sufficiently maintained to be able to administer
the dosage form in compliance with a prescribed dosage regimen as
desired.
[0231] With the exception of capsule shells, it is noted that all
excipients used in the pharmaceutical compositions or dosage forms
provided herein preferably meet or exceed the standards for
pharmaceutical ingredients and combinations thereof in the USP/NF.
The purpose of the USP/NF is to provide authoritative standards and
specifications for materials and substances and their preparations
that are used in the practice of the healing arts. The USP/NF
establish titles, definitions, descriptions, and standards for
identity, quality, strength, purity, packaging and labeling, and
also, where practicable, provide bioavailability, stability,
procedures for proper handling and storage and methods for their
examination and formulas for their manufacture or preparation.
[0232] The stability of a pharmaceutical product may be defined as
the capability of a particular formulation, in a specific
container, to remain within its physical, chemical,
microbiological, therapeutic and toxicological specification,
although there are exceptions, and to maintain at least about 80%,
preferably about 90%, more preferably about 95% of labeled potency
level. Thus, for example, expiration dating is defined as the time
in which the pharmaceutical product will remain stable when stored
under recommended conditions.
[0233] Many factors affect the stability of a pharmaceutical
product, including the stability of the therapeutic ingredient(s),
the potential interaction between therapeutic and inactive
ingredients and the like. Physical factors such as heat, light and
moisture may initiate or accelerate chemical reactions.
[0234] 5.2.1 Oral Dosage Forms
[0235] Pharmaceutical compositions provided herein that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington: The Science
and Practice of Pharmacy, 20.sup.th Ed. (2000).
[0236] Typical oral dosage forms are prepared by combining the
active ingredients in an intimate admixture with at least one
excipient according to conventional pharmaceutical compounding
techniques. Excipients can take a wide variety of forms depending
on the form of preparation desired for administration.
[0237] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0238] Large-scale production of pharmaceutical compositions or
dosage forms in accordance with the present disclosure may require,
in addition to the therapeutic drug ingredients, excipients or
additives including, but not limited to, diluents, binders,
lubricants, disintegrants, colorants, flavors, sweetening agents
and the like or mixtures thereof. By the incorporation of these and
other additives, a variety of dosage forms (e.g., tablets,
capsules, caplets, troches and the like) may be made. These
include, for example, hard gelatin capsules, caplets, sugar-coated
tablets, enteric-coated tablets to delay action, multiple
compressed tablets, prolonged-action tablets, tablets for solution,
effervescent tablets, buccal and sublingual tablets, troches and
the like.
[0239] Hence, unit dose forms or dosage formulations of a
pharmaceutical composition provided herein, such as a troche, a
tablet or a capsule, may be formed by combining a desired amount of
each of the active ingredients with one or more pharmaceutically
compatible or acceptable excipients, as described below, in
pharmaceutically compatible amounts to yield a unit dose dosage
formulation the desired amount of each active ingredient. The dose
form or dosage formulation may be formed by methods well known in
the art.
[0240] Tablets are often a preferred dosage form because of the
advantages afforded both to the patient (e.g., accuracy of dosage,
compactness, portability, blandness of taste as well as ease of
administration) and to the manufacturer (e.g., simplicity and
economy of preparation, stability as well as convenience in
packaging, shipping and dispensing). Tablets are solid
pharmaceutical dosage forms containing therapeutic drug substances
with or without suitable additives.
[0241] Tablets are typically made by molding, by compression or by
generally accepted tablet forming methods. Accordingly, compressed
tablets are usually prepared by large-scale production methods
while molded tablets often involve small-scale operations. For
example, there are three general methods of tablet preparation: (1)
the wet-granulation method; (2) the dry-granulation method; and (3)
direct compression. These methods are well known to those skilled
in the art. See, Remington: The Science and Practice of Pharmacy,
20.sup.th Ed. (2000). See, also, U.S. Pharmacopeia XXI, U.S.
Pharmacopeial Convention, Inc., Rockville, Md. (1985).
[0242] Various tablet formulations may be made in accordance with
the methods and compositions provided herein. These include tablet
dosage forms such as sugar-coated tablets, film-coated tablets,
enteric-coated tablets, multiple-compressed tablets, prolonged
action tablets and the like. Sugar-coated tablets (SCT) are
compressed tablets containing a sugar coating. Such coatings may be
colored and are beneficial in covering up drug substances
possessing objectionable tastes or odors and in protecting
materials sensitive to oxidation. Film-coated tablets (FCT) are
compressed tablets that are covered with a thin layer or film of a
water-soluble material. A number of polymeric substances with
film-forming properties may be used. The film coating imparts the
same general characteristics as sugar coating with the added
advantage of a greatly reduced time period required for the coating
operation. Enteric-coated tablets are also suitable for use in
methods and compositions provided herein. Enteric-coated tablets
(ECT) are compressed tablets coated with substances that resist
dissolution in gastric fluid but disintegrate in the intestine.
Enteric coating can be used for tablets containing drug substances
that are inactivated or destroyed in the stomach, for those which
irritate the mucosa or as a means of delayed release of the
medication.
[0243] Multiple compressed tablets (MCT) are compressed tablets
made by more than one compression cycle, such as layered tablets or
press-coated tablets. Layered tablets are prepared by compressing
additional tablet granulation on a previously compressed
granulation. The operation may be repeated to produce multilayered
tablets of two, three or more layers. Typically, special tablet
presses are required to make layered tablets. See, for example,
U.S. Pat. No. 5,213,738, incorporated herein in its entirety by
reference thereto.
[0244] Press-coated tablets are another form of multiple compressed
tablets. Such tablets, also referred to as dry-coated tablets, are
prepared by feeding previously compressed tablets into a tableting
machine and compressing another granulation layer around the
preformed tablets. These tablets have all the advantages of
compressed tablets, i.e., slotting, monogramming, speed of
disintegration, etc., while retaining the attributes of sugar
coated tablets in masking the taste of the drug substance in the
core tablet. Press-coated tablets can also be used to separate
incompatible drug substances. Further, they can be used to provide
an enteric coating to the core tablets. Both types of tablets
(i.e., layered tablets and press-coated tablets) may be used, for
example, in the design of prolonged-action dosage forms.
[0245] Pharmaceutical compositions or unit dosage forms provided
herein in the form of prolonged-action tablets may comprise
compressed tablets formulated to release the drug substance in a
manner to provide medication over a period of time. There are a
number of tablet types that include delayed-action tablets in which
the release of the drug substance is prevented for an interval of
time after administration or until certain physiological conditions
exist. Repeat action tablets may be formed that periodically
release a complete dose of the drug substance to the
gastrointestinal fluids. Also, extended release tablets that
continuously release increments of the contained drug substance to
the gastrointestinal fluids may be formed.
[0246] In order for medicinal substances or therapeutic ingredients
provided herein, with or without excipients, to be made into solid
dosage forms (e.g., tablets) with pressure, using available
equipment, it is necessary that the material, either in crystalline
or powdered form, possess a number of physical characteristics.
These characteristics can include, for example, the ability to flow
freely, as a powder to cohere upon compaction, and to be easily
released from tooling. Since most materials have none or only some
of these properties, methods of tablet formulation and preparation
have been developed to impart these desirable characteristics to
the material which is to be compressed into a tablet or similar
dosage form.
[0247] As noted, in addition to the drugs or therapeutic
ingredients, tablets and similar dosage forms may contain a number
of materials referred to as excipients or additives. These
additives are classified according to the role they play in the
formulation of the dosage form such as a tablet, a caplet, a
capsule, a troche or the like. One group of additives include, but
are not limited to, binders, diluents (fillers), disintegrants,
lubricants, and surfactants. In one embodiment the diluent, binder,
disintegrant, and lubricant are not the same.
[0248] A binder is used to provide a free-flowing powder from the
mix of tablet ingredients so that the material will flow when used
on a tablet machine. The binder also provides a cohesiveness to the
tablet. Too little binder will give flow problems and yield tablets
that do not maintain their integrity, while too much can adversely
affect the release (dissolution rate) of the drugs or active
ingredients from the tablet. Thus, a sufficient amount of binder
should be incorporated into the tablet to provide a free-flowing
mix of the tablet ingredients without adversely affecting the
dissolution rate of the drug ingredients from the tablet. With
lower dose tablets, the need for good compressibility can be
eliminated to a certain extent by the use of suitable diluting
excipients called compression aids. The amount of binder used
varies upon the type of formulation and mode of administration, and
is readily discernible to those of ordinary skill in the art.
[0249] Binders suitable for use with dosage formulations provided
herein include, but are not limited to, corn starch, potato starch,
or other starches, gelatin, natural and synthetic gums such as
acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone (povidone),
methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl
cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline
cellulose or mixtures thereof. Suitable forms of microcrystalline
cellulose can include, for example, the materials sold as AVICEL
PH-101, AVICEL PH-103 and AVICEL PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa., U.S.A.).
[0250] Fillers or diluents arc used to give the powder (e.g., in
the tablet or capsule) bulk so that an acceptable size tablet,
capsule or other desirable dosage form is produced. Typically,
therapeutic ingredients are formed in a convenient dosage form of
suitable size by the incorporation of a diluent therewith. As with
the binder, binding of the drug(s) to the filler may occur and
affect bioavailability. Consequently, a sufficient amount of filler
should be used to achieve a desired dilution ratio without
detrimentally affecting release of the drug ingredients from the
dosage form containing the filler. Further, a filler that is
physically and chemically compatible with the therapeutic
ingredient(s) of the dosage form should be used. The amount of
filler used varies upon the type of formulation and mode of
administration, and is readily discernible to those of ordinary
skill in the art. Examples of fillers include, but are not limited
to, lactose, glucose, sucrose, fructose, talc, calcium carbonate
(e.g., granules or powder), microcrystalline cellulose, powdered
cellulose, dextrates, kaolin, mannitol, xylitol, silicic acid,
sorbitol, starch, pre-gelatinized starch, or mixtures thereof.
[0251] Disintegrants are used to cause the dose form (e.g., tablet)
to disintegrate when exposed to an aqueous environment. Too much of
a disintegrant will produce tablets which may disintegrate in the
bottle due to atmospheric moisture. Too little may be insufficient
for disintegration to occur and may thus alter the rate and extent
of release of drug(s) or active ingredient(s) from the dosage form.
Thus, a sufficient amount of disintegrant that is neither too
little nor too much to detrimentally alter the release of the drug
ingredients should be used to form the dosage forms provided
herein. The amount of disintegrant used varies based upon the type
of formulation and mode of administration, and is readily
discernible to the skilled artisan. Examples of disintegrants
include, but are not limited to, agar-agar, alginic acid, calcium
carbonate, microcrystalline cellulose, croscarmellose sodium,
crospovidone, polacrilin potassium, sodium starch glycolate, potato
or tapioca starch, other starches, pre-gelatinized starch, clays,
other algins, other celluloses, gums, or mixtures thereof.
[0252] When a dose form that dissolves fairly rapidly upon
administration to the subject, e.g., in the subject's stomach is
desired, a super disintegrant can be used, such as, but not limited
to, croscarmellose sodium or sodium starch glycolate. The term
"super disintegrant," as used herein, means a disintegrant that
results in rapid disintegration of drug or active ingredient in the
stomach after oral administration. Use of a super disintegrant can
facilitate the rapid absorption of drug or active ingredient(s)
which may result in a more rapid onset of action.
[0253] Adhesion of the dosage form ingredients to blender walls,
hoppers, screens, transfer containers, and all equipment surfaces,
including but not limited to punches of the manufacturing machine
(e.g., a tableting machine) and dosators of the capsule
manufacturing machine must be minimized or ideally avoided.
Adhesion is a particular issue for the composition provided herein.
For example, when drug accumulates on the punch surfaces, it causes
the tablet surface to become pitted and therefore unacceptable.
Also, sticking of drug or excipients in this way requires
unnecessarily high ejection forces when removing the tablet from
the die. Excessive ejection forces may lead to a high breakage rate
and increase the cost of production not to mention excessive wear
and tear on the dies. In practice, it is possible to reduce
sticking by wet-massing or by the use of lubricants, e.g.,
magnesium stearate, and other anti-adherent excipients. However,
selection of a drug salt with good anti-adhesion properties can
also minimize these problems.
[0254] As noted, the lubricant is used to enhance the flow of the
tableting powder mix to the tablet machine and to prevent sticking
of the tablet in the die after the tablet is compressed. Too little
lubricant will not permit satisfactory tablets to be made and too
much may produce a tablet with a water-impervious hydrophobic
coating, which can form because lubricants are usually hydrophobic
materials such as stearic acid, magnesium stearate, calcium
stearate and the like. Further, a water-impervious hydrophobic
coating can inhibit disintegration of the tablet and dissolution of
the drug ingredient(s). Thus, a sufficient amount of lubricant
should be used that readily allows release of the compressed tablet
from the die without forming a water-impervious hydrophobic coating
that detrimentally interferes with the desired disintegration
and/or dissolution of the drug ingredient(s).
[0255] Example of suitable lubricants for use with the compositions
provided herein include, but are not limited to, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl
laurate, agar, or mixtures thereof. Additional lubricants include,
for example, a syloid silica gel (AEROSIL 200, manufactured by W.R.
Grace Co. of Baltimore Md.), a coagulated aerosol of synthetic
silica (marketed by Deaussa Co. of Plano, Tex.), CAB-O-SIL (a
pyrogenic silicon dioxide product sold by Cabot Co. of Boston,
Mass.) or mixtures thereof.
[0256] Surfactants are used in dosage forms to improve the wetting
characteristics and/or to enhance dissolution, and are particularly
useful in pharmaceutical compositions or dosage forms containing
poorly soluble or insoluble drug(s) or active ingredients. Examples
of surfactants include, but are not limited to, polyoxyethylene
sorbitan fatty acid esters, such as those commercially available as
TWEENs (e.g. Tween 20 and Tween 80), polyethylene glycols,
polyoxyethylene stearates, polyvinyl alcohol, polyvinylpyrrolidone,
poly(oxyethylene)/poly(oxypropylene) block co-polyers such as
poloxamers (e.g., commercially available as PLURONICs), and
tetrafunctional block copolymers derived from sequential addition
of propylene oxide and ethylene oxide to ethylenediamine, such as
polyxamines (e.g., commercially as TETRONICs (BASF)), dextran,
lecithin, dialkylesters of sodium sulfosuccinic acid, such as
Aerosol OT, sodium lauryl sulfate, alkyl aryl polyether sulfonates
or alcohols, such as TRITON X-200 or tyloxapol,
p-isononylphenoxypoly (glycidol) (e.g. Olin-10G or Surfactant 10-G
(Olin Chemicals), or mixtures thereof. Other pharmaceutically
acceptable surfactants are well known in the art, and are described
in detail in the Handbook of Pharmaceutical Excipients.
[0257] Other classes of additives for use with the pharmaceutical
compositions or dosage forms provided herein include, but are not
limited to, anti-caking or antiadherent agents, antimicrobial
preservatives, coating agents, colorants, desiccants, flavors and
perfumes, plasticizers, viscosity increasing agents, sweeteners,
buffering agents, humectants and the like.
[0258] Examples of anti-caking agents include, but are not limited
to, calcium silicate, magnesium silicate, silicon dioxide,
colloidal silicon dioxide, talc, or mixtures thereof.
[0259] Examples of antimicrobial preservatives include, but are not
limited to, benzalkonium chloride solution, benzethonium chloride,
benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium
chloride, chlorobutanol, cresol, dehydroacetic acid, ethylparaben,
methylparaben, phenol, phenylethyl alcohol, phenylmercuric acetate,
phenylmercuric nitrate, potassium sorbate, propylparaben, sodium
benzoate, sodium dehydroacetate, sodium propionate, sorbic acid,
thimersol, thymol, or mixtures thereof.
[0260] Examples of colorants for use with compositions provided
herein include, but are not limited to, pharmaceutically acceptable
dyes and lakes, caramel, red ferric oxide, yellow ferric oxide or
mixtures thereof. Examples of desiccants include, but are not
limited to, calcium chloride, calcium sulfate, silica gel or
mixtures thereof.
[0261] Flavors that may be used include, but are not limited to,
acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde,
caraway, caraway oil, cardamom oil, cardamom seed, compound
cardamom tincture, cherry juice, cinnamon, cinnamon oil, clove oil,
cocoa, coriander oil, eriodictyon, eriodictyon fluidextract, ethyl
acetate, ethyl vanillin, eucalyptus oil, fennel oil, glycyrrhiza,
pure glycyrrhiza extract, glycyrrhiza fluidextract, lavender oil,
lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg
oil, orange flower oil, orange flower water, orange oil, sweet
orange peel tincture, compound orange spirit, peppermint,
peppermint oil, peppermint spirit, pine needle oil, rose oil,
stronger rose water, spearmint, spearmint oil, thymol, tolu balsam
tincture, vanilla, vanilla tincture, and vanillin or mixture
thereof.
[0262] Examples of sweetening agents include, but are not limited
to, aspartame, dextrates, mannitol, saccharin, saccharin calcium,
saccharin sodium, sorbitol, sorbitol solution, or mixtures
thereof.
[0263] Exemplary plasticizers for use with the compositions
provided herein include, but are not limited to, castor oil,
diacetylated monoglycerides, diethyl phthalate, glycerin, mono-and
di-acetylated monoglycerides, polyethylene glycol, propylene
glycol, and triacetin or mixtures thereof. Suitable viscosity
increasing agents include, but are not limited to, acacia, agar,
alamic acid, aluminum monostearate, bentonite, bentonite magma,
carbomer 934, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, carboxymethylcellulose sodium 12,
carrageenan, cellulose, microcrystalline cellulose, gelatin, guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose (Nos. 2208; 2906; 2910), magnesium aluminum
silicate, methylcellulose, pectin, polyvinyl alcohol, povidone,
silica gel, colloidal silicon dioxide, sodium alginate, tragacanth
and xanthan gum or mixtures thereof.
[0264] Buffering agents that may be used in the compositions
provided herein include, but are not limited to, magnesium
hydroxide, aluminum hydroxide and the like, or mixtures thereof.
Examples of humectants include, but are not limited to, glycerol,
other humectants or mixtures thereof.
[0265] The dosage forms provided herein may further include one or
more of the following: (1) dissolution retarding agents, such as
paraffin; (2) absorption accelerators, such as quaternary ammonium
compounds; (3) wetting agents, such as, for example, cetyl alcohol
and glycerol monostearate; (4) absorbents, such as kaolin and
bentonite clay; (5) antioxidants, such as water soluble
antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium
bisulfate, sodium metabisulfate, sodium sulfite and the like), oil
soluble antioxidants (e.g., ascorbyl palmitate, hydroxyanisole
(BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate,
alpha-tocopherol and the like); and (6) metal chelating agents,
such as citric acid, ethylenediamine tetracetic acid (EDTA),
sorbitol, tartaric acid, phosphoric acid and the like.
[0266] Dosage forms provided herein, such as a tablet or caplet,
may optionally be coated. Inert coating agents typically comprise
an inert film-forming agent dispersed in a suitable solvent, and
may further comprise other pharmaceutically acceptable adjuvants,
such as colorants and plasticizers. Suitable inert coating agents,
and methods for coating, are well known in the art, including
without limitation aqueous or non-aqueous film coating techniques
or microencapsulation. Examples of film-forming or coating agents
include, but are not limited to, gelatin, pharmaceutical glaze,
shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline
wax, celluloses, such as methylcellulose, hydroxymethyl cellulose,
carboxymethylcellulose, cellulose acetate phthalate, hydroxypropyl
methylcellulose (e.g., Nos.: 2208, 2906, 2910), hydroxypropyl
cellulose, hydroxypropyl methyl cellulose phthalate (e.g., Nos.:
200731, 220824), hydroxyethylcellulose,
methylhydroxyethylcellulose, ethylcellulose which may optionally be
cross-linked, and sodium carboxymethyl cellulose; vinyls, such as
polyvinyl pyrrolidione, polyvinyl acetate phthalate,; glycols, such
as polyethylene glycols; acrylics, such as dimethylaminoethyl
methacrylate-methacrylate acid ester copolymer, and
ethylacrylate-methylmethacrylate copolymer; and other carbohydrate
polymers, such as maltodextrins, and polydextrose, or mixtures
thereof. The amount of coating agent and the carrier vehicle
(aqueous or non-aqueous) used varies upon the type of formulation
and mode of administration, and is readily discernible to those of
ordinary skill in the art.
[0267] A coating of a film forming polymer may optionally be
applied to a tablet or caplet (e.g., a capsule shaped tablet) by
using one of several types of equipment such as a conventional
coating pan, Accelacota, High-Cola or Worster air suspension
column. Such equipment typically has an exhaust-system to remove
dust and solvent or water vapors to facilitate quick drying. Spray
guns or other suitable atomizing equipment may be introduced into
the coating pans to provide spray patterns conducive to rapid and
uniform coverage of the tablet bed. Normally, heated or cold drying
air is introduced over the tablet bed in a continuous or alternate
fashion with a spray cycle to expedite drying of the film coating
solution.
[0268] The coating solution may be sprayed by using positive
pneumatic displacement or peristaltic pump systems in a continuous
or intermittent spray-dry cycle. The particular type of spray
application is selected depending upon the drying efficiency of the
coating pan. In most cases, the coating material is sprayed until
the tablets are uniformly coated to the desired thickness and the
desired appearance of the tablet is achieved. Many different types
of coatings may be applied such as enteric, slow release coatings
or rapidly dissolving type coatings for fast acting tablets.
Preferably, rapidly dissolving type coatings are used to permit
more rapid release of the active ingredients, resulting in hastened
onset. The thickness of the coating of the film forming polymer
applied to a tablet, for example, may vary. However, it is
preferred that the thickness simulate the appearance, feel (tactile
and mouth feel) and function of a gelatin capsule. Where more rapid
or delayed release of the therapeutic agent(s) is desired, one
skilled in the art would easily recognize the film type and
thickness, if any, to use based on characteristics such as desired
blood levels of active ingredient, rate of release, solubility of
active ingredient, and desired performance of the dosage form.
[0269] A number of suitable film forming agents for use in coating
a final dosage form, such as tablets include, for example,
methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6
cps), polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10
cps), various derivatives of methacrylic acids and methacrylic acid
esters, cellulose acetate phthalate or mixtures thereof.
[0270] The method of preparation and the excipients or additives to
be incorporated into dosage form (such as a tablet or caplet) are
selected in order to give the tablet formulation the desirable
physical characteristics while allowing for ease of manufacture
(e.g., the rapid compression of tablets). After manufacture, the
dose form preferably should have a number of additional attributes,
for example, for tablets, such attributes include appearance,
hardness, disintegration ability and uniformity, which are
influenced both by the method of preparation and by the additives
present in the tablet formulation.
[0271] Further, it is noted that tablets or other dosage forms of
the pharmaceutical compositions provided herein should retain their
original size, shape, weight and color under normal handling and
storage conditions throughout their shelf life. Thus, for example,
excessive powder or solid particles at the bottom of the container,
cracks or chips on the face of a tablet, or appearance of crystals
on the surface of tablets or on container walls are indicative of
physical instability of uncoated tablets. Hence, the effect of
mild, uniform and reproducible shaking and tumbling of tablets
should be undertaken to insure that the tablets have sufficient
physical stability. Tablet hardness can be determined by
commercially available hardness testers. In addition, the in vitro
availability of the active ingredients should not change
appreciably with time.
[0272] The tablets, and other dosage forms of the pharmaceutical
compositions provided herein, such as dragees, capsules, pills and
granules, may optionally be scored or prepared with coatings and
shells, such as enteric coatings and other coatings well known in
the pharmaceutical formulating art.
[0273] 5.2.2 Parenteral Dosage Forms
[0274] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms arc preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0275] Suitable vehicles that can be used to provide parenteral
dosage forms provided herein are well known to those skilled in the
art. Examples include, but are not limited to: Water for Injection
USP; aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
[0276] Compounds that increase the solubility of one or more of the
active ingredients (i.e., the compounds used in methods and
compositions provided herein) disclosed herein can also be
incorporated into the parenteral dosage forms.
[0277] 5.2.3 Transdermal, Topical and Mucosal Dosage Forms
[0278] Transdermal, topical, and mucosal dosage forms provided
herein include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th
eds., Mack Publishing, Easton Pa. (1980 & 1990); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Transdermal dosage forms include
"reservoir type" or "matrix type" patches, which can be applied to
the skin and worn for a specific period of time to permit the
penetration of a desired amount of active ingredients.
[0279] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms provided herein are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied.
[0280] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients provided herein. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue.
[0281] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts or solvates (e.g.,
hydrates) of the active ingredients can be used to further adjust
the properties of the resulting composition.
[0282] 5.2.4 Compositions with Enhanced Stability
[0283] The suitability of a particular excipient may also depend on
the specific active ingredients in the dosage form. For example,
the decomposition of an active ingredient, e.g., transnorsertraline
or a pharmaceutically acceptable salt or solvate thereof, may be
accelerated by certain excipients. Certain saccharides,
particularly mono- or di-saccharides, may accelerate the
decomposition of the active ingredient of a composition provided
herein. For example, compositions comprising transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof should
contain little, if any, lactose, mannose, xylose, or
microcrystalline cellulose.
[0284] Further provided are anhydrous pharmaceutical compositions
and dosage forms comprising active ingredients, since water can
facilitate the degradation of some compounds. For example, the
addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0285] Anhydrous pharmaceutical compositions and dosage forms
provided herein can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms provided herein may be
anhydrous if substantial contact with moisture and/or humidity
during manufacturing, packaging, and/or storage is expected.
[0286] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0287] Also provided herein are pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the
rate by which an active ingredient will decompose. Such compounds,
which are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0288] Specific non-limiting examples of stable pharmaceutical
compositions are provided herein in Examples 6.1 to 6.13.
[0289] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients.
[0290] 5.2.5 Delayed Release Dosage Forms
[0291] Active ingredients used in methods and compositions provided
herein can be administered by controlled release means or by
delivery devices that are well known to those of ordinary skill in
the art. Examples include, but are not limited to, those described
in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and
4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543,
5,639,476, 5,354,556, and 5,733,566, each of which is incorporated
herein by reference. Such dosage forms can be used to provide slow
or controlled-release of one or more active ingredients using, for
example, hydroxypropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the compounds used in methods and
compositions provided herein. Thus, provided herein are single unit
dosage forms suitable for oral administration such as, but not
limited to, tablets, capsules, gelcaps, and caplets that are
adapted for controlled-release.
[0292] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0293] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release other amounts of drug to maintain this level of
therapeutic or prophylactic effect over an extended period of time.
In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0294] 5.2.6 Kits
[0295] In some cases, active ingredients used in methods and
compositions provided herein are preferably not administered to a
patient at the same time or by the same route of administration.
Therefore, provided are kits which, when used by the medical
practitioner, can simplify the administration of appropriate
amounts of active ingredients to a patient.
[0296] In one embodiment, the kit comprises a single unit dosage
form of the compounds used in methods and composition provided
herein, or a pharmaceutically acceptable salt, solvate, or
stereoisomer thereof, and a single unit dosage form of another
agent that may be used in combination with those compounds. Kits
provided herein can further comprise devices that are used to
administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.
[0297] Kits provided herein can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
[0298] Certain embodiments are exemplified in the following
non-limiting examples. It will be apparent to those skilled in the
art that many modifications, both to materials and methods, can be
practiced without departing from the spirit and scope of this
disclosure.
[0299] 5.3 Methods of Treatment, Prevention and Management
[0300] In one embodiment, provided herein is a method of treating,
preventing, or managing a central nervous system disorder
comprising administering to a subject (e.g., patient) a
therapeutically or prophylactically effective amount of a
formulation of salt or polymorph of transnorsertraline as disclosed
herein.
[0301] In one embodiment, provided herein is a method of effecting
an anti-depressant-like effect. The method comprises administering
to a subject a therapeutically effective amount of a formulation,
salt or polymorph of transnorsertraline as disclosed herein.
Anti-depressant-like effects may be measured using an animal model
of disease, such as those known in the art and those described
herein.
[0302] In other embodiments, the neurological disorder is:
depression (e.g., major depressive disorder, bipolar depression,
unipolar disorder, dysthymia and seasonal affective disorder);
cognitive deficits; fibromyalgia; pain (e.g., neuropathic pain);
sleep related disorders (e.g., sleep apnea, insomnia, narcolepsy,
cataplexy) including those sleep disorders which are produced by
psychiatric conditions; chronic fatigue syndrome; attention deficit
disorder (ADD); attention deficit hyperactivity disorder (ADHD);
restless leg syndrome; schizophrenia; anxieties (e.g., general
anxiety disorder, social anxiety disorder, panic disorder);
obsessive compulsive disorder; posttraumatic stress disorder;
seasonal affective disorder (SAD); premenstrual dysphoria;
post-menopausal vasomotor symptoms (e.g., hot flashes, night
sweats); neurodegenerative disease (e.g., Parkinson's disease,
Alzheimer's disease and amyotrophic lateral sclerosis); manic
conditions; dysthymic disorder; cyclothymic disorder; obesity; and
substance abuse or dependency (e.g., cocaine addiction, nicotine
addiction). In another embodiment, the compounds provided herein
are useful to treat two or more conditions/disorders, which are
comorbid, such as cognitive deficit and depression.
[0303] In certain embodiments, neurological disorders include
cerebral function disorders, including without limitation, senile
dementia, Alzheimer's type dementia, cognition, memory loss,
amnesia/amnestic syndrome, epilepsy, disturbances of consciousness,
coma, lowering of attention, speech disorders, Lennox syndrome,
autism, and hyperkinetic syndrome.
[0304] Neuropathic pain includes without limitation post herpetic
(or post-shingles) neuralgia, reflex sympathetic
dystrophy/causalgia or nerve trauma, phantom limb pain, carpal
tunnel syndrome, and peripheral neuropathy (such as diabetic
neuropathy or neuropathy arising from chronic alcohol use).
[0305] Other exemplary diseases and conditions that may be treated,
prevented, and/or managed using the methods and/or compositions
provided herein include, but are not limited to: obesity; migraine
or migraine headache; urinary incontinence, including without
limitation involuntary voiding of urine, dribbling or leakage of
urine, stress urinary incontinence (SUI), urge incontinence,
urinary exertional incontinence, reflex incontinence, passive
incontinence, and overflow incontinence; and sexual dysfunction, in
men or women, including without limitation sexual dysfunction
caused by psychological and/or physiological factors, erectile
dysfunction, premature ejaculation, vaginal dryness, lack of sexual
excitement, inability to obtain orgasm, and psycho-sexual
dysfunction, including without limitation, inhibited sexual desire,
inhibited sexual excitement, inhibited female orgasm, inhibited
male orgasm, functional dyspareunia, functional vaginismus, and
atypical psychosexual dysfunction.
[0306] In one embodiment, the neurological disorder is depression.
In another embodiment, the neurological disorder is anxiety
disorder. In another embodiment, the neurological disorder is pain.
In another embodiment, the neurological disorder is neuropathic
pain. In another embodiment, the neuropathic pain is diabetic
neuropathy.
[0307] In one embodiment, the neurological disorder is a
neurodegenerative disease. In one embodiment, the neurodegenerative
disease is Parkinson's disease. In another embodiment, the
neurodegenerative disorder is Alzheimer's disease.
[0308] In one embodiment, the neurological disorder is
incontinence, for example, urinary incontinence. In another
embodiment, the neurological disorder is sexual dysfunction.
[0309] In one embodiment, the neurological disorder is obesity, and
the therapeutically effective amount of compound to supply to a
patient is sufficient so that said patient feels satiated.
[0310] In one embodiment, the compounds described herein treat,
prevent, and/or manage a central nervous disorder, without causing
addiction to said compounds.
[0311] In some embodiments, the methods provided herein may
optionally comprise the administration of one or more of other
active agents. Such other agents include, but are not limited to,
those drugs or therapies conventionally used for the treatment,
prevention, and/or management of neurological disorders provided
herein.
[0312] Any suitable route of administration can be employed for
providing the patient with a therapeutically or prophylactically
effective dose of an active ingredient. For example, oral, mucosal
(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral
(e.g., intravenous, intramuscular), transdermal, and subcutaneous
routes can be employed. Exemplary routes of administration include
oral, transdermal, and mucosal. Suitable dosage forms for such
routes include, but are not limited to, transdermal patches,
ophthalmic solutions, sprays, and aerosols. Transdermal
compositions can also take the form of creams, lotions, and/or
emulsions, which can be included in an appropriate adhesive for
application to the skin or can be included in a transdermal patch
of the matrix or reservoir type as are conventional in the art for
this purpose. An exemplary transdermal dosage form is a "reservoir
type" or "matrix type" patch, which is applied to the skin and worn
for a specific period of time to permit the penetration of a
desired amount of active ingredient. The patch can be replaced with
a fresh patch when necessary to provide constant administration of
the active ingredient to the patient.
[0313] The amount to be administered to a subject (e.g., patient)
to treat, prevent, and/or manage the disorders described herein
will depend upon a variety of factors including the activity of the
particular compound employed, the route of administration, the time
of administration, the rate of excretion or metabolism of the
particular compound being employed, the duration of the treatment,
other drugs, compounds and/or materials used in combination with
the particular compound employed, the age, sex, weight, condition,
general health, and prior medical history of the patient being
treated, and like factors well known in the medical arts.
[0314] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount required.
For example, the physician or veterinarian could start doses of the
compounds employed at levels lower than that required in order to
achieve the desired therapeutic effect and gradually increase the
dosage until the desired effect is achieved.
[0315] In general, a suitable daily dose of a compound provided
herein will be that amount of the compound which is the lowest dose
effective to produce a therapeutic or prophylactic effect. Such an
effective dose will generally depend upon the factors described
above. Generally, oral, intravenous, intracerebroventricular and
subcutaneous doses of the compounds provided herein for a patient
will range from about 0.005 mg per kilogram to about 5 mg per
kilogram of body weight per day. In one embodiment, the oral dose
of a compound provided herein will range from about 0.05 mg to
about 5 g per day. In one embodiment, the oral dose of a compound
provided herein will range from about 0.1 mg to about 3 g per day.
In one embodiment, the oral dose of a compound provided herein will
range from about 0.25 mg to about 2 g per day. In one embodiment,
the oral dose of a compound provided herein will range from about
0.5 mg to about 1 g per day. In one embodiment, the oral dose of a
compound provided herein will range from about 1 mg to about 500 mg
per day. In another embodiment, the oral dose of a compound
provided herein will range from about 2 mg to about 250 mg per day.
In another embodiment, the oral dose of a compound provided herein
will range from about 3 mg to about 300 mg per day. In one
embodiment, the oral dose of a compound provided herein will range
from about 5 mg to about 300 mg per day. In another embodiment, the
oral dose of a compound provided herein will range from about 10 mg
to about 100 mg per day. In another embodiment, the oral dose of a
compound provided herein will range from about 25 mg to about 50 mg
per day. In another embodiment, the oral dose of a compound
provided herein will range from about 30 mg to about 200 mg per
day. Each of the above-recited dosage ranges may be formulated as a
single or multiple unit dosage formulations.
6. EXAMPLES
[0316] 6.1 Stable Formulations of Transnorsertraline
[0317] Solid dosage forms of transnorsertraline, or
pharmaceutically acceptable salts or solvates thereof, are desired
for ease of dosing to subjects and patients as well as providing
easy to administer formulations for out-of-clinic dosing. These
dosage forms should be manufacturable on automated equipment and
have acceptable chemical and physical stability that can exceed 1
year.
[0318] Multiple excipient mixtures with transnorsertraline or a
pharmaceutically acceptable salt or solvate thereof were prepared
and evaluated for chemical stability and manufacturing feasibility.
These excipients included several diluents: dibasic calcium
phosphate anhydrous, dibasic calcium phosphate dihydrate,
pregelatinized starch, microcrystalline cellulose, lactose, and
mannitol; disintegrants: croscarmellose sodium, pregelatinized
starch, and sodium starch glycolate; glidants: talc, colloidal
silica, and fumed silica; and several lubricants: stearic acid,
sodium stearyl fumarate, hydrogenated vegetable oil and magnesium
stearate. Most combinations were unacceptable due to poor chemical
stability; some combinations were also unacceptable due to poor
manufacturing attributes, including poor blend homogeneity, low
drug content in capsules, and variable drug content in
capsules.
[0319] For example, when hard gelatin capsules were formulated, it
was found that the combination of transnorsertraline hydrochloride
with the excipients found in Zoloft.RTM. (sertraline) tablets
resulted in a formulation with poor chemical stability, and in
particular with multiple oxidation products. These excipients are
dibasic calcium phosphate dihydrate, microcrystalline cellulose,
sodium starch glycolate, magnesium stearate, as well as other
excipients that are likely in the coating of these tablets. See
Physician's Desk Reference entry for Zoloft.RTM. (sertraline).
[0320] Additionally, most of the combinations tested using the
above excipients were unacceptable due to poor chemical stability.
Some combinations were also unacceptable due to poor manufacturing
attributes, including poor blend homogeneity, low drug content in
capsule and variable drug content in capsules. Stable combinations
included mannitol, sodium starch glycolate, talc, and magnesium
stearate in a clear or colored hard gelatin capsule shell.
[0321] Stability Study Results
[0322] The following blends or blends-in-capsules were prepared
while developing a stable transnorsertraline hydrochloride capsule
formulation. In some cases, the length of testing varies. However,
uniform analytical methods were used for all samples. Degradation
is reported as total impurities based on an Area % from HPLC
analysis of the formulations, as is common when reporting such
results when a change is prior to a complete characterization of
the degradation. Percent degradation was measured after storage at
40.degree. C./75% relative humidity, a typical and required storage
condition.
TABLE-US-00001 TABLE 1 Stability of Transnorsertraline HCl
Excipient Blends Blend: TNS TNS TNS TNS TNS HCl A.sup.1 HCl A.sup.1
HCl A.sup.1 HCl A.sup.1 HCl A.sup.1 A-Tab.sup.2 PRUV.sup.3 Stearic
Di-Tab.sup.4 Di-Tab.sup.4 Acid Starch MCC.sup.6 MCC.sup.6
1500.sup.5 AcDiSol.sup.7 Talc % Deg..sup.8: 0.93% 1.12% 0.39% 1.49%
0.88% Time: 5 weeks 2 weeks 4 weeks 5 weeks 5 weeks Blend: TNS HCl
A.sup.1 TNS HCl M.sup.9 TNS HCl M.sup.9 mannitol mannitol
A-Tab.sup.2 Citric acid % Deg..sup.8: 0.26% 0.20% 0.40% Time: 2
weeks 5 weeks 5 weeks .sup.1transnorsertraline hydrochloride
anhydrate. .sup.2dibasic calcium phosphate, anhydrous. .sup.3sodium
stearyl fumarate. .sup.4dibasic calcium phosphate dihydrate.
.sup.5pregelatinized starch. .sup.6microcrystalline cellulose.
.sup.7croscarmellose sodium .sup.8% degradation when stored at
40.degree. C./75% relative humidity. .sup.9transnorsertraline
hydrochloride monohydrate.
[0323] As a result of the stability study, the following
formulation was selected. Capsule formulations of
transnorsertraline hydrochloride were prepared at 1.0 mg strength
(based on the free base) per capsule. The capsule formulations
include mannitol, sodium starch glycolate, talc and magnesium
stearate in a colored hard gelatin capsule shell:
[0324] 6.2 1.0 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate
TABLE-US-00002 Ingredient Form. 1 Form. 2 Transnorsettraline HCl
1.125 mg 1.125 mg Anhydrate Talc 2.875 mg 2.875 mg Pearlitol 160C
(mannitol) 275.0 mg 293.0 mg Sodium starch glycolate 18.0 mg --
(Primojel) Magnesium stearate 3.0 mg 3.0 mg TOTAL 300.0 mg 300.0 mg
Size #1 Swedish Orange 1 each 1 each capsule shell # 4188
[0325] Stable 1.0 mg strength (based on free base) capsules of
transnorsertraline hydrochloride anhydrate (1.125 mg of HCl salt)
were prepared according to formulation 1. The formulation was
initially prepared by hand, showing acceptable blend and capsule
homogeneity; a stability study showed improved chemical stability
of these capsules compared to other formulations. Manufacturing
feasibility was demonstrated when a batch according to formulation
1 was manufactured on typical pharmaceutical equipment; acceptable
blend and capsule homogeneity, as well as improved chemical
stability was shown for this batch.
[0326] Manufacturing feasibility was demonstrated on a larger blend
size when a batch according to formulation 1 was manufactured on
typical pharmaceutical equipment; acceptable blend and capsule
homogeneity, as well as improved chemical stability have been shown
for this batch. Another capsule may be prepared according to
formulation 2, wherein no sodium starch glycolate is present.
[0327] 6.3 0.5 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate
TABLE-US-00003 Ingredient Form. 1 Form. 2 Transnorsertraline HCl
0.5625 mg 0.5625 mg Anhydrate Talc 1.4375 mg 1.4375 mg Pearlitol
160C (mannitol) 137.5 mg 146.5 mg Sodium starch glycolate 9.0 mg --
(Primojel) Magnesium stearate 1.5 mg 1.5 mg TOTAL 150.0 mg 150.0 mg
Size #1 Swedish Orange 1 each 1 each capsule shell # 4188
[0328] Stable 0.5 mg strength (based on free base) capsules of
transnorsertraline hydrochloride anhydrate (0.5625 mg of HCl salt)
were prepared according to formulation 1. Manufacturing feasibility
was demonstrated on a large blend size when a batch of formulation
1 was manufactured on typical pharmaceutical equipment; acceptable
blend and capsule homogeneity, as well as improved chemical
stability have been shown for this batch. Another capsule may be
prepared according to formulation 2, wherein no sodium starch
glycolate is present.
[0329] 6.4 2.0 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate
TABLE-US-00004 Ingredient Form. 1 Form. 2 Transnorsertraline HCl
Anhydrate 2.25 mg 2.25 mg Talc 4.75 mg 4.75 mg Pearlitol 160C
(mannitol) 272.0 mg 290.0 mg Sodium starch glycolate (Primojel)
18.0 mg -- Magnesium stearate 3.0 mg 3.0 mg TOTAL 300.0 mg 300.0 mg
Size #1 Swedish Orange capsule shell # 1 each 1 each 4188
[0330] Stable 2.0 mg strength (based on free base) capsules of
transnorsertraline hydrochloride anhydrate (2.25 mg of HCl salt)
were prepared according to formulation 1. Manufacturing feasibility
was demonstrated on a large blend size when a batch of formulation
1 was manufactured on typical pharmaceutical equipment; acceptable
blend and capsule homogeneity, as well as improved chemical
stability have been shown for this batch. Another capsule may be
prepared according to formulation 2, wherein no sodium starch
glycolate is present.
[0331] 6.5 0.5 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate in Various Capsule
Sizes
TABLE-US-00005 Ingredient Size # 2 Size # 3 Size # 4
Transnorsertraline HCl 0.5625 mg 0.5625 mg 0.5625 mg Anhydrate Talc
1.4375 mg 1.4375 mg 1.4375 mg Mannitol 184.0 mg 137.5 mg 91.0 mg
Sodium starch 12.0 mg 9.0 mg 6.0 mg glycolate (Primojel) Magnesium
stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg Size
#2 hard gelatin 1 each -- -- capsule shell Size #3 hard gelatin --
1 each -- capsule shell Size #4 hard gelatin -- -- 1 each capsule
shell
[0332] Representative 0.5 mg strength (based on free base) capsules
of transnorsertraline hydrochloride anhydrate (0.5625 mg) may be
prepared in three fill weights of 200.0 mg, 150.0 mg and 100.0 mg
for capsules of various sizes as shown above.
[0333] 6.6 1.0 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate in Various Capsule
Sizes
TABLE-US-00006 Ingredient Size # 2 Size # 3 Size # 4
Transnorsertraline HCl 1.125 mg 1.125 mg 1.125 mg Anhydrate Talc
1.4375 mg 1.4375 mg 1.4375 mg Mannitol 183.44 mg 136.94 mg 90.44 mg
Sodium starch 12.0 mg 9.0 mg 6.0 mg glycolate (Primojel) Magnesium
stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg Size
#2 hard gelatin 1 each -- -- capsule shell Size #3 hard gelatin --
1 each -- capsule shell Size #4 hard gelatin -- -- 1 each capsule
shell
[0334] Representative 1.0 mg strength (based on free base) capsules
of transnorsertraline hydrochloride anhydrate (1.125 mg of HCl
salt) may be prepared in three fill weights of 200.0 mg, 150.0 mg
and 100.0 mg for capsules of various sizes as shown above.
[0335] 6.7 2.0 mg Strength Capsule Formulations of
Transnorsertraline Hydrochloride Anhydrate in Various Capsule
Sizes
TABLE-US-00007 Ingredient Size # 2 Size # 3 Size # 4
Transnorsertraline HCl 2.25 mg 2.25 mg 2.25 mg Anhydrate Talc 4.75
mg 4.75 mg 4.75 mg Mannitol 179.0 mg 132.5 mg 86.0 mg Sodium starch
glycolate 12.0 mg 9.0 mg 6.0 mg (Primojel) Magnesium stearate 2.0
mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg Size #2 hard
gelatin capsule 1 each -- -- shell Size #3 hard gelatin capsule --
1 each -- shell Size #4 hard gelatin capsule -- -- 1 each shell
[0336] Representative 2.0 mg strength (based on free base) capsules
of transnorsertraline hydrochloride anhydrate (2.25 mg of HCl salt)
may be prepared in three fill weights of 200.0 mg, 150.0 mg and
100.0 mg for capsules of various sizes as shown above.
[0337] In above examples, if transnorsertraline hydrochloride
monohydrate is used in place of transnorsertraline hydrochloride
anhydrate, a conversion factor of 1.186 mg of transnorsertraline
hydrochloride monohydrate equivalent to 1.0 mg transnorsertraline
free base can be applied to each formulation.
[0338] 6.8 Manufacturing Processes for Capsule Formulations of
Transnorsertraline
[0339] Blends for capsules formulations containing
transnorsertraline or a pharmaceutically acceptable salt or solvate
thereof may be manufactured using a process in which
transnorsertraline hydrochloride is first blended with talc; this
mixture is then blended with mannitol in geometric dilution. The
remaining mannitol and sodium starch glycolate are blended with the
mixture; lastly, magnesium stearate is blended with the previous
mixture. The blend may be encapsulated on a manual, semi-automatic
or fully automatic capsule filling machine or device.
[0340] The process may be modified such that transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof is first
blended with a portion of talc plus mannitol; this mixture is then
blended with additional mannitol. Then the remaining mannitol and
sodium starch glycolate are blended with the mixture; lastly,
magnesium stearate is blended with the previous mixture. The blend
may be encapsulated on a manual, semi-automatic or fully automatic
capsule filling machine or device.
[0341] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a portion of talc plus mannitol; this
mixture is then blended with a mixture of mannitol plus sodium
starch glycolate; lastly, magnesium stearate is blended with the
previous mixture. The blend may be encapsulated on a manual,
semi-automatic or fully automatic capsule filling machine or
device.
[0342] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol plus sodium
starch glycolate; this mixture is then blended with the remaining
excipients (minus the magnesium stearate). Lastly, magnesium
stearate is blended with the previous mixture. The blend may be
encapsulated on a manual, semi-automatic or fully automatic capsule
filling machine or device.
[0343] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus sodium starch
glycolate; this mixture is then blended with the mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be encapsulated on a manual, semi-automatic or fully automatic
capsule filling machine or device.
[0344] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with talc; this mixture is then blended with the
mannitol. Lastly, magnesium stearate is blended with the previous
mixture. The blend may be encapsulated on a manual, semi-automatic
or fully automatic capsule filling machine or device.
[0345] Another modification of the process may be performed by
transnorsertraline or a pharmaceutically acceptable salt or solvate
thereof with a mixture of talc plus mannitol; this mixture is then
blended with the remaining mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0346] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with mannitol; this mixture is then blended with
a mixture of talc plus mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0347] Another modification of the process may be performed by
blending a portion of magnesium stearate with transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof in each of
the above processes. Lastly, the rest of the magnesium stearate is
blended with the previous mixture. The blend may be encapsulated on
a manual, semi-automatic or fully automatic capsule filling machine
or device.
[0348] 6.9 0.5 mg Strength Tablet Formulations of
Transnorsertraline Hydrochloride Anhydrate of Various Tablet
Sizes
TABLE-US-00008 Tablet Ingredient Tablet size #1 Tablet size #2 size
#3 Transnorsertraline HCl 0.5625 mg 0.5625 mg 0.5625 mg Anhydrate
Talc 1.4375 mg 1.4375 mg 1.4375 mg Mannitol 184.0 mg 137.5 mg 91.0
mg Sodium starch glycolate 12.0 mg 9.0 mg 6.0 mg (Primojel)
Magnesium stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg
100.0 mg Transnorsertraline HCl 0.5625 mg 0.5625 mg 0.5625 mg
Anhydrate Talc 1.4375 mg 1.4375 mg 1.4375 mg Mannitol 196.0 mg
146.5 mg 97.0 mg Magnesium stearate 2.0 mg 1.5 mg 1.0 mg TOTAL
200.0 mg 150.0 mg 100.0 mg
[0349] Representative 0.5 mg strength (based on free base) tablets
of transnorsertraline hydrochloride anhydrate (0.5625 mg of HCl
salt) may be prepared in three sizes as shown above, with or
without the use of sodium starch glycolate (Primojel).
[0350] 6.10 1.0 mg Strength Tablet Formulations of
Transnorsertraline Hydrochloride Anhydrate of Various Tablet
Sizes
TABLE-US-00009 Tablet Ingredient Tablet size #1 Tablet size #2 size
#3 Transnorsertraline HCl 1.125 mg 1.125 mg 1.125 mg Anhydrate Talc
1.4375 mg 1.4375 mg 1.4375 mg Mannitol 183.44 mg 136.94 mg 90.44 mg
Sodium starch glycolate 12.0 mg 9.0 mg 6.0 mg (Primojel) Magnesium
stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg
Transnorsertraline HCl 1.125 mg 1.125 mg 1.125 mg Anhydrate Talc
1.4375 mg 1.4375 mg 1.4375 mg Mannitol 195.44 mg 145.94 mg 96.44 mg
Magnesium stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg
100.0 mg
[0351] Representative 1.0 mg strength (based on free base) tablets
of transnorsertraline hydrochloride anhydrate (1.125 mg of HCl
salt) may be prepared in three sizes as shown above, with or
without the use of sodium starch glycolate (Primojel).
[0352] 6.11 2.0 mg Strength Tablet Formulations of
Transnorsertraline Hydrochloride Anhydrate of Various Tablet
Sizes
TABLE-US-00010 Tablet Tablet Tablet Ingredient size #1 size #2 size
#3 Transnorsertraline HCl 2.25 mg 2.25 mg 2.25 mg Anhydrate Talc
4.75 mg 4.75 mg 4.75 mg Mannitol 179.0 mg 132.5 mg 86.0 mg Sodium
starch glycolate 12.0 mg 9.0 mg 6.0 mg (Primojel) Magnesium
stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg
Transnorsertraline HCl 2.25 mg 2.25 mg 2.25 mg Anhydrate Talc 4.75
mg 4.75 mg 4.75 mg Mannitol 191.0 mg 141.5 mg 92.0 mg Magnesium
stearate 2.0 mg 1.5 mg 1.0 mg TOTAL 200.0 mg 150.0 mg 100.0 mg
[0353] Representative 2.0 mg strength (based on free base) tablets
of transnorsertraline hydrochloride anhydrate (2.25 mg of HCl salt)
may be prepared in three sizes as shown above, with or without the
use of sodium starch glycolate (Primojel).
[0354] In above examples, if transnorsertraline hydrochloride
monohydrate is used in place of transnorsertraline hydrochloride
anhydrate, a conversion factor of 1.186 mg of transnorsertraline
hydrochloride monohydrate equivalent to 1.0 mg transnorsertraline
free base can be applied.
[0355] 6.12 Manufacturing Processes for Uncoated Tablet
Formulations of Transnorsertraline
[0356] Blends for tablet formulations containing transnorsertraline
or a pharmaceutically acceptable salt or solvate thereof may be
manufactured using a process in which transnorsertraline or a
pharmaceutically acceptable salt or solvate thereof is first
blended with talc; this mixture is then blended with mannitol in
geometric dilution. Then the remaining mannitol and sodium starch
glycolate are blended with the mixture; lastly, magnesium stearate
is blended with the previous mixture. The blend may be compressed
on a tablet press or machine.
[0357] The process for manufacturing uncoated tablets may be
modified such that transnorsertraline or a pharmaceutically
acceptable salt or solvate thereof is first blended with a portion
of talc plus mannitol; this mixture is then blended with additional
mannitol. Then the remaining mannitol and sodium starch glycolate
are blended with the mixture; lastly, magnesium stearate is blended
with the previous mixture. The blend may be compressed on a tablet
press or machine.
[0358] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a portion of talc plus mannitol; this
mixture is then blended with a mixture of mannitol plus sodium
starch glycolate; lastly, magnesium stearate is blended with the
previous mixture. The blend may be compressed on a tablet press or
machine.
[0359] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol plus sodium
starch glycolate; this mixture is then blended with the remaining
excipients (minus the magnesium stearate). Lastly, magnesium
stearate is blended with the previous mixture. The blend may be
compressed on a tablet press or machine.
[0360] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus sodium starch
glycolate; this mixture is then blended with the mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be compressed on a tablet press or machine.
[0361] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with talc; this mixture is then blended with the
mannitol. Lastly, magnesium stearate is blended with the previous
mixture. The blend is compressed on a tablet press or machine.
[0362] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with a mixture of talc plus mannitol; this
mixture is then blended with the remaining mannitol. Lastly,
magnesium stearate is blended with the previous mixture. The blend
may be compressed on a tablet press or machine.
[0363] Another modification of the process may be performed by
blending transnorsertraline or a pharmaceutically acceptable salt
or solvate thereof with mannitol; this mixture is then blended with
a mixture of talc plus mannitol. Lastly, magnesium stearate is
blended with the previous mixture. The blend may be compressed on a
tablet press or machine.
[0364] Another modification of the process may be performed by
blending a portion of magnesium stearate with transnorsertraline or
a pharmaceutically acceptable salt or solvate thereof in each of
the above processes. Lastly, the rest of the magnesium stearate is
blended with the previous mixture. The blend may be compressed on a
tablet press or machine.
[0365] 6.13 Manufacturing Processes for Coated Tablets of
Transnorsertraline
[0366] Each of the tablets described above may also be manufactured
as a coated tablet. The coating may be one of three types; these
include compression coating, film-coating, or gelatin coating. The
coatings each may or may not contain a coloring agent; these
coloring agents may be titanium dioxide, and/or soluble colorants,
such as dyes, and/or insoluble colorants such as lakes and/or
colored iron oxides.
[0367] 6.14 Solid Forms of Transnorsertraline Salts
[0368] Sixteen salts of transnorsertraline were investigated using
polarized light microscopy (PSM) in order to identify salts of
transnorsertraline in crystalline form: hydrochloride, citrate,
fumarate, maleate, phosphate, succinate, sulfate, L-tartrate,
besylate, tosylate, L-malate, S-mandelate, acetate, benzoate,
hydrobromide and pyroglutamate.
[0369] Samples were observed using the Nikon Microphot polarizing
light microscope. Samples were prepared in Cargille liquid with a
refractive index of 1.600. Samples were observed using
cross-polarized light and imaged using cross-polarized light with a
quarter wave plate. Initial determination of crystallinity of
transnorsertraline salts was performed by direct observation under
cross-polarized light (Table 2). Any salt tested that contained
solid material lacking birefringence when observed under
cross-polarized light, indicating amorphous or partially amorphous
solids, was rejected.
TABLE-US-00011 TABLE 2 PLM Observations for Transnorsertraline
Salts Salt Crystallinity Crystal Habit/Description HCl Yes Long
Needles Citrate Yes Rods and Needles Fumarate Yes Small Needles
Maleate Yes Small Plates Phosphate Yes Agglomerated Fines Succinate
Partial Large Plates and Amorphous Solids Sulfate Yes Agglomerated
Fines L-tartrate Yes Large Plates Besylate Yes Large Rods Tosylate
Yes Needles L-malate Yes Very Small Plates, Agglomerates
S-mandelate Yes Large Rods Acetate Yes Large Thin Plates Benzoate
Yes Thick Rods HBr (18) Yes Fine Needles Pyroglutamate Yes Large
Plates and Very Small Plates "Fine or Fines" are defined in this
report as particles having widths <10 .mu.m
[0370] Each salt, with the exception of the succinate salt,
exhibited good birefringence under cross-polarized light,
indicating a crystalline solid. Crystal habits ranged from fine
needles to large plates (Table 2).
[0371] 6.15 Thermal Properties of Transnorsertraline Salts
[0372] Each of the salts of transnorsertraline of Example 6.14 were
analyzed using direct scanning calorimetry (DSC) or hotstage. All
DSC analyses were performed using Perkin Elmer DSC 7 Differential
Scanning calorimeter. Each sample was analyzed in a crimped pan
with a pinhole, heated under a nitrogen purge at a rate of
10.degree. C./min, from a starting temperature of 25.degree. C. up
to a final temperature of 325.degree. C. Hotstage samples were
analyzed using the Nikon Microphot Polarized Light Microscope
equipped with a Linkam Hotstage THMS 600. Each sample was placed on
a cover slip, located on hotstage furnace, insulated from above by
2 layers (2 cover slips with air space between layers) and hotstage
cover, and heated at a rate of 10.degree. C./min. DSC and hotstage
results are shown in Table 3.
TABLE-US-00012 TABLE 3 DSC and Hotstage Results for
Transnorsertraline Salts Salt Peak (.degree. C.) Onset (.degree.
C.) .DELTA.H.sub.f (J/g) Hotstage Observations HCl 299.7 298.5
108.3 Sublimes at 170.degree. C. Sublimate melts at 250.degree. C.
Citrate not measured not measured not measured Melts at 119.degree.
C. Fumarate 226.7 223.9 178.9 Sublimes at 181.degree. C. Sublimate
melts at 225.degree. C. Maleate 177.4 174.8 49.1 Melts at
168.degree. C. Phosphate not measured not measured not measured
Melts at 158.degree. C. Recrystallizes at 172.degree. C. Melt at
239.degree. C. Succinate not measured not measured not measured not
measured Sulfate 125.5, 196.1, 114.1, not 33.2, not Melts at 190
and 204.degree. C. 224.6 measured, not measured, not Exotherm:
148.2 measured. measured. L-tartrate 128.7, 204.5 115.3, 198.6
10.6, 171.7 Melts at 120 and 200.degree. C. Besylate 192.2 190.7
52.1 Melts at 187.degree. C. Tosylate 248.9 247.0 54.7 Melts at
237.degree. C. L-malate 179.9 177.3 79.9 Melts at 165.degree. C.
S-mandelate not measured. not measured not measured Melts at
80.degree. C. Acetate 146.5 143.5 137.3 Melts at 112.degree. C.
Benzoate 151.4 149.4 83.5 Melts at 127.degree. C. HBr 294.5 292.5
118.5 Sublimes at 189.degree. C. Sublimate melts at 288.degree. C.
Pyroglutamate not measured not measured not measured not
measured
[0373] 6.16 Moisture Content and Hygroscopicity of
Transnorsertraline Salts
[0374] The sixteen salts of transnorsertraline of Example 6.14 were
analyzed for moisture content and hygroscopicity. Each salt was
analyzed by coulometric titration using an EM Scientific Aquastar
C3000 titrator to determine water content. Sample size ranged from
18 mg to 134 mg. Each salt was analyzed using a Perkin Elmer TGA 7
Thermal Gravimetric Analyzer (TGA). Samples were heated from an
initial temperature of 25.degree. C. to 325.degree. C. at a rate of
10.degree. C./min. Moisture sorption isotherms for each salt were
generated using the VTI SGA-100 Symmetric Vapor Sorption Analyzer.
Samples were run as received without pre-analysis drying.
Equilibrium criteria were the lesser of 0.01 wt % change in 5
minutes or 180 minutes at each relative humidity (RH) step.
Temperature was fixed at 25.degree. C. and the relative humidity
steps (25 to 95% to 25%) were in 5% increments. Analysis was
repeated for each sample in consecutive analyses (sample was not
removed from analyzer). Sample sizes ranged from 18 mg to 35
mg.
[0375] VTI moisture isotherm data, moisture content (KF), and TGA
data is summarized in Table 4.
TABLE-US-00013 TABLE 4 KF, TGA, and VTI Results for
Transnorsertraline Salts Initial TGA VTI Adsorp. VTI Desorp. KF (%
wt (% wt gain 25 (% wt loss 95 Salt (% H.sub.2O) loss) to 95% RH)
to 25% RH) HCl 0.02 0.00 0.01 0.02 0.01 0.02 Citrate 0.31 n.m. 2.59
3.96 3.24 3.61 Fumarate 0.40 0.81 0.18 0.17 0.17 0.16 Maleate 0.06
0.02 0.10 0.09 0.08 0.08 Phosphate 0.16 n.m. 3.00 1.37 2.14 1.20
Succinate 1.03 n.m. 3.25 3.17 n.m. n.m. Sulfate 3.34 4.20 10.19
9.51 7.25 n.m. L-tartrate 0.62 n.m. 3.52 1.36 1.37 n.m. Besylate
<0.01 0.07 0.05 0.05 0.05 0.05 Tosylate 0.09 0.16 0.06 0.06 n.m.
n.m. L-malate 0.05 0.07 0.08 0.08 0.06 n.m. S-mandelate 0.32 n.m.
3.24 3.95 3.79 3.02 Acetate 0.03 0.53 0.07 0.08 0.08 0.09 Benzoate
0.27 0.05 0.10 0.10 0.08 0.07 HBr 0.04 0.06 0.35 0.30 0.31 n.m.
Pyroglutamate 0.10 n.m. 17.28 n.m. n.m. n.m. n.m. = not
measured
[0376] VTI showed that the citrate, phosphate, succinate, sulfate,
L-tartrate, S-mandelate, and pyroglutamate salts of
transnorsertraline exhibited significant moisture uptake (2.7 to
17.3%) from 25 to 95% RH (Table 4).
[0377] 6.17 Water Solubility of Transnorsertraline Salts
[0378] Twelve salts of transnorsertraline were investigated for
their solubility in water: hydrochloride, fumarate, maleate,
phosphate, succinate, sulfate, L-tartrate, besylate, tosylate,
L-malate, acetate and benzoate. For each salt, saturated solutions
with excess solids in deionized water were prepared in 20 mL clear
glass scintillation vials with screw caps. All samples were shaken
at 300 rpm at ambient conditions for up to nine days until
equilibrium was achieved. Solubility was determined using a HPLC
method (Table 5).
TABLE-US-00014 TABLE 5 Solubility of Transnorsertraline Salts in
De-Ionized Water Solubility in Free Base Equivalents Salt mgA/mL pH
HCl 1.81 5.32 Fumarate 0.52 5.30 Maleate 1.88 3.98 Phosphate 4.16
3.27 Succinate 1.04 3.89 Sulfate 0.44 2.73 L-tartrate 0.44 2.63
Besylate 0.99 6.00 Tosylate 0.53 6.16 L-malate 3.04 4.15 Acetate
5.49 6.31 Benzoate 0.59 6.34
[0379] The hydrochloride, maleate, phosphate, succinate, besylate,
L-malate, and acetate were among the salts tested that exhibited
adequate solubility in water (0.99-5.49 mgA/mL).
[0380] 6.18 Solubility of Transnorsertraline Salts in Aqueous
Buffer
[0381] The twelve salts of transnorsertraline of Example 6.4 were
investigated for their solubility in the following aqueous buffer
systems: simulated gastric fluid (SGF), 0.05 M acetate buffer (pH
4.5) and simulated intestinal fluid (SIF). Saturated solutions with
excess solids were prepared in 20 mL clear glass scintillation
vials. Simulated gastric fluid (pH 1.0, .about.0.1N HCl, 0.03M
NaCl, no enzymes), simulated intestinal fluid (pH 6.8, 0.05M
KH.sub.2PO.sub.4, .about.0.02N NaOH, no enzymes), and acetate
buffer (pH 4.5, 0.02M sodium acetate, 0.03M acetic acid) were
prepared in accordance with USP28 (USP28 Test Solutions p2855,
Volumetric Solutions p2863). All samples were shaken at 300 rpm at
ambient conditions up to nine days until equilibrium was attained.
Solubility was determined using a HPLC method. (Table 6).
TABLE-US-00015 TABLE 6 Solubility of Transnorsertraline Salts in
Aqueous Buffer Systems Solubility in Salt (Suffix) Freebase
Equivalents mgA/mL pH Test Solvent: Simulated Gastric Fluid.sup.a
HCl 0.13 1.28 Fumarate <0.01 1.25 Maleate 0.08 1.25 Phosphate
<0.01 1.24 Succinate 0.08 1.27 Sulfate 0.09 1.13 L-tartrate
<0.01 1.24 Besylate <0.01 1.18 Tosylate 0.06 1.10 L-malate
0.08.sup.b 1.15 Acetate 0.07 1.26 Benzoate <0.01 1.25 Test
Solvent: 0.05M Acetate Buffer (pH 4.5) HCl 2.15 4.58 Fumarate 0.69
4.60 Maleate 1.23 4.52 Phosphate 2.63 4.55 Succinate 0.57 4.50
Sulfate 0.55 4.48 L-tartrate 0.03 4.58 Besylate 1.10 4.59 Tosylate
0.63 4.56 L-malate 1.59.sup.b 4.42 Acetate 3.12 4.79 Benzoate 0.79
4.61 Test Solvent: Simulated Intestinal Fluid.sup.a HCl 0.24 6.75
Fumarate 0.30 6.63 Maleate 0.28 6.47 Phosphate 0.27 6.49 Succinate
0.18 6.46 Sulfate 0.26 6.58 L-tartrate 0.27 6.73 Besylate 0.24 6.70
Tosylate 0.21 6.78 L-malate 0.38 6.68 Acetate 0.25 6.63 Benzoate
0.11 6.77 .sup.aenzymes were not included in buffer
.sup.bequilibrium not reached after 9 days
[0382] 6.19 Characterization of Transnorsertraline Salts Recovered
from Solubility Experiments
[0383] Solids recovered from solubility experiment suspensions
(Examples 6.17 and 6.18) were vacuum filtered and dried at
40.degree. C. overnight. Each sample was analyzed using a Perkin
Elmer DSC 7 differential scanning calorimeter. Each sample was
heated in a crimped pan with a pinhole under a nitrogen purge at a
rate of 10.degree. C./min, from a starting temperature of
25.degree. C. up to a final temperature of 325.degree. C. See Table
7.
[0384] As shown in Table 7, the hydrochloride salt of
transnorsertraline appeared to convert to a monohydrate form when
solids were equilibrated in deionized (DI) water and SGF. The DSC
for the hydrochloride monohydrate salt showed an endotherm around
100.degree. C. followed by a melt of the anhydrous sublimate at
.about.300.degree. C. (confirmed by hotstage). This hydration was
also marked by a crystal habit change from rods to plates. See
FIGS. 1A and 1B. Additional salts tested appeared to convert to the
HCl monohydrate during solubility experiments in SGF (Table 7).
This conversion was not unexpected since SGF contains sufficient
hydrochloric acid (0.23M) to form the hydrochloride salt, which in
turn may convert to the monohydrate. Recovered solids from
solubility experiments in acetate buffer did not appear to change
from their original salt form. It appears that some of the salts
(acetate, maleate, besylate, and L-malate) all converted to a
similar form in SIF (Table 7). The DSC for this unknown form shows
a single endotherm around 100.degree. C. with a small heat of
fusion (29-49 J/g).
TABLE-US-00016 TABLE 7 DSC Results for Solids Recovered from
Solubility Experiments Salt Test Solvent DSC Peak (.degree. C.) DSC
.DELTA.H.sub.f (J/g) HCl As-is Solid 299.7 99.9 Water.sup.c 101.4,
297.8 113.7, 100.9 SGF.sup.a,c 101.4, 297.4 106.1, 106.6 0.05M
Acetate (pH 4.5) 296.9 105.1 SIF.sup.b n.o. n.o Fumarate As-is
Solid 226.7 173.2 Water 229.2 160.9 SGF.sup.a 101.9, 297.2 105.9,
91.1 0.05M Acetate (pH 4.5) 230.3 155.0 SIF.sup.b n.o. n.o. Maleate
As-is Solid 177.7 53.0 Water 178.4 55.0 SGF.sup.a 101.0, 296.7
112.2, 102.9 0.05M Acetate (pH 4.5) n.m. n.m. SIF.sup.b 107.2 29.0
Besylate As-is Solid 192.1 54.7 Water 193.0 53.1 SGF.sup.a 102.9,
293.9 112.1, 91.5 0.05M Acetate (pH 4.5) 191.9 55.2 SIF.sup.b 93.0
30.5 L-Malate As-is Solid 180.3 81.3 Water 109.1, 178.8 54.5, 64.6
SGF.sup.a 100.0, 296.1 93.4, 85.4 0.05M Acetate (pH 4.5) 188.2 83.7
SIF.sup.b 98.3 49.2 Acetate As-is Solid 146.3 132.2 Water 146.4
128.9 SGF.sup.a 93.0, 296.0 108.7, 100.1 0.05M Acetate (pH 4.5)
145.4 121.4 SIF.sup.b 98.9 49.4 Benzoate As-is Solid 151.2 83.4
Water 151.5 84.8 SGF.sup.a 99.7, 296.9 102.4, 103.0 0.05M Acetate
(pH 4.5) 151.7 85.4 SIF.sup.b n.m. n.m. .sup.aSimulated Gastric
Fluid ("SGF"), USP, pH 0.9, without pepsin .sup.bSimulated
Intestinal Fluid ("SIF"), USP, pH 6.8, without pancreatin
.sup.cRecovered solids from water and SGF had 4.8% water (KF) and
4.9% weight loss (TGA), which is consistent with a monohydrate
n.m.: not measured n.o.: none observed
[0385] 6.20 Repeat Experiments for the Hydrochloride, Acetate and
L-Malate Salts
[0386] The following experiments were repeated. Additional lots of
the hydrochloride, acetate and L-malate salts of transnorsertraline
were tested for (i) consistent thermal properties by DSC and/or
hotstage and (ii) consistent moisture properties by KF, TGA and VTI
data.
[0387] A second lot of the hydrochloride salt of transnorsertraline
sublimed at 166.degree. C. and the sublimate melted at 249.degree.
C. as measured by hotstage according to the procedure of Example
6.2 above. These results were in good agreement with those of the
first lot (sublimed at 170.degree. C., sublimate melted at
250.degree. C.).
[0388] The second and third lots of transnorsertraline acetate
demonstrated similar thermal properties as the first acetate lot as
measured by DSC according to the procedure of Example 6.15 above.
(Table 8).
TABLE-US-00017 TABLE 8 DSC Results for Transnorsertraline Acetate
Peak Onset .DELTA.H.sub.fs Hotstage Salt Lot (.degree. C.)
(.degree. C.) (J/g) Observations Acetate 1 146.5 143.5 137.3 Melts
at 112.degree. C. 2 144.9 142.2 131.2 n.m. 3 144.8 142.4 120.1 n.m.
n.m.: not measured
[0389] The second lot of transnorsertraline L-malate demonstrated
similar thermal properties as the first acetate lot as measured by
DSC; however the third lot melted approximately 8.degree. C. lower
than other lots (Table 9). All experiments were performed according
to the procedure of Example 6.15 above.
TABLE-US-00018 TABLE 9 DSC Results for Transnorsertraline L-Malate
Peak Onset .DELTA.H.sub.fs Hotstage Salt Lot (.degree. C.)
(.degree. C.) (J/g) Observations L-malate 1 179.9 177.3 79.9 Melts
at 165.degree. C. 2 180.2 178.3 82.4 n.m. 3 171.9 167.8 68.1 n.m.
n.m.: not measured
[0390] A second lot of the hydrochloride salt of transnorsertraline
was analyzed for hygroscopicity by VTI according to the procedure
of Example 6.16 above. Results were similar as compared to the
first hydrochloride lot (VTI adsorption of 0.01% weight gain from
25 to 95% relative humidity; VTI desorption of 0.01% weight loss
from 95% to 25% relative humidity).
[0391] Second and third lots of the acetate and L-malate salts of
transnorsertraline were also analyzed and compared to the results
of the first lot according to the procedure of Example 6.3 above.
Results are shown in Table 10. All tested second and third lots had
similar moisture isotherms as first lots, with the exception of
L-malate lot 3, which adsorbed >5% more moisture than other
L-malate lots from 25 to 95% relative humidity.
TABLE-US-00019 TABLE 10 KF, TGA and VTI Data for Transnorsertraline
L-Malate and Transnorsertraline Acetate TGA VTI Adsorp. VTI Desorp.
Initial KF (% wt (% wt gain 25 (% wt loss 95 to Salt Lot (%
H.sub.2O) loss) to 95% RH) 25% RH) L-malate 1 0.05 0.08 0.08 0.08
0.06 n.m. 2 0.08 n.m. 0.06 0.07 0.07 0.06 3 0.04 n.m. 5.31 5.23
n.m. n.m. Acetate 1 0.03 0.43 0.07 0.08 0.08 0.09 2 0.07 n.m. 0.22
0.23 0.23 0.23 3 0.05 n.m. 0.33 0.38 0.35 0.35 n.m.: not
measured
[0392] 6.21 Solid Stability of Transnorsertraline Salts
[0393] Salts of transnorsertraline were tested for solid stability
under various conditions. Solid samples of the HCl salt were placed
in double-polyehylene lined high density polyethylene (HDPE)
containers closed with HDPE lids and stored at 25.degree. C./60%
relative humidity or 40.degree. C./75% relative humidity. Samples
were analyzed by HPLC. Transnorsertraline hydrochloride anhydrate
was stable at both conditions for at least 6 months and at
25.degree. C./60% relative humidity for 2 years, exhibiting less
than 0.05% and less than 0.1% impurities, respectively.
[0394] 6.22 Polymorphic Conversion Study of Transnorsertraline
Hydrochloride
[0395] Transnorsertraline hydrochloride exists in at least two
crystalline forms. Form A is a crystalline anhydrous material and
Form B is a crystalline monohydrate. Polarized light microscopy
images show that the two crystalline forms have distinct crystal
habits. The anhydrous form displays long thin blades (FIG. 1A),
whereas the hydrate form shows thin, approximately square plates
(FIG. 1B). Both samples show birefringence and extinguish under
cross polarizers upon rotation of the stage.
[0396] The study of the conversion of anhydrous transnorsertraline
hydrochloride to the hydrate form in aqueous media was
investigated, using in-situ Raman monitoring. The system was shown
to be suitable for Raman monitoring, with a limit of detection of
hydrate form in an anhydrous/hydrate slurry in water at 70 mg/mL
below 5.7%.
[0397] Raman spectroscopy was performed using a Kaiser Optical
Systems Inc. dispersive RamanRXN3 for on-line or in-situ reaction
monitoring. The RamanRXN3 system uses an excitation wavelength of
785 nm, with an external cavity-stabilized, diode laser. All
spectra were acquired using a 1/4'' immersion probe with
approximately 100 mW of laser power at the tip of the probe.
Different exposure times and numbers of spectrum accumulations were
used for the analysis of the two dry samples. An exposure time of 4
seconds with 2 accumulations was used for the monitoring of all
form conversions experiments. Wavelength and laser wavelength
calibration were performed using an internal neon standard, and
diamond Raman shift standard, respectively. The intensity
calibration was performed using a Kaiser Raman calibration
accessory.
[0398] Raman spectra acquired for the two forms in the 2850-3150
cm.sup.-1 and 200-1600 cm.sup.-1 regions showed that the two forms
can be differentiated by Raman. Regions 660-715 cm.sup.-1 and
1430-1490 cm.sup.-1 in particular show little overlapping of the
peaks characteristic of each form. Experimental results confirmed
that no peaks in the regions 660-720 cm.sup.-1 and 1430-1490
cm.sup.-1 were likely to overlap with peaks of interest to follow
the conversion between the two crystalline forms of
transnorsertraline hydrochloride.
[0399] The conversion of anhydrous transnorsertraline hydrochloride
to the monohydrate form was monitored in water. The peak ratio
I(677 cm.sup.-1)/I(695 cm.sup.-1) was observed for a slurry of
anhydrous transnorsertraline hydrochloride in water. Based on the
peak intensity ratio I(677 cm.sup.-1)/I(695 cm.sup.-1), an
induction time of approximately 1.1 hour was seen before the
beginning of the conversion. The end of the conversion was
estimated at approximately 2 hours from the beginning of the
slurry. The Raman region 660-710 cm.sup.-1 showed the appearance of
a peak characteristic of the hydrate form and the disappearance of
a peak characteristic of the anhydrous form of transnorsertraline
hydrochloride. XRPD analysis of the solids collected at the end of
the Raman monitoring of the conversion (after approximately 2 h 10
min) was consistent with the hydrate form, with a small amount of
anhydrous form detectable. The small amount of anhydrous form may
be due to solids present on the walls of the vessel which did not
convert. Additionally, the Raman limit of detection of the
anhydrous form in the mixture was not estimated.
[0400] The conversion of anhydrous transnorsertraline hydrochloride
to the hydrate form in water, simulated gastric fluid (SGF) and
simulated intestinal fluid (SIF) without enzymes, and 0.1N HCl was
monitored at 37.degree. C. The form conversion in water, SGF and
0.1N HCl was shown to begin after approximately 1.3 hours (water
and SGF) to 2 hours (0.1N HCl) and be completed within 3 to 4
hours. The form conversion was significantly slower in SIF, which
started at approximately 10 hours on small scale and 19 hours on a
larger scale and ended after approximately 12.5 hours (small scale)
to 36 hours (large scale).
[0401] Overall, similar results were obtained in water and
simulated gastric fluid, with the start of the form conversion
detected at approximately 1.3 hours, with a slightly faster
conversion in simulated gastric fluid compared to water. The
complete conversion was estimated to occur within 3 to 4 hours in
the two media. Slightly longer induction times were observed in
0.1N HCl, approximately 2 to 2.3 hours at larger scale. Complete
conversion was observed at approximately 4 hours. Results suggest
that the form conversion of transnorsertraline hydrochloride in
simulated intestinal fluid is very slow, estimated at 10 hours at
small scale and 19 hours at larger scale, and ending after
approximately 12.5 hours (small scale) to 36 hours (large scale).
XPRD analysis of the solids collected at the end of each
experiments were consistent with the hydrate form, with or without
some anhydrous form present. The small amount of anhydrous form may
be due to residual solids on the walls of the vessel at the time of
the slurry.
[0402] 6.23 Characterization of Anhydrous Crystalline
Transnorsertraline Hydrochloride
[0403] A sample of anhydrous transnorsertraline hydrochloride (Form
A) was submitted for single crystal structure analysis. The
structure was determined by single crystal X-ray diffraction. The
data collection, reduction and structure determination were not
performed according to cGMP specifications.
[0404] Experimental
[0405] A thin colorless needle of C.sub.16H.sub.16Cl.sub.3N having
approximate dimensions of 0.29.times.0.08.times.0.02 mm, was coated
with Paratone N oil, suspended in a small fiber loop and placed in
a cooled nitrogen gas stream in a random orientation. Preliminary
examination and data collection were performed with Cu
K.sub..alpha. radiation (.lamda.=1.54178 .ANG.) on a Bruker D8 APEX
II CCD sealed tube diffractometer.
[0406] Data collection, indexing and initial cell refinements were
all carried out using APEX II. See APEX II, 2005, Bruker AXS, Inc.,
Analytical X-ray Systems, 5465 East Cheryl Parkway, Madison Wis.
53711-5373. Frame integration and final cell refinements were done
using SAINT software. Refinements were performed on an PC using
SHELXTL. See SAINT Version 6.45A, 2003, Bruker AXS, Inc.,
Analytical X-ray Systems, 5465 East Cheryl Parkway, Madison Wis.
53711-5373; SHELXTL V6.12, 2002, Bruker AXS, Inc., Analytical X-ray
Systems, 5465 East Cheryl Parkway, Madison Wis. 53711-5373.
[0407] The final cell parameters and an orientation matrix for data
collection were determined from least-squares refinement on 1553
reflections in the range 5.26.degree.<.theta.<58.04.degree..
The space group was determined to be C2 (no. 5) by the program
XPREP. See Bruker, XPREP in SHELXTL version 6.12, Bruker AXS Inc.,
Madison, Wis., USA, 2002.
[0408] The data were collected using a series of combinations of
phi and omega scans with 30 second frame exposures and 0.5.degree.
frame widths at a temperature of 173.+-.2 K. The data were
collected to a maximum 2.theta. value of 116.08.degree..
[0409] A total of 2910 reflections were collected, of which 1533
were unique. Lorentz and polarization corrections were applied to
the data. The linear absorption coefficient is 52.75 cm.sup.-1 for
Cu K.sub..alpha. radiation. An empirical absorption correction
using SADABS was applied. See Blessing, R. H., SADABS, Program for
absorption correction using Siemens CCD. Based on Blessing R. Acta
Cryst. 1995, A51, 33. Transmission coefficients ranged from 0.3099
to 0.9018. Intensities of equivalent reflections were averaged. The
agreement factor for the averaging was 4.1% based on intensity.
[0410] Structure Solution and Refinement
[0411] The structure was solved by direct methods using SHELXS-97.
See Sheldrick, G. M. SHELX97, A Program for the Solution of Crystal
Structure, University of Gottingen, Germany, 1997. Hydrogen atoms
were placed at their expected chemical positions using the HFIX
command or were located in a final difference Fourier and were
included in the final cycles of least squares with isotropic
U.sub.ij's related to the atom to which they are bonded. All
non-hydrogen atoms were refined anisotropically. The structure was
refined in full-matrix least-squares by minimizing the
function:
.SIGMA.w(|F.sub.o|.sup.2-|F.sub.c|.sup.2).sup.2
The weight w is defined as
1/[.sigma..sup.2(F.sub.o.sup.2)+(0.0450P).sup.2+(0.3158P)], where
P=(F.sub.o.sup.2+2F.sub.c.sup.2)/3. Scattering factors were taken
from the "International Tables for Crystallography." International
Tables for Crystallography, Vol. C, Kluwer Academic Publishers:
Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4. Of
the 3171 reflections used in the refinements, only the reflections
with F.sub.o.sup.2>2.sigma.(F.sub.o.sup.2) were used in
calculating R. A total of 1553 reflections were used in the
calculation. The final cycle of refinement included variable
parameters and converged (largest parameter shift was essentially
equal to its estimated standard deviation) with unweighted and
weighted agreement factors of:
R=.SIGMA.|F.sub.o-F.sub.c|/.SIGMA.F.sub.o=0.0566
R.sub.w= {square root over
((.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}{square root over
((.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}=0.1470
The standard deviation of an observation of unit weight was 1.074.
The highest peak in the final difference Fourier had a height of
1.115 e/.ANG..sup.3. The minimum negative peak had a height of
-0.288 e/.ANG..sup.3. The factor for the determination of the
absolute structure refined to 0.04(4). See Flack, H. D. Acta Cryst.
1983, A39, 876.
[0412] Results
[0413] The monoclinic cell parameters and calculated volume are:
a=16.834(3), b=5.2264(9), c=19.059(3) .ANG., .alpha.=90.00,
.beta.=113.103(6), .gamma.=90.00.degree., V=1542.4(4) .ANG..sup.3.
The formula weight for transnorsertraline is 328.65 g/mol with Z=4
and a calculated density of 1.415 g cm.sup.-3. The space group was
determined to be C2 (no. 5). A summary of the crystal data and
crystallographic data collection parameters are provided in Table
11.
[0414] The quality of the structure obtained is considered to be
moderate to high, as indicated by the R-value of 0.0566 (5.66%).
The R-value for this structure is just inside the R-value range of
0.02 to 0.06 which are quoted for the most reliably determined
structures. Glusker, Jenny Pickworth; Trueblood, Kenneth N. Crystal
Structure Analysis: A Primer, 2.sup.nd ed.; Oxford University
press: New York, 1985; p. 87.
TABLE-US-00020 TABLE 11 Crystal Data and Data Collection Parameters
for Anhydrous Transnorsertraline Hydrochloride Empirical formula
C.sub.16H.sub.16Cl.sub.3N Formula weight 328.65 Temperature 173(2)
K Wavelength 1.54178 .ANG. Crystal system Monoclinic Space group C2
Unit cell dimensions a = 16.834(3) .ANG. .alpha. = 90.degree.. b =
5.2264(9) .ANG. .beta. = 113.103(6).degree.. c = 19.059(3) .ANG.
.gamma. = 90.degree.. Volume 1542.4(4) .ANG..sup.3 Z 4 d.sub.calc,
g cm.sup.-3 1.415 Absorption coefficient 5.275 mm.sup.-1 F(000) 680
Crystal size 0.29 .times. 0.08 .times. 0.02 mm.sup.3 Theta range
for data collection 5.26 to 58.04.degree.. Index ranges -18 <= h
<= 17, -5 <= k <= 5, -20 <= l <= 20 Reflections
collected 2910 Independent reflections 1533 [R (int) = 0.0409]
Completeness to theta = 58.04.degree. 89.2% Absorption correction
Semi-empirical from equivalents Max. and min. transmission 0.9018
and 0.3099 Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 1533/1/181 Goodness-of-fit on F.sup.2
1.074 Final R indices [I > 2.sigma.(I)] R1 = 0.0566, wR2 =
0.1470 R indices (all data) R1 = 0.0655, wR2 = 0.1550 Absolute
structure parameter 0.04(4) Largest diff. peak and hole 1.115 and
-0.288 e..ANG..sup.-3
[0415] Calculated X-ray Powder Diffraction Pattern
[0416] A calculated X-ray Powder Diffraction Pattern (XRPD) pattern
was generated for Cu radiation using PowderCell 2.3 and the atomic
coordinates, space group, and unit cell parameters from the single
crystal data. See PowderCell for Windows Version 2.3 Kraus, W.;
Nolze, G. Federal Institute for Materials Research and Testing,
Berlin Germany, EU, 1999.
[0417] The calculated XRPD pattern of anhydrous transnorstertraline
hydrochloride is shown in FIG. 2. The experimental XRPD pattern is
shown in FIG. 3. All peaks in the experimental patterns are
represented in the calculated XRPD pattern, indicating the bulk
material is likely a single phase. The differences in the
calculated and observed intensities in the XRPD patterns are likely
due to preferred orientation. Preferred orientation is the tendency
for crystals, usually plates or needles, to align themselves with
some degree of order. Preferred orientation can affect peak
intensities, but not peak positions, in XRPD patterns. The slight
shifts in peak location are likely the result of slight shifts in
the unit cell parameters as a function of temperature. The
calculated XRPD patterns in generated from the single crystal data
which was collected at 173 K, while the experimental powder pattern
was collected at ambient temperature. Collecting data at low
temperature is typically used in single crystal analysis to improve
the quality of the structure.
[0418] ORTEP and Packing Diagrams
[0419] The ORTEP diagram was prepared using ORTEP III. See Johnson,
C. K. ORTEPIII, Report ORNL-6895, Oak Ridge National Laboratory,
TN, U.S.A. 1996. OPTEP-3 for Windows V1.05 Farrugia, L. J., J.
Appl. Cryst. 1997, 30, 565. Atoms are represented by 50%
probability anisotropic thermal ellipsoids. Packing diagrams were
prepared using CAMERON modeling software. See Watkin, D. J.; Prout,
C .K.; Pearce, L. J. CAMERON, Chemical Crystallography Laboratory,
University of Oxford, Oxford, 1996. Additional figures were
generated using Mercury 1.3 modeling software. See Bruno, I. J.
Cole, J. C. Edgington, P. R. Kessler, M. K. Macrae, C. F. McCabe,
P. Pearson, J. and Taylor, R. Acta Crystallogr., 2002 B58, 389.
Hydrogen bonding is represented as dashed lines.
[0420] An ORTEP drawing of anhydrous transnorsertraline
hydrochloride is shown in FIG. 4. The asymmetric unit shown in FIG.
4 contains a single protonated transnorsertraline molecule and a
chloride anion.
[0421] Absolute Configuration
[0422] The absolute configuration of anhydrous transnorsertraline
hydrochloride can be determined by analysis of anomalous X-ray
scattering by the crystal. The differences in intensities of the
anomalous scattering are then compared with calculated scattering
intensities for each enantiomer. These measured and calculated
intensities can then be fit to a parameter, the Flack factor. See
Flack, H. D.; Bernardinelli, G. Acta Cryst. 1999, A55, 908; Flack,
H. D.; Bernardinelli, G. J. Appl. Cryst. 2000, 33, 1143. After a
structure is solved the quality of the data is assessed for its
inversion-distinguishing power, this is done by an examination of
the standard uncertainty of the Flack parameter. For anhydrous
transnorsertraline hydrochloride, the standard uncertainty, (u),
equals 0.07, which is classified as enantiopure-sufficient
distinguishing power. The measured Flack factor for the crystal
structure of anhydrous transnorsertraline hydrochloride shown in
FIG. 4 is -0.13 with a standard uncertainty of 0.04. The molecule
contains two chiral centers located at C7 and C14 (refer to FIG.
4), which were assigned as S and R configurations,
respectively.
[0423] 6.24 X-ray Powder Diffraction Analysis of Anhydrous
Transnorsertraline Hydrochloride
[0424] X-ray powder diffraction (XRPD) analyses of anhydrous
transnorsertraline hydrochloride were performed using an Inel
XRG-3000 diffractometer equipped with a CPS (Curved Position
Sensitive) detector with a 2.theta. range of 120.degree.. Real time
data were collected using Cu-K.alpha. radiation starting at
approximately 4.degree. 2.theta. at a resolution of 0.03.degree.
2.theta.. The tube voltage and amperage were set to 40 kV and 30
mA, respectively. The monochromator slit was set at 5 mm by 160
.mu.m. The pattern is displayed from 2.5-40.degree. 2.theta..
Samples were prepared for analysis by packing them into thin-walled
glass capillaries. Each capillary was mounted onto a goniometer
head that is motorized to permit spinning of the capillary during
data acquisition. The samples were analyzed for 300 seconds.
Instrument calibration was performed using a silicon reference
standard. The experimental XRPD patterns were collected according
to cGMP specifications. Table 12 shows observed XRPD peaks for
anhydrous transnorsertraline hydrochloride.
TABLE-US-00021 TABLE 12 Observed XRPD Peaks for Anhydrous
Transnorsertraline HCl .degree.2.theta. d space (.ANG.) Intensity
(%) 5.00 .+-. 0.10 17.687 .+-. 0.361 33 11.37 .+-. 0.10 7.783 .+-.
0.069 23 11.85 .+-. 0.10 7.466 .+-. 0.063 26 14.11 .+-. 0.10 6.279
.+-. 0.045 33 14.87 .+-. 0.10 5.959 .+-. 0.040 74 17.78 .+-. 0.10
4.989 .+-. 0.028 73 18.85 .+-. 0.10 4.707 .+-. 0.025 29 19.23 .+-.
0.10 4.615 .+-. 0.024 97 20.96 .+-. 0.10 4.237 .+-. 0.020 30 21.48
.+-. 0.10 4.136 .+-. 0.019 33 21.83 .+-. 0.10 4.071 .+-. 0.019 47
22.84 .+-. 0.10 3.894 .+-. 0.017 41 23.29 .+-. 0.10 3.820 .+-.
0.016 78 23.81 .+-. 0.10 3.738 .+-. 0.016 37 24.57 .+-. 0.10 3.624
.+-. 0.015 100 25.19 .+-. 0.10 3.535 .+-. 0.014 80 25.95 .+-. 0.10
3.433 .+-. 0.013 30 26.79 .+-. 0.10 3.328 .+-. 0.012 31 28.66 .+-.
0.10 3.115 .+-. 0.011 23 29.14 .+-. 0.10 3.064 .+-. 0.010 27
[0425] Table 13 shows prominent XRPD peaks for anhydrous
transnorsertraline hydrochloride. Differences between calculated
and experimental peaks are due to preferred orientation and
particle statistic effects.
TABLE-US-00022 TABLE 13 Prominent XRPD Data for Anhydrous
Transnorsertraline HCl Calculated (.degree.2.theta.) Experimental
(.degree.2.theta.) 5.05 5.00 15.00 14.87 18.00 17.78 19.45 19.23
22.00 21.83 23.50 23.29 24.75 24.57 25.35 25.19
[0426] 6.25 Characterization of Crystalline Transnorsertraline
Hydrochloride Monohydrate
[0427] A sample of transnorsertraline hydrochloride monohydrate
(Form B) was submitted for single crystal structure analysis. The
single crystal data collection, structure solution and refinement
were not performed according to cGMP specifications.
[0428] Experimental
[0429] A colorless needle of transnorsertraline hydrochloride
monohydrate, C.sub.16H.sub.18Cl.sub.3NO
[Cl,C.sub.16H.sub.16Cl.sub.2N,H.sub.2O], having approximate
dimensions of 0.60.times.0.40.times.0.07 mm, was mounted on a glass
fiber in random orientation. Preliminary examination and data
collection were performed with Mo K.sub..alpha. radiation
(.lamda.=0.71073 .ANG.) on a Nonius KappaCCD diffractometer
equipped with a graphite crystal, incident beam monochromator.
Refinements were performed on an LINUX PC using SHELX97. See
Sheldrick, G. M. SHELX97, A Program for Crystal Structure
Refinement, University of Gottingen, Germany, 1997.
[0430] Cell constants and an orientation matrix for data collection
were obtained from least-squares refinement using the setting
angles of 6712 reflections in the range
3.degree.<.theta.<27.degree.. The refined mosaicity from
DENZO/SCALEPACK was 0.47.degree. indicating good crystal quality.
See Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307. The
space group was determined by the program ABSEN. See McArdle, P. C.
J. Appl. Cryst. 1996, 29, 306. From the systematic presence of the
following condition: 0k0 k=2n, and from subsequent least-squares
refinement, the space group was determined to be P2.sub.1 (no. 4).
This is a chiral space group. The data were collected to a maximum
2.theta. value of 54.92.degree., at a temperature of 150.+-.1
K.
[0431] Frames were integrated with DENZO-SMN. See Otwinowski, Z.;
Minor, W. Methods Enzymol. 1997, 276, 307. A total of 6712
reflections were collected, of which 3171 were unique. Lorentz and
polarization corrections were applied to the data. The linear
absorption coefficient is 0.543 mm.sup.-1 for Mo K.sub..alpha.
radiation. An empirical absorption correction using SCALEPACK was
applied. Id. Transmission coefficients ranged from 0.892 to 0.963.
Intensities of equivalent reflections were averaged. The agreement
factor for the averaging was 4.5% based on intensity.
[0432] Structure Solution and Refinement
[0433] The structure was solved by direct methods using SIR2004.
See Burla et al., J. Appl. Cryst. 2005, 38, 381. The remaining
atoms were located in succeeding difference Fourier syntheses.
Hydrogen atoms were included in the refinement but restrained to
ride on the atom to which they are bonded. The structure was
refined in full-matrix least-squares by minimizing the
function:
.SIGMA.w(|F.sub.o|.sup.2-|F.sub.c|.sup.2).sup.2
The weight w is defined as 1/[.sigma..sup.2(F.sub.o.sup.2)+(0.0450
P).sup.2+(0.3158 P)], where P=(F.sub.o.sup.2+2F.sub.c.sup.2)/3.
Scattering factors were taken from the "International Tables for
Crystallography." International Tables for Crystallography, Vol. C,
Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992,
Tables 4.2.6.8 and 6.1.1.4. Of the 3171 reflections used in the
refinements, only the reflections with
F.sub.o.sup.2>2.sigma.(F.sub.o.sup.2) were used in calculating
R. A total of 2757 reflections were used in the calculation. The
final cycle of refinement included 210 variable parameters and
converged (largest parameter shift was essentially equal to its
estimated standard deviation) with unweighted and weighted
agreement factors of:
R=.SIGMA.|F.sub.o-F.sub.c|/.SIGMA.F.sub.o=0.041
R.sub.w= {square root over
(.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2)/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}{square root over
(.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2)/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}=0.093
The standard deviation of an observation of unit weight was 1.04.
The highest peak in the final difference Fourier had a height of
0.35 e/.ANG..sup.3. The minimum negative peak had a height of -0.37
e/.ANG..sup.3. The factor for the determination of the absolute
structure refined to -0.13(7). See Flack, H. D. Acta Cryst. 1983,
A39, 876.
[0434] Results
[0435] The monoclinic cell parameters and calculated volume are:
a=7.2962(2) .ANG., b=7.5569(2) .ANG., c=15.2870(5) .ANG.,
.alpha.=90.00, .beta.=90.0852(14), .gamma.=90.00.degree.,
V=842.87(4) .ANG..sup.3. For the monohydrate, the formula weight is
346.69 g/mol with Z=2 resulting in a calculated density of 1.366 g
cm.sup.-3. The space group was determined to be P2.sub.1 (no. 4),
which is a chiral space group. A summary of the crystal data and
crystallographic data collection parameters are provided in Table
14. The quality of the structure obtained is high, as indicated by
the R-value of 0.041 (4.1%). Usually R-values in the range of 0.02
to 0.06 are quoted for the most reliably determined structures.
Glusker, Jenny Pickworth; Trueblood, Kenneth N. Crystal Structure
Analysis: A Primer, 2 ed.; Oxford University press: New York, 1985;
p. 87.
TABLE-US-00023 TABLE 14 Crystal Data and Data Collection Parameters
for Transnorsertraline Hydrochloride Monohydrate formula
C.sub.16H.sub.18Cl.sub.3NO formula weight 346.69 space group
P2.sub.1 (No. 4) a, .ANG. 7.2962(2) b, .ANG. 7.5569(2) c, .ANG.
15.2870(5) .beta., deg 90.0852(14) V, .ANG..sup.3 842.87(4) Z 2
d.sub.calc, g cm.sup.-3 1.366 crystal dimensions, mm 0.60 x 0.40 x
0.07 temperature, K 150. radiation (wavelength, .ANG.) Mo K.sub.a
(0.71073) monochromator graphite linear abs coef, mm.sup.-1 0.543
absorption correction applied empirical.sup.a transmission factors:
min, max 0.892 to 0.963 diffractometer Nonius KappaCCD h, k, l
range -9 to 9 -9 to 8 -19 to 19 2 .theta. range, deg 5.33-54.92
mosaicity, deg 0.47 programs used SHELXTL F.sub.000 360.0 weighting
1/[.sigma..sup.2(F.sub.o.sup.2) + (0.0450P).sup.2 + 0.3158P] where
P = (F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 data collected 6712 unique
data 3171 R.sub.int 0.045 data used in refinement 3171 cutoff used
in R-factor calculations F.sub.o.sup.2 > 2.0.sigma.
(F.sub.o.sup.2) data with I > 2.0.sigma. (I) 2757 number of
variables 210 largest shift/esd in final cycle 0.00 R (F.sub.o)
0.041 R.sub.w (F.sub.o.sup.2) 0.093 goodness of fit 1.043 absolute
structure determination Flack parameter.sup.b (-0.13(7))
.sup.aOtwinowski Z. & Minor, W. Methods Enzymol., 1997, 276,
307. .sup.bFlack, H. D. Acta Cryst., 1983 A39, 876.
[0436] Calculated X-Ray Powder Diffraction Pattern
[0437] A calculated X-ray Powder Diffraction Pattern (XRPD) pattern
was generated for Cu radiation using PowderCell 2.3 and the atomic
coordinates, space group, and unit cell parameters from the single
crystal data. See PowderCell for Windows Version 2.3 Kraus, W.;
Nolze, G. Federal Institute for Materials Research and Testing,
Berlin Germany, EU, 1999.
[0438] The calculated XRPD pattern of transnorstertraline
hydrochloride monohydrate is shown in FIG. 5. The experimental XRPD
pattern is shown in FIG. 6. All peaks in the experimental patterns
are represented in the calculated XRPD pattern, indicating the bulk
material is likely a single phase. The slight shifts in peak
location are likely the result of slight shifts in the unit cell
parameters as a function of temperature. The calculated XRPD
patterns in generated from the single crystal data which was
collected at 150 K, while the experimental powder pattern was
collected at ambient temperature. Collecting data at low
temperature is typically used in single crystal analysis to improve
the quality of the structure.
[0439] ORTEP and Packing Diagrams
[0440] The ORTEP diagram was prepared using ORTEP III. See Johnson,
C. K. ORTEPIII, Report ORNL-6895, Oak Ridge National Laboratory,
TN, U.S.A. 1996. OPTEP-3 for Windows V1.05 Farrugia, L. J., J.
Appl. Cryst. 1997, 30, 565. Atoms are represented by 50%
probability anisotropic thermal ellipsoids. Packing diagrams were
prepared using CAMERON modeling software. See Watkin, D. J.; Prout,
C .K.; Pearce, L. J. CAMERON, Chemical Crystallography Laboratory,
University of Oxford, Oxford, 1996. Additional figures were
generated using Mercury 1.4.1. See Bruno, I. J. Cole, J. C.
Edgington, P. R. Kessler, M. K. Macrae, C. F. McCabe, P. Pearson,
J. and Taylor, R. Acta Crystallogr., 2002 B58, 389. Hydrogen
bonding is represented as dashed lines.
[0441] An ORTEP drawing of transnorsertraline hydrochloride
monohydrate is shown in FIG. 7. The asymmetric unit shown contains
a single protonated transnorsertraline hydrochloride monohydrate
molecule, a chloride anion and a fully occupied water of hydration.
Salt formation was confirmed by locating the hydrogen atoms on the
primary amine and the water molecule directly from the Fourier
map.
[0442] Absolute Configuration
[0443] The absolute configuration of transnorsertraline
hydrochloride monohydrate can be determined by analysis of
anomalous X-ray scattering by the crystal. The differences in
intensities of the anomalous scattering are then compared with
calculated scattering intensities for each enantiomer. These
measured and calculated intensities can then be fit to a parameter,
the Flack factor. See Flack, H. D.; Bemardinelli, G. Acta Cryst.
1999, A55, 908; Flack, H. D.; Bernardinelli, G. J. Appl. Cryst.
2000, 33, 1143. After a structure is solved the quality of the data
is assessed for its inversion-distinguishing power, this is done by
an examination of the standard uncertainty of the Flack parameter.
The measured Flack factor for the crystal structure of
transnorsertraline hydrochloride monohydrate shown in FIG. 7 is
-0.13 with a standard uncertainty of 0.07. The standard
uncertainty, (u), equals 0.07, which is classified as
enantiopure-sufficient distinguishing power. An error of this
magnitude means that a priori biological, chemical or physical
evidence is required to show that the compound is truly
enantiopure, and to prove that the absolute structure determination
is valid. While the measured Flack factor is outside the range to
allow validation based solely on the crystallographic data, the
absolute configuration can be confirmed by comparison to the
transnorsertraline hydrochloride molecule from the anhydrous
crystal structure. Therefore, the absolute configuration of the
model in FIG. 7 is correct. The transnorsertraline hydrochloride
monohydrate molecule contains two chiral centers located at C1 and
C4 (refer to FIG. 7), which were assigned as S and R configuration,
respectively.
[0444] 6.26 X-Ray Powder Diffraction Analysis of Transnorsertraline
Hydrochloride Monohydrate
[0445] X-ray powder diffraction (XRPD) analyses of
transnorsertraline hydrochloride monohydrate were performed using
an Inel XRG-3000 diffractometer equipped with a CPS (Curved
Position Sensitive) detector with a 2.theta. range of 120.degree..
Real time data were collected using Cu-K.alpha. radiation starting
at approximately 4.degree. 2.theta. at a resolution of 0.03.degree.
2.theta.. The tube voltage and amperage were set to 40 kV and 30
mA, respectively. The monochromator slit was set at 5 mm by 160
.mu.m. The pattern is displayed from 2.5-40.degree. 2.theta..
Samples were prepared for analysis by packing them into thin-walled
glass capillaries. Each capillary was mounted onto a goniometer
head that is motorized to permit spinning of the capillary during
data acquisition. The samples were analyzed for 300 seconds.
Instrument calibration was performed using a silicon reference
standard. The experimental XRPD patterns were collected according
to cGMP specifications. Table 15 shows observed XRPD peaks for
transnorsertraline hydrochloride monohydrate.
TABLE-US-00024 TABLE 15 Observed XRPD Peaks for Transnorsertraline
HCl Monohydrate .degree.2.theta. d space (.ANG.) Intensity (%)
11.55 .+-. 0.10 7.660 .+-. 0.067 35 12.07 .+-. 0.10 7.331 .+-.
0.061 60 13.01 .+-. 0.10 6.806 .+-. 0.053 54 13.35 .+-. 0.10 6.631
.+-. 0.050 40 16.40 .+-. 0.10 5.405 .+-. 0.033 38 16.78 .+-. 0.10
5.283 .+-. 0.031 85 17.30 .+-. 0.10 5.126 .+-. 0.030 38 17.75 .+-.
0.10 4.997 .+-. 0.028 64 20.38 .+-. 0.10 4.357 .+-. 0.021 66 20.90
.+-. 0.10 4.250 .+-. 0.020 51 21.11 .+-. 0.10 4.209 .+-. 0.020 51
23.43 .+-. 0.10 3.797 .+-. 0.016 60 24.19 .+-. 0.10 3.679 .+-.
0.015 100 24.92 .+-. 0.10 3.573 .+-. 0.014 36 26.17 .+-. 0.10 3.406
.+-. 0.013 44 27.07 .+-. 0.10 3.294 .+-. 0.012 55 28.77 .+-. 0.10
3.104 .+-. 0.011 35 29.35 .+-. 0.10 3.043 .+-. 0.010 32 29.94 .+-.
0.10 2.984 .+-. 0.010 33
[0446] Table 16 shows prominent XRPD peaks for transnorsertraline
hydrochloride monohydrate. Differences between calculated and
experimental peaks are due to preferred orientation and particle
statistic effects.
TABLE-US-00025 TABLE 16 Prominent XRPD Data for Transnorsertraline
HCl Monohydrate Calculated (.degree.2.theta.) Experimental
(.degree.2.theta.) 12.10 12.07 13.05 13.01 16.90 16.78 17.85 17.75
20.50 20.38 21.00 20.90 21.25 21.11 23.55 23.43 24.30 24.19 26.30
26.17 27.20 27.07
[0447] 6.27 Additional Transnorsertraline HCl Stability Studies
[0448] In a typical stability study, the excipient blend or
completed dosage form was prepared with the active drug. The
material was stored in a sealed container, preferably a
high-density polyethylene (HDPE) bottle sealed with a heat
induction foil. The material was placed in an oven with controlled
humidity such that the samples were exposed to about 40.degree. C.
and about 75% relative humidity (RH) for a period of about 2 weeks
to about 6 months.
[0449] Table 17 shows the assay and impurities data for the tablets
through six months storage using HPLC. A typical HPLC chromatogram
is shown in FIG. 8. At t.sub.0, assay was .about.93% while total
impurities were 0.89%, 0.17% of which could be attributed to
tetralone. An unknown impurity (RT .about.18 minutes, 0.67%) was
also detected during t.sub.0 analysis. From an initial value of
93.4%, assay values for tablets stored at 30.degree. C./65% RH and
25.degree. C./60% RH remained above 90% through the six month time
point while those stored at 40.degree. C./75% RH dropped to 80%. At
40.degree. C./75% RH, the major degradant was tetralone; levels
increased from an initial value of 0.17% to 4.63% at six months. In
contrast, the unknown impurity levels at 25.degree. C./60% RH rose
from an initial value of 0.67% to 1.84% within a month,
subsequently dropping to 0.23% at the six month time point.
TABLE-US-00026 TABLE 17 Assay and Impurities Data of
Transnorsertraline HCl 1 mg Tablets % Total Time % % impu- % point
Condition Degradant Tetralone rities Assay t.sub.0 -- 0.67 0.17
0.89 93.4 1 Month 25.degree. C./60% RH 1.84 0.12 2.23 93.9
40.degree. C./75% RH 0.17 0.80 2.19 91.0 2 Months 25.degree. C./60%
RH 1.19 0.16 1.64 88.5 40.degree. C./75% RH 0.09 1.39 2.94 84.7 3
Months 25.degree. C./60% RH 0.75 0.31 1.45 92.3 30.degree. C./65%
RH 0.24 0.55 1.34 92.0 40.degree. C./75% RH 0.09 2.68 4.69 86.2 6
Months 25.degree. C./60% RH 0.23 0.39 1.04 91.4 30.degree. C./65%
RH 0.24 0.70 1.54 90.3 40.degree. C./75% RH 0.07 4.63 6.77 80.6
[0450] The structure of the degradant was confirmed by its HPLC
retention time, UV spectrum and LC-MS result as having formula II.
The degradant has a molecular weight of 454, and its chemical
structure is shown below:
##STR00004##
[0451] The data from additional studies indicated that 0.005% of
mannose in mannitol resulted in conjugate degradant formation of
about 0.12% in two weeks, and that of 0.01% of mannose in mannitol
resulted in conjugate degradant formation of about 0.25% in two
weeks. The amount of conjugate degradant leveled off at about two
weeks and then slightly declined as stress time increases.
Formation of the degradant of formula II also depends on the
temperature. At higher temperature (e.g., >35.degree. C.), the
degradant of formula II underwent decomposition.
[0452] 6.28 Analysis of Mannitol Excipient Purity
[0453] Further stability studies on capsules have shown that the
blends in tablets packaged in Aclar.RTM.
(polychlorotrifluoroethylene film, Honeywell Int'l Inc.) are more
stable (approximately 4 times) than blends in open dish conditions.
The presence of mannose in mannitol was determined using
HPLC-Corona charged Aerosol Detector (HPLC-CAD) and Ion
Chromatography (IC) methods as shown in Table 18:
TABLE-US-00027 TABLE 18 Analysis of Mannitol Purity % Mannose in
Mannitol Mannitol Lot HPLC-CAD IC 1 0.001 0.001 2 0.001 0.000 3
0.001 0.001 4 0.001 0.000 5 0.001 0.000 6 0.002 0.000 7 0.001 0.000
8 0.011 0.012 9 0.017 0.043 10 0.005 0.005 11 0.005 0.004 12 0.072
0.079 13 0.049 0.068 14 0.035 0.033 15 0.004 0.001 16 0.003 0.003
17 0.002 0.001 18 0.001 0.001
[0454] HPLC-CAD method. In this method, the following
instrument/conditions were used: [0455] Column: Sugar SZ5532 [0456]
Column Size: 6 mm ID.times.150 mm L [0457] Column Temperature:
65.degree. C. [0458] Detector: Corona CAD [0459] Mobile Phase: 80%
Acetonitrile in Water [0460] Flow Rate: 1 mL/min [0461] Volume
Injected: 100 .mu.L
[0462] The HPLC column eluent is nebulized with nitrogen and the
droplets are dried, producing analyte particles. A secondary stream
of nitrogen becomes positively charged and transfers the charge to
analyte particles. The charge is then measured, generating a signal
in direct proportion to the quantity of analyte present.
[0463] Ion Chromatography (IC) Method. In this method, the
following instrument/conditions were used:
TABLE-US-00028 Mobile Phase: A: 30 mM NaOH; B: 200 mM NaOH Flow
Rate: 1.0 mL/minute, Pressure ~2040 psi Analytical Column: CarboPac
PA 10, 4 .times. 250 mm Guard Column: CarboPac PA 10, 4 .times. 50
mm Column Temperature: 30.degree. C. Detector Mode: Integrated
Amperometry Detector Range: 1 .mu.C Working Electrode: Gold
Reference Electrode: pH, Ag/AgCl Autosampler Temperature: Ambient
Injector Volume: 25 .mu.L Run Time: 30 minutes
[0464] The gradient program used for the IC method: 100% Mobile
Phase A at 0 min; 100% Mobile Phase B at 18 min; 100% Mobile Phase
B at 30 min.
[0465] Applied Potential Wave Form, IC method:
TABLE-US-00029 Time (Seconds) Potential (V) Integration 0.00 0.10
0.20 0.10 Start 0.40 0.10 End 0.41 -2.00 0.42 -2.00 0.43 0.60 0.44
-0.10 0.50 -0.10
[0466] While the results of each method were generally comparable,
the IC method was selected for further analysis due to greater
sensitivity as compared to the HPLC-CAD method (sample
concentration 1 mg/mL vs. 100 mg/mL mannitol). The Quantitation
Limit (QL) of Ion Chromatography (IC) method is 0.005% of mannose
in mannitol. Several lots of mannitol (see Table 18) were analyzed
and the mannose values are given in below:
TABLE-US-00030 % Mannose in Mannitol* Type of Mannitol Mannitol Lot
IC Method Crystalline 1 0.0009 Crystalline 2 0.0003 Crystalline 3
0.0008 Crystalline 4 0.0002 Crystalline 5 0.0002 Crystalline 6
0.0002 Crystalline 7 0.0000 Spray Dried 8 0.0115 Spray Dried 9
0.0434 Spray Dried 16 0.0026 Spray Dried 17 0.0009 Spray Dried 18
0.0010 *Though the QL of the IC method is 0.005% of mannose in
mannitol, in order to estimate the amount of mannose, the % mannose
in mannitol was calculated using mannose peak area observed versus
that of external mannose standard.
[0467] Of the 2 lots of mannitol used from the above table, spray
dried lot 8 (0.0115% mannose) formed the conjugate degradant
whereas crystalline mannitol lot 1 (0.0009% Mannose, <QL) did
not form the conjugate degradant. The amount of mannose in mannitol
appeared to be the controlling factor, not the type of mannitol
used in transnorsertraline HCl formulation (i.e., crystalline vs.
spray dried). This was later confirmed from the results obtained
using recrystallized mannitol samples spiked with mannose in the
stability study of transnorsertraline HCl formulations.
[0468] 6.29 Transnorsertraline HCl Capsule Stability Study
[0469] The excipient blend or completed dosage form was prepared
with the active drug. The material was stored in a HDPE bottle
sealed with a heat induction foil. The material was placed in an
oven with controlled humidity such that the samples are exposed to
about 40.degree. C. and about 75% RH for a period of 8 weeks.
Capsule samples were prepared as follows:
TABLE-US-00031 Minimum Number of Capsules Weight of Strength
Required for Composite for Conc. of (mg/ Duplicate Sample Single
Sample Volumetric Active, capsule) Preparation Preparation, mg
Flask, mL mg/mL 0.5 30 4200 50 0.14 1 15 2100 50 0.14 5 6 840 100
0.14 10 6 840 200 0.14
[0470] Sample diluent was prepared as follows. For each liter
prepared, accurately measure 600 mL of water, 200 mL of THF and 200
mL of acetonitrile into a suitable container. Add 0.5 mL of
trifluoroacetic acid and mix thoroughly.
[0471] HPLC analytic method. A Zorban SB-CN 5 .mu.M, 25
cm.times.4.6 mm analytical column using a 0.05% trifluoroacetic
acid in a 80:20 water:acetonitrile solution (Mobile Phase A)
followed by a 0.05% trifluoroacetic acid in a 15:85
water:acetonitrile solution (Mobile Phase B) was used. Column
temperature: 30.degree. C. The flow rate: 1.0 mL/min. Injection
volume: 50 .mu.L. Wavelength: 220 nm. Minimum run time: 50 min (15
min delay). Mobile Phase gradient:
TABLE-US-00032 Time (min) % A % B 0 100 0 20 70 30 40 0 100 50 0
100 55 100 0 65 100 0
[0472] For HPLC sample preparation, the contents were transferred
to a 50 mL volumetric flask. A mixture of
water/actonitrile/THF/trifluoroacetic acid in the ratio
60/20/20/0.05 was used as sample diluent. After filling the flask
3/4 full with sample diluent, it was vigorously shaken by hand and
then subjected to wrist action shaking for 30 minutes, sonication
for 20 minutes and wrist action shaking again for 30 minutes. After
cooling to room temperature, the volume was made up to 50 mL using
sample diluent, mixed well and filtered the supernatant using 25 mm
diameter 0.45 .mu.m PTFE GD/X syringe filter in to a HPLC vial and
analyzed using the HPLC conditions shown above. The concentration
of active in the samples was 0.14 mg/mL.
[0473] Table 19 shows that the same degradants are formed at
different amounts in different strength capsules. 1 mg capsules
contained more total degradants than 5 and/or 10 mg strengths.
TABLE-US-00033 TABLE 19 Stability of Transnorsertraline Prototype
Capsules 40.degree. C./75% RH Stability Chamber 8 Weeks 1 mg B3 5
mg B1 10 mg B1 Impurity RRT* Aclar PVDC Aclar PVDC Aclar PVDC 0.683
0.45 0.75 0.24 0.33 0.09 0.12 0.764 0.63 1.04 0.43 0.56 0.17 0.22
0.803 0.25 0.45 0.30 0.34 0.13 0.14 0.861 0.20 0.28 0.25 0.25 0.12
0.11 Synthetic Impurity 1 0.884 0.05 -- -- -- -- -- Synthetic
Impurity 2 1.064 -- 0.05 -- -- -- -- Cis diastereomer 1.076 -- 0.06
0.05 0.06 -- -- 1.276 0.19 0.06 -- -- -- -- 1.393 0.19 0.24 0.08
0.12 -- 0.05 1.549 0.19 0.24 0.08 0.12 -- 0.05 1.649 0.33 0.45 0.15
0.20 0.08 0.10 (Tetralone) 1.703 -- 0.06 0.05 0.07 -- -- Total
2.26% 3.71% 1.69% 2.08% 0.73% 0.86% Impurities *Impurities at or
above 0.05% are listed Assumed RRF (relative response factor) of
impurities = 1 PVDC = polyvinylidine chloride
[0474] Similar degradants were observed using open dish conditions.
Wide-mouth open dish containers (.about.20 mL scintillation vials)
were subjected to 40.degree. C. and about 75% RH for 3 weeks. 7.88
mg of transnorsertraline HCl and the appropriate amount of
excipient(s) (active to excipient ratio of 1:1, 1:124 and/or 1:372)
were weighed into the containers.
TABLE-US-00034 TABLE 20 Open Dish Study Impurity RRT* 1 mg B3 5 mg
B1 10 mg B1 0.683 0.53 0.13 0.05 0.764 0.82 0.26 0.11 0.803 0.41
0.20 0.08 0.861 Synthetic Impurity 1 0.28 0.20 0.11 0.884 Synthetic
Impurity 2 0.05 0.05 0.05 1.549 0.14 0.07 -- 1.649 (Tetralone) 0.32
0.14 0.07 1.703 (TSA) 0.05 -- -- 1.937 0.05 -- -- Total Impurities
2.77% 1.12% 0.53% *Impurities at or above 0.05% are listed Assumed
RRF (relative response factor) of impurities = 1
[0475] Comparison of the results presented in Tables 19 and 20
revealed that the same degradants formed at slightly different
levels, and that degradation in open dish is faster. HPLC
chromatograms obtained for capsule stability study and open dish
study are shown in FIG. 9.
[0476] Because the 1 mg capsules produced the most
impurities/degradants, the ratio of transnorsertraline (active) to
excipients in the samples were kept similar to that in 1 mg
capsules (1 mg of transnorsertraline is equivalent to 1.125 mg of
transnorsertraline hydrochloride):
TABLE-US-00035 TABLE 21 Compositions of 1 mg Transnorsertraline HCl
Capsule Capsule Formulation (mg/capsule) Transnorsertraline HCl
1.125 Talc (Imperial 500) 1.125 Starch 1500 139 A-Tab 139 Ac-Di-Sol
18.00 Mallinckrodt #2257 Mag. St. 1.50 Totals: 299.75
The following lots of excipients were used with various lots of
Active (e.g., "Active 1"):
TABLE-US-00036 Excipient TALC Starch 1500 1 Starch 1500 2 A-TAB 1
A-TAB 2 A-TAB 3 A-TAB 4 Ac-Di-Sol Mg Stearate
[0477] Conclusions. The compatibility degradation study of
transnorsertraline HCl and its excipients demonstrated that the
larger the surface area of the active, the larger the amount of the
degradation. Of the 5 excipients present in 1.0, 5.0 and 10.0 mg
capsules, only the use of A-TAB allowed for degradation of
transnorsertraline HCl, similar to that observed when developmental
capsules per se were stressed, and the extent of degradation caused
by A-TAB depended on the lot used. The mechanism leading to
degradation of active, apparently exacerbated by the presence of
A-TAB, was not determined. Individual degradants may be isolated,
for example, by placing a mixture of 2 g of Active 3 and 248 g of
A-TAB 2 in an open dish for 3 weeks at 40.degree. C./75% RH. The
individual degradants were isolated in about 5 to 10 mg
quantities.
[0478] 6.30 Open Dish Stability Study Examples
[0479] Transnorsertraline HCl (1) ("Active 1") was mixed with each
excipient present in 1 mg capsule strength respectively. The
samples contained two different ratios (1:1 and as in the 1 mg
capsules) of active and excipients.
[0480] Set 1a Sample Matrix
TABLE-US-00037 Samples Placed at 40.degree. C./75 RH for 3 Weeks*
Active Starch Sample # 1 Talc 1500 1 A-TAB 1 Ac-Di-Sol Mg St. 1
7.88 mg -- -- -- -- -- 2 7.88 mg 7.88 mg -- -- -- -- 3 7.88 mg --
7.88 mg -- -- -- 4 7.88 mg -- -- 7.88 mg -- -- 5 7.88 mg -- -- --
7.88 mg -- 6 7.88 mg -- -- -- -- 7.88 mg *The ratio of active to
excipient is 1:1
[0481] Set 1b Sample Matrix
TABLE-US-00038 Samples Placed at 40.degree. C./75 RH for 3 Weeks*
Active Starch Sample # 1 Talc 1500 1 A-TAB 1 Ac-Di-Sol Mg St. 7
7.88 mg -- 974 mg 8 7.88 mg -- -- 974 mg 9 7.88 mg -- -- -- 126 mg
10 7.88 mg -- -- -- -- 10.5 mg 11 -- 7.88 mg -- -- -- -- 12 -- --
974 mg -- -- -- 13 -- -- -- 974 mg -- -- 14 -- -- -- -- 126 mg --
15 -- -- -- -- -- 10.5 mg *The ratio of active to excipient is as
in 1 mg capsules
[0482] The results obtained for Set 1 experiments are shown in
Tables 6 and 7.
TABLE-US-00039 TABLE 22 Stability of Set 1a Samples % Impurities
Active 1 + Active 1 + Active 1 + Active 1 + Active 1 + Peaks RRT
Active 1 Starch 1 A-TAB 1 AC-Di-Sol Mg Stearate Talc 0.764 0.05
0.04 0.05 0.03 0.04 0.05 0.862, Synthetic 0.04 0.04 0.04 0.03 0.04
0.04 Impurity 1 0.885, Synthetic 0.05 0.05 0.05 0.05 0.05 0.06
Impurity 2 1.07, cis- 0.12 0.10 0.10 0.10 0.11 0.10 diastereomer
1.386 0.07 0.07 0.06 0.05 0.06 0.07 1.642, Tetralone -- -- -- --
0.02 -- % Total Impurities 0.33 0.30 0.30 0.26 0.32 0.32 % Active
99.68 99.69 99.70 99.74 99.68 99.68 *The ratio of Active to
excipient is 1:1
[0483] As shown in Table 22, when the ratio of active 1 to
excipient is 1:1, no appreciable impurities formed due to the
presence of various excipients. Only a small amount of tetralone
was observed.
[0484] When the ratio was changed to that as in 1 mg capsules,
excipients such as starch, formulations containing Ac-Di-Sol,
magnesium stearate demonstrated a small growth of the tetralone
impurity (RRT 1.64, Table 7). A-TAB 1 appeared to cause the most
degradation. The unknown impurities/degradants at RRT 0.61, 0.68,
0.78, 0.80, 1.34, 1.53 and 1.70 are present at or above 0.10%
levels in this sample, and some degradants approached the 1.0%
level. Known impurities such as synthetic impurity 1, the
cis-diastereomer and tetralone grew 3-4 times more with A-TAB 1
than in active 1 alone.
TABLE-US-00040 TABLE 23 Stability of Set 1b Samples % Impurities
Active 1 + Active 1 + Active 1 + Active 1 + Mg Active 1 + Peaks RRT
Active 1 Starch 1 A-TAB 1 Ac-Di-Sol Stearate Talc 0.606 -- -- 0.09
-- -- -- 0.683 -- -- 0.54 -- -- -- 0.764 0.05 0.05 0.45 0.05 0.04
0.05 0.803 -- -- 0.53 -- -- -- 0.862, Synthetic 0.04 0.03 0.11 0.05
0.04 0.04 Impurity 1 0.885, Synthetic 0.05 0.05 0.05 0.05 0.05 0.06
Impurity 2 0.939 -- -- 0.03 -- -- -- 1.07, cis- 0.12 0.11 0.43 0.08
0.09 0.10 diastereomer 1.127 -- -- 0.03 -- -- -- 1.271 -- -- 0.07
-- -- -- 1.343 -- -- 0.13 -- -- -- 1.386 0.07 0.06 0.02 0.06 0.05
0.07 1.526 -- -- 0.18 -- -- -- 1.642, Tetralone -- 0.09 0.23 0.05
0.03 -- 1.696 -- -- 0.12 -- -- -- % Total Impurities 0.33 0.39 3.01
0.34 0.30 0.32 % ACTIVE 99.68 99.61 97.00 99.74 99.68 99.68 *The
ratio of active to excipient is as in 1 mg capsules
[0485] For Set 2 experiments, 3 different lots of active were mixed
with each of 3 different lots of A-TAB separately and in 3
different ratios (1:124, 1:372) as shown in Set 2a and Set 2b,
respectively.
[0486] Set 2a Sample Matrix
TABLE-US-00041 Open Dish - Samples at 40.degree. C./75% RH for 2
Weeks* Sample Active Active Active A-TAB 4 # 1 2 3 A-TAB 2 A-TAB 3
(Powder) 10 7.88 mg -- -- 974 mg -- -- 11 -- 7.88 mg -- 974 mg --
-- 12 -- -- 7.88 mg 974 mg -- -- 13 7.88 mg -- -- -- 974 mg -- 14
-- 7.88 mg -- -- 974 mg -- 15 -- -- 7.88 mg -- 974 mg -- 16 7.88 mg
-- -- -- -- 974 mg 17 -- 7.88 mg -- -- -- 974 mg 18 -- -- 7.88 mg
-- -- 974 mg The ratio of active to excipient is 1:124
[0487] Set 2b Sample Matrix
TABLE-US-00042 Open Dish - Samples at 40.degree. C./75% RH for 2
Weeks* Sample Active Active Active A-TAB 4 # 1 2 3 A-TAB 2: A-TAB 3
(Powder) 19 7.88 mg -- -- 2.92 g -- -- 20 -- 7.88 mg -- 2.92 g --
-- 21 -- -- 7.88 mg 2.92 g -- -- 22 7.88 mg -- -- -- 2.92 g -- 23
-- 7.88 mg -- -- 2.92 g -- 24 -- -- 7.88 mg -- 2.92 g -- 25 7.88 mg
-- -- -- -- 2.92 g 26 -- 7.88 mg -- -- -- 2.92 g 27 -- -- 7.88 mg
-- -- 2.92 g The ratio of active to excipient is 1:372
[0488] The results from the samples in Set 2a containing active and
excipient in the ratio 1:124 are tabulated in Table 24.
TABLE-US-00043 TABLE 24 Stability of Set 2a Samples* % Impurities
Active Active Active Active Active Active Active Active Active 1 +
2 + 2 + 2 + 3 + 3 + 3 + 1 + 1 + A-TAB A-TAB A-TAB A-TAB A-TAB A-TAB
A-TAB Peaks RRT A-TAB 2 A-TAB 3 4 2 3 4 2 3 4 0.683 0.04 0.03 --
0.10 0.05 -- 0.21 0.10 -- 0.764 0.08 0.06 0.05 0.12 0.08 0.04 0.29
0.11 0.04 0.803 0.07 0.02 -- 0.20 0.09 - 0.6 0.13 -- 0.862, 0.07
0.05 0.03 0.14 0.06 0.05 0.36 0.06 0.05 Synthetic Impurity 1 0.885,
0.06 0.05 0.05 0.05 0.04 0.04 0.06 0.06 0.07 Synthetic Impurity 2
1.07, cis- 0.14 0.11 0.07 0.12 0.07 0.02 0.27 0.14 0.06
diastereomer 1.127, 0.02 -- -- -- -- -- -- 0.02 0.03 Sertraline
1.271 -- -- -- 0.03 -- -- 0.05 0.03 -- 1.343 -- -- -- 0.03 -- --
0.05 0.02 -- 1.386 0.03 0.05 0.05 -- -- -- -- -- -- 1.526 -- -- --
0.04 -- -- 0.09 0.03 -- 1.642, 0.05 0.04 0.06 0.07 0.06 0.06 0.14
0.10 0.06 Tetralone 1.696 - -- -- -- -- -- 0.04 -- -- 1.931 0.02 --
-- -- -- -- -- -- -- % Total 0.58 0.41 0.31 0.90 0.45 0.21 2.16
0.80 0.31 Impurities % Active 99.41 99.60 99.69 99.08 99.56 99.80
97.81 99.20 99.68 *The ratio of active to excipient is 1:124
[0489] The results of Table 24 show that varying the amount of
A-TAB while keeping the amount of Active fixed resulted in the most
degradation. Varying the amount of Active while keeping the amount
of A-TAB fixed resulted in Active 3 providing the most impurities.
The combination of Active 3 and A-TAB 2 provided the greatest
amount of total impurities/degradation. The surface area of the
lots of Active decreased from Active 3 to Active 4 to Active 2 to
Active 1. Thus, the surface area of Active may play a part in the
susceptibility of Active to degradation.
[0490] A-TAB 4, the powdered lot, provided only a small amount of
tetralone. When the ratio of active to excipient was increased to
1:372, three times more than that present in 1 mg capsules, the
total impurities formed remained almost the same as that found in
1:124 ratio. See Tables 24 and 25. It appears that the total
impurities formed reached a plateau at a certain ratio of active to
excipient.
TABLE-US-00044 TABLE 25 Stability of Set 2b Samples* % Impurities
Active + Active + Active + Active + Active + Active 3 + A- A- A- A-
A- Active + Active 3 + Active 3 + A- TAB TAB TAB TAB TAB A- A- A-
TAB Peaks RRT 2 3 4 2 3 TAB 4 TAB 2 TAB 3 4 0.683 0.07 0.02 -- 0.09
0.11 0.01 0.18 0.10 0.05 0.764 0.1 0.06 0.05 0.1 0.12 0.04 0.23
0.11 -- 0.803 0.12 -- -- 0.14 0.16 -- 0.50 0.13 -- 0.862, Synthetic
0.07 0.06 0.04 0.10 0.10 0.05 0.30 0.06 0.04 Impurity 1 0.885,
Synthetic 0.06 0.06 0.06 0.05 0.04 0.04 0.07 0.06 0.07 Impurity 2
1.07, cis-diastereomer 0.17 0.12 0.11 0.11 0.12 0.02 0.25 0.14 0.04
1.127, Sertraline -- -- -- -- -- -- -- 0.02 -- 1.271 -- -- -- -- --
-- 0.05 0.03 -- 1.343 0.03 -- -- -- -- -- 0.07 0.02 -- 1.386 0.03
0.04 0.05 0.03 -- -- -- -- -- 1.526 0.03 -- 0.02 -- -- 0.03 0.09
0.03 0.03 1.642, Tetralone 0.07 0.04 0.05 0.07 0.11 0.11 0.13 0.1
0.07 1.696 -- -- -- -- -- -- 0.03 -- -- 1.931 0.04 -- -- -- -- --
-- -- -- % Total Impurities 0.79 0.40 0.38 0.69 0.76 0.30 1.90 0.80
0.30 % Active 99.2 99.60 99.62 99.29 99.23 99.7 98.06 99.20 99.70
*The ratio of active to excipient is 1:372
[0491] 6.31: Isolation and Identification of Degradants of Formula
(III)
[0492] Samples used for preparation and isolation of degradants of
formula (III) were prepared as follows: To a 500 mL brown glass
bottle, 2.25 g of Active and 278 g of A-TAB were mixed by hand for
1 minute. The resulting mixture was passed through 35 mesh sieve,
twice, such that the material remaining in the sieve was minimal.
The sample was mixed again in a Turbula mixer at 22 rpm for 20
minutes. The mixture was then transferred to a crystallizing dish
and the open container was placed at 40.degree. C./75% RH for 3
weeks. An aliquot of the mixture was analyzed at 2 and 3 weeks. The
sample was removed from the heating chamber after 3 weeks and
stored refrigerated.
[0493] From the degraded sample, 62 g of the mixture was weighed in
to a 1-L erlenmeyer flask. A volume of 500 mL of methanol was added
and stirred at room temperature using a magnetic stir bar for 1
hour. The stirred mixture was allowed to settle for 30 minutes. The
supernatant was vacuum filtered using a MAGNA, Nylon supported,
plain, 0.45 um filter. The small amount of powder on the filter
paper was washed with methanol and the rinses combined. The
filtrate was analyzed using the HPLC method described below. The
sample diluent was methanol. The total area obtained by adding the
peak areas of active and the impurities was quantitated using a
standard solution of active. The amount of active and all the
impurities thus extracted was 369.2 mg. The solid in the erlenmeyer
flask was treated again with another 500 mL of methanol.
[0494] By repeating the same procedure as described above, the
amount of active and all the impurities extracted the second time
was 38.5 mg. The two filtrates were combined and methanol was
removed using a rotary evaporator. An orange yellow solid remained
at the bottom of the flask. A mixture of 6.5 mL of methanol and 3
mL of water was added. The solid dissolved forming an orange yellow
solution. This solution was centrifuged at room temperature and the
clear supernatant was transferred to a 10 mL glass vial and stored
refrigerated.
[0495] HPLC Separation of the 4 major degadants. The following
semi-preparative HPLC conditions were developed and used to
separate the 4 major impurities from the open dish forced degraded
sample solution prepared as described above.
TABLE-US-00045 HPLC column: Zorbax SB-CN (Agilent), 9.2 mm x 250
mm, 5 .mu.m Mobile phase A: 0.1% formic acid in water Mobile phase
B: 0.1% formic acid in acetonitrile Wavelength: 220 nm Volume
injected: 10 .mu.L Flow rate: 4 mL/min Run time: 44 minutes Time in
minutes % A % B Gradient used: 0 80 20 20 80 20 22 0 100 30 0 100
32 80 20 44 80 20
[0496] Only the 4 major impurities were fraction collected. Active
and other impurities were washed off the column. Approximately 35
injections were made and the fractions of each degradant were
pooled separately. Each of the 4 pools was then analyzed using
HPLC. The analytical column separation of the 4 pools is shown in
FIG. 9. Impurities 1 and 3 were each 100% pure. Impurity 2 was 98%
pure. Fraction 4 was found to be a mixture of impurities 4 and 5
present in the ratio 63:37.
[0497] Structural Identification of Deagradants of Formula (III).
Degradation products of active were isolated using semi-preparative
HPLC (Zorbax SB-SN, 5 um, 9.2.times.250 mm; 20% ACN/H.sub.2O with
0.1% formic acid as mobile phase, 4 ml/min) with the aforementioned
open dish degradation sample. Fractions containing these impurities
were neutralized with 0.1 M NH.sub.4OAc before drying under vacuum
to prevent possible decomposition.
[0498] All impurities were initially analyzed with LC-MS,
fragmentation and high resolution MS--analyses. Degradants III-a
and III-b showed almost identical mass spectral characteristics.
[M+H.sup.+] at m/z 308 for both compounds was observed while the
isotopic pattern confirmed the bis-chloro nature of the molecules,
indicating their transnorsertraline origin. The difference of 16
mass units in molecular weight of transnorsertraline versus that of
Degradants III-a and III-b suggested that both impurities could be
oxidation products of transnorsertraline in the form of hydroxyl
group. The loss of H.sub.2O (-18 mu) in MS fragmentation suggested
that the hydroxyl group might reside on the aliphatic ring.
[0499] Isolation effort for Degradant III-a yielded a small amount
of relatively pure compound. The .sup.1 H NMR spectrum of Degradant
III-a in ACN-d3 revealed that (a) the aromatic rings of
transnorsertraline were not altered as evidenced by the aromatic
proton signals and patterns, and (b) one of the benzylic protons of
transnorsertraline was substituted as only one was observed at 4.16
ppm. Because the mass spectral data had confirmed that the amino
group was not changed in this impurity, the only other position for
a benzylic hydroxyl group is the position 4. Therefore, Degradant
III-a was identified as 4-hydroxy transnorsertraline.
[0500] Isolated Degradant III-b showed a very similar pattern in
its .sup.1H NMR spectrum, i.e., unaltered aromatic rings and the
disappearance of one benzylic proton. This information together
with its mass spectral data led to the conclusion that impurities 1
and 2 were a diastereomeric pair of 4-hydroxy
transnorsertraline.
##STR00005##
[0501] Impurities 3 and 4 share the same molecular weight of 323
with almost identical MS fragmentation pattern. After the isolation
and drying process, it was noticed that impurities 3 and 4 were
converted to impurities 1 and 2 respectively (by HPLC retention
time, MS data and .sup.1H NMR spectrum). As noted above, in order
to minimize the possible decomposition during the isolation
process, NH.sub.4OAc was used to neutralize the formic acid in the
collected fractions, which may have resulted in the conversion.
[0502] Additional experiments showed that freshly isolated
Degradant-III-c and III-d fractions without NH.sub.4OAc were
relatively stable even after a few days at room temperature.
However, in the presence of NH.sub.4OAc, almost 50% of the
compounds were converted after 24 hours. Furthermore, it was
observed that upon drying under vacuum, Degradants III-c and III-d
were converted to Degradants III-a and III-b independent of the
presence of NH.sub.4OAc. Because the molecular formula difference
between Degradants III-c and III-a was one oxygen atom as measured
by HR-MS, it was concluded that Degradants II-c and III-d were a
diasteromeric pair of 4-hydroperoxy transnorsertraline. The
conversions from impurity 3 and Degradant III-d to Degradants III-a
and III-b may be by a decomposition process of hydroperoxides.
##STR00006##
[0503] 6.31: Stability Studies of Transnorsertraline with
Mannitol
[0504] Three recrystallized mannitol lots spiked with mannose were
selected for further study based on their % mannose values.
Crystalline mannitol and spray dried mannitol were used as
controls. The recrystallized spray dried mannitol lot was also used
in the study to determine whether the type of mannitol used
(crystalline vs. spray dried) was significant. Transnorsertraline
HCl blends were made using the selected mannitol lots and placed at
30.degree. C./65% RH under open dish conditions and analyzed
initially and then at 2, 4 and 6 weeks using HPLC. The results are
shown in Table 26.
TABLE-US-00046 TABLE 26 Amount of Degradant II in
Transnorsertraline HCl Blends Active % % Blend Mannitol % Mannose
Degradant % Degradant Degradant Lot Lot (IC Method) in 2 weeks in 4
weeks in 6 weeks 1 1 0.000 0.00 0.00 0.00 2 2 0.001 0.02 0.06 0.05
3 3 0.005 0.12 0.12 0.12 4 4 0.012 0.24 0.19 0.16 5 5 0.033 0.67
0.62 0.61 6 6 0.079 0.93 1.28 0.99
[0505] All of the patents, patent applications and publications
referred to in this application are incorporated herein in their
entireties. Moreover, citation or identification of any reference
in this application is not an admission that such reference is
available as prior art.
* * * * *