Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL POLYMORPHS OF AZABICYCLOHEXANE
This application claims priority to United States Patent Application Serial
No.
10/920,748, filed August 18, 2004, which is converted to a provisional
application.
Salts of the (+) isomer of phenyl azabicyclohexane having the formula
CI
H
N
H
are known for use in treating depression. As set forth in Lippa et al., U.S.
Patent No.
6,372,919, the compound of formula I whose chemical name is (+)-1-(3, 4-
dichlorophenyl)-3-azabicyclo[3.1.0]hexane in its (+) isomeric form has been
found to have
potent anti-depressive activity.
While the azabicyclohexanes of formula I have been prepared as described in
various U.S. patents such as U.S. Patents 4,231,935, 4,131,611, 4,435,419,
4,118,417 and
4,196,120, these compounds were prepared in racemic form. In the procedure of
Lippa et
al., U.S. Patent No. 6.372,919, the (+) optical antipode was produced as a
mixture of
various isomeric polymorphic forms which heretofore have been unrecognized. A
pure
crystalline form of the (+) isomer of the compound of formula I is of
particular importance
since it could be formulated into various pharmaceutical dosage forms such as
for example
tablets or capsules for treatment of patients. Variations in crystal structure
of a
pharmaceutical drug substance are known to affect the dissolution,
manufacture, stability
and bioavailability of a pharmaceutical drug product, particularly in solid
oral dosage
forms. Therefore it is important to produce the (+) isomer of the compound of
formula I
in a pure form comprising a single thermodynamically stable crystal structure.
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SUMMARY OF INVENTION
In accordance with this invention, it has been discovered that the (+) optical
antipode of the compound of formula 1 as prepared in Lippa et al., U.S. Patent
6,372,919
exists as a mixture of two crystalline polymorphic structures, one being the
hemi-hydrate
form, which is designated as polymorph form A, and the other being the
anhydrous form,
which is designated as polymorph form B. A dehydrated form designated as
polymorph
form C has also been found. When the (+) optical antipode of the compound of
formula I
is produced by prior art procedures, it has been found that it was produced as
a mixture of
polymorph form A and polymorph form B which do not readily separate into their
pure
polymorphic crystalline forms.
In accordance with this invention, a method of forming these polymorphs as
pure
independent polymorph forms has been discovered. In addition we have found
that the
polymorph form A of the (+) optical antipode of the compound of formula I in
its pure
crystalline structure produced in accordance with this invention is a
thermodynamically
stable polymorph form. Therefore, form A is the preferred crystalline form of
the (+)
optical antipode of the acid addition salt of the compound of formula I for
formulation into
pharmaceutical drug products.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, it has been discovered that the (+) optical
antipode of acid addition salts of the compound of formula I exists in three
different
crystalline polymorphic forms designated as polymorph form A, polymorph form B
and
polymorph form C and that polymorph form A, which is the hemi-hydrate form, is
a
thermodynamically stable form.
Polymorph form A may be characterized as the hemi-hydrate of acid addition
salts
of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. It is the hemi-
hydrate
crystalline form, which uniquely characterizes polymorph form A from polymorph
form B
and polymorph form C of acid addition salts of the compound of formula I.
Polymorph
form B and polymorph form C of acid addition salts of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane do not exist as hemi-hydrates.
The polymorphs of acid addition salts of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane may also be characterized by their X-ray powder
diffraction
patterns (XRPD) and/or their Raman spectroscopy peaks. With respect to X-ray
powder
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diffraction, the relative intensities of the X-ray powder diffraction peaks of
a given
polymorph may vary depending upon the crystal size of the polymorph used to
determine
the pattern. This is a phenomenon of preferred orientation. Preferred
orientation is caused
by the morphology of crystals. In this case, the XRPD analysis should be
carried out with
the sample spinning in the sample holder during XRPD analysis to reduce the
preferred
orientation effects. Samples for XPRD analysis for determination of the
presence and
nature of their polymorph status in accordance with this invention should be
lightly ground
and/or sieved to a crystal size of from about 10 to 40 microns for XPRD
analysis.
A Bragg-Brentano instrument, which includes the Shimadzu system, used for the
X-ray powder diffraction pattern measurements reported herein, gives a
systematic peak
shift (all peaks can be shifted at a given " 20" angle) which result from
sample preparation
errors as described in Chen et al.; J Pharmaceutical and Biomedical Analysis,
2001; 26,
63. Therefore, any " 20" angle reading of a peak value is subject to an error
of about (f)
0.2 .
The X-ray powder diffraction pattern (XRPD) analyses of polymorph forms A, B
and C were performed with a Shimadzu XRD-6000 X-ray powder diffractometer
using Cu
Ka radiation. In this procedure the compound as a hydrochloride salt was
loaded onto the
machine as a crystalline powder. The instrument was equipped with a long fine
focus X-
ray tube. The tube voltage and amperage were set to 40 kV and 40 mA,
respectively. The
divergence and scattering slits were set at 1 and the receiving slit was set
at 0.15 mm.
Diffracted radiation was detected by a Nal scintillation detector. A theta-two
theta
continuous scan at 3 /min (0.4 sec/0.02 step) from 2.5 to 40 20 was used. A
silicon
standard was analyzed to check the instrument alignment. Data were collected
and
analyzed using XRD-6000 v. 4.1.
The following Table 1 shows the peaks of the X-ray powder diffraction pattern
of
purified polymorph form A of the hydrochloride salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
This
pattern is given in terms of the " 20" angles of the peaks subject to the
angle error set forth
above. With respect to the percent value of relative intensity (I/1o) given in
Table 1, Io
represents the value of the maximum peak determined by XRPD for the sample for
all
" 20" angles and I represents the value for the intensity of a peak measured
at a given
" 20" angle". The angle " 20" is a diffraction angle which is the angle
between the
incident X-rays and the diffracted X-rays. The values for the relative
intensities for a
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given peak set forth in percent and the " 20" angles where said peaks occur
are given in
Table 1 below.
Table 1
XRPD Peaks ( 20) and Relative Intensities (1/lo) for Polymorph Form A
Form A
29 I/lo 29 I/lo
4.55 25 33.42 9
9.10 15 34.24 6
13.65 6 35.08 15
17.14 60 35.65 16
17.85 11 36.31 14
18.24 23 37.11 26
18.49 14 37.78 9
19.27 14 39.85 9
19.62 22
21.74 15
21.96 100
22.24 12
23.01 7
24.52 43
24.79 10
26.74 52
27.44 11
27.63 17
28.36 16
28.48 26
29.00 14
29.20 19
29.40 27
29.57 27
30.24 18
31.01 13
31.62 17
32.20 24
32.93 12
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The following Table 2 shows the peaks of the X-ray powder diffraction pattern
of
purified polymorph form B of the hydrochloride salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
The values
for the relative intensities for a given peak set forth in percent and the "
29" angles where
said peaks occur for polymorph form B of the hydrochloride salt of (+)-1 -(3,4-
dichlorophenyl)-3-azabicyclo[3. 1.0]hexane having a crystal size of about 10
to 40 microns
are given in Table 2 below.
Table 2
XRPD Peaks ( 20) and Relative Intensities (1/lo) for Polymorph Form B
Form B
2e Ino 2e ulo
10.50 6 32.14 10
13.34 12 32.31 7
15.58 42 32.80 7
17.12 6 32.95 6
17.36 8 33.45 44
17.52 26 33.74 12
18.21 11 35.25 10
20.40 7 35.40 12
21.35 97 35.58 9
21.61 17 36.75 8
21.93 11 37.55 18
22.64 6 39.01 15
23.04 79 39.22 7
24.09 6 39.37 7.
24.52 14 39.86 11
25.43 96
26.24 53
26.36 73
26.75 11
26.88 7
27.44 6
27.94 12
28.36 20
28.54 30
29.39 10
29.72 9
30.07 7
30.58 8
30.72 100
31.07 14
31.38 12
31.55 7
31.78 12
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The following Table 3 shows the peaks of the X-ray powder diffraction pattern
of
purified polymorph form C of the hydrochloride salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
The values
for the relative intensities for a given peak set forth in percent and the "
20" angles where
said peaks occur for polymorph form C of the hydrochloride salt of (+)-1-(3,4-
dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of about 10 to
40 microns
are given in Table 3 below.
Table 3
XRPD Peaks ( 20) and Relative Intensities (Ulo) for Polymorph Form C
Form C
020 I/lo 26 I/lo
5.46 6 27.90 54
5.66 20 28.14 8
6.37 6 28.56 32
7.26 6 28.74 17
8.75 6 29.20 6
13.34 25 29.72 6
13.94 11 29.92 26
15.65 7 30.54 13
16.26 7 30.72 19
17.01 8 30.96 31
17.38 9 31.42 7
17.64 83 31.68 11
17.92 15 31.80 15
18.23 40 31.97 6
19.08 7 32.43 21
19.38 46 33.26 12
19.86 20 33.40 15
20.07 100 33.64 25
21.16 17 33.84 18
21.32 94 34.11 15
21.64 37 34.70 11
22.42 25 35.07 8
22.70 12 35.64 11
22.97 70 35.91 8
23.31 6 36.09 21
24.09 15 37.80 12
24.86 94 38.06 6
25.24 32 38.17 6
25.38 49 39.04 6
26.12 13 39.23 8
26.32 90 39.77 7
26.87 18
27.21 39
However, there are key major peaks at given angles in these X-ray powder
diffraction patterns which are unique to each given polymorph form. These
peaks are
present in the XRPD patterns of each of the polymorph forms having a crystal
size of
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about 10 to 40 microns. Any of these major peaks, either alone or in any
distinguishing
combination, are sufficient to distinguish one of the polymorph forms from the
other two
polymorph forms. For polymorph form A, the " 20" angles of these major peaks
which
characterize polymorph form A, subject to the error set forth above, are as
follows:
17.14;
19.62;
21.96;
24.52;
and
26.74.
Any of these major peaks, either alone or in any distinguishing combination,
are sufficient
to distinguish polymorph form A from the other two polymorph forms.
Also, there are key major peaks at given angles in the XRPD of polymorph form
B
which are unique to polymorph form B as the hydrochloride salt having a
crystal size of
about 10 to 40 microns that are typically present in the XRPD pattern of
polymorph form
B as the hydrochloride salt irrespective of the particle size. Any of these
major peaks,
either alone or in any distinguishing combination, are sufficient to
distinguish polymorph
form B from the other two polymorph forms. For polymorph form B, the " 20"
angles of
these major peaks which characterize polymorph form B, subject to the error
set forth
above, are as follows:
15.58;
17.52;
21.35;
23.04;
25.43;
and
30.72.
Also, there are key major peaks at given angles in the XRPD of polymorph form
C
which are unique to polymorph form C as the hydrochloride salt, having a
crystal size of
about 10 to 40 microns, that are typically present in the XRPD pattern of
polymorph form
C as a hydrochloride salt irrespective of the particle size. Any of these
major peaks, either
alone or in any distinguishing combination, are sufficient to distinguish
polymorph form C
from the other two polymorph forms. For polymorph form C, the " 20" angles of
these
major peaks which characterize polymorph form C, subject to the error set
forth above, are
as follows:
13.34;
17.64;
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20.07;
21.32;
22.97;
24.86;
26.32;
and
27.90.
Another method of characterizing the three polymorphs of (+)- 1 -(3,4-
dichlorophenyl)-3-azabicyclo[3.1.0]hexane is through Raman spectroscopy. The
procedure for carrying out Raman Spectroscopy is described on pages 260-275 of
Skoog
and West, Principles of Instrumental Analysis (2nd Ed.); Saunders College,
Philadelphia
(1980).
Briefly, Raman spectra were obtained using a FT-Raman 960 (or 860)
spectrometer (Thermo Nicolet) interfaced to an 860 FT-IR. This spectrometer
uses an
excitation wavelength of 1064 nm. Approximately 0.912 W of Nd:YVO4 laser power
was
used to irradiate the samples. The Raman spectra were measured with an indium
gallium
arsenide (InGaAs) detector. The samples were pressed into pellets for
analysis. A total of
128 sample scans were collected from 3600 or 3700 - 98 cm"I at a spectral
resolution of
about ( ) 4 cm-', using Happ-Genzel apodization. Wavelength calibration was
performed
using sulfur and cyclohexane. The Raman spectra peak positions given below in
wavenumbers (cm') for the purified polymorph forms A, B and C of the
hydrochloride
salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are subject to an
error of
about ( ) 4 cm ' .
The Raman spectra peak positions in wavenumbers (cm"1) for polymorph form A
of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane are
given in Table 4.
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Table 4
Raman Peak Listing for Polymorph Form A (peaks> 400 cm"1)
Peak Positions In Wavenumbers (cm-1)
Form A
436 1135
479 1189
534 1229
549 1274
646 1309
691 1338
680 1366
762 1393
812 1453
836 1484
892 1557
921 1597
959 2890
982 2969
998 2982
1030 3017
1056 3046
1099 3064
1122
The Raman spectra peak positions in wavenumbers (cm-1) for polymorph form B
of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane are
listed in Table 5.
Table 5
Raman Peak Listing for Polymorph Form B (peaks> 400 cm 1)
Peak Positions In Wavenumbers (cm"1)
Form A
418 1245
446 1278
478 1309
533 1343
648 1380
676 1398
686 1456
767 1483
825 1557
852 1593
895 2895
964 2963
979 2993
1031 3027
1054 3066
1070
1099
1136
1189
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The Raman spectra peak positions in wavenumbers (cm"1) for polymorph form C
of the hydrochloride salt of (+)-l -(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane are
given in Table 6.
Table 6
Raman Peak Listing for Polymorph Form C (peaks> 400 cm"1)
Peak Positions In Wavenumbers (cm 1)
Form C
441 1246
474 1266
532 1279
648 1309
674 1343
690 1398
767 1456
811 1471
826 1557
856 1595
895 2900
970 2966
1031 2992
1059 3048
1094 3070
1122
1137
1189
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Table 4, Table 5 and Table 6 provide the complete patterns of the Raman peak
positions with respect to the hydrochloride salts of polymorph forms A, B and
C
respectively. However, there are certain key peaks, within these patterns,
which are unique
to each of the hydrochloride salts of these polymorphs. Any of these key
peaks, either
alone or in any distinguishing combination, are sufficient to distinguish one
of the
polymorph forms from the other two polymorph forms. These peak positions,
expressed in
wavenumbers (cm"1) for the hydrochloride salt of polymorph form A are:
Peak Positions In Wavenumbers (cm"1) for Polymorph Form A
762;
636;
921;
959;
1393;
1597;
2890;
2982;
and
3064.
Any of these key peaks, either alone or in any distinguishing combination, are
sufficient to
distinguish polymorph form A from the other two polymorph forms
The characterizing peak positions expressed in wavenumbers (cm"1) for the
hydrochloride salt of polyinorph form B are:
Peak Positions In Wavenumbers (cm"1) for Polymorph
Form B
1245;
1380;
2963;
2993;
3027;
and
3066.
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Any of these key peaks, either alone or in any distinguishing combination, are
sufficient to
distinguish polymorph form B from the other two polymorph forms.
The characterizing peak positions expressed in wavenumbers (cm 1) for the
hydrochloride salt of polymorph form C are:
Peak Positions in Wavenumbers (cm-1) for Polymorph Form C
1059;
1094;
1266;
1343;
1595;
2900;
2966;
and
3070.
Any of these key peaks, either alone or in any distinguishing combination, are
sufficient to
distinguish polymorph form C from the other two polymorph forms
In accordance with this invention, each of the crystalline polymorph forms of
the
acid addition salt (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be
obtained
substantially free of its other enantlomeric, geometric and polymorphic
isomeric forms.
The term "substantially free" of its other enantiomeric, geometric and
polymorphic
isomeric forms designates that the crystalline material is at least about 95%
by weight pure
in that it contains no more than about 5% w/w of its other enantiomeric,
geometric and
polymorphic isomeric forms.
In the past, preparation of acid addition salts of (+)-1-(3,4-dichlorophenyl)-
3-
azabicyclo[3.1.0]hexane has resulted in a mixture of the A and B polymorph
forms. This
mixture constituted an approximately 50% by weight mixture of each polymorph
which
could not be easily separated. In addition, it has been found that there was
some inter-
conversion of polymorph forms A and B upon standing at ambient temperature or
inter-
conversion, upon heating, of this 50% mixture to form a mixture of polymorph
forms A, B
and C. However, these mixtures could not be easily separated. Therefore, the
purified
isomeric forms of these individual polymorph forms substantially free of its
other
enantiomeric, geometric and polymorphic isomeric forms could not be obtained.
In accordance with this invention, it has been discovered that polymorph forms
A,
B and C of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, particularly
as
hydrochloride acid addition salts, can each be prepared substantially free of
its other
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enantiomeric, geometric and polymorphic isomeric forms through re-
crystallization of a
mixture of the A and B polymorph forms produced in accordance with prior art
procedures. Depending upon the particular solvent, conditions and
concentrations of
materials utilized to re-crystallize the mixture of polymorph forms A and B,
one can
selectively produce the desired polymorph form of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane, substantially free of its other enatiomeric,
geometric and
polymorphic isomers.
In preparing polymorph forms A and B substantially free of other polymorph
forms, crystallization from a mixture of A and B is generally utilized.
However, the
crystallization technique with regard to producing each of these polymorph
forms
substantially free of other polymorph forms is different. In preparing
polymorph form A,
which is the hemi-hydrate of the acid addition salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane, it is best to utilize a solvent medium to dissolve a
solid
containing polymorph form A such as a mixture of polymorph forms A and B in an
organic solvent which contains water. The preferred organic solvents that can
be utilized
in this procedure include lower alkanol solvents such as methanol, butanol,
ethanol or
isopropanol as well as other solvents such as acetone, dichloromethane and
tetrahydrofuran. In forming the purified polymorph form A substantially free
of other
polymorph forms, it is best to incorporate water in these solvents when
preparing the
medium for crystallization. Once the solid, preferably a mixture of polymorph
forms A
and B, is dissolved in this medium, the solvent should be allowed to evaporate
at room
temperature over a long period of time while the solution is exposed to the
atmosphere.
Room temperature can constitute any temperature from about 15 C to 35 C. The
evaporation can take place until all of the solvent medium is removed leaving
the purified
crystals of polymorph form A. Preferably evaporation may be carried out
naturally such
as by slow evaporation. Depending upon the amount of the solution and its
concentration,
evaporation can take place over a period from three to fifteen days or longer
until the
solvent is completed evaporated leaving a dry solid crystalline residue which
is
polymorphic form A substantially free of other polymorph forms.
Polymorph form B is the anhydrous form of the acid addition salt of (+)-1-(3,4-
dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Polymorph form B of the acid
addition salt of
(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be prepared from a
solid
containing polymorph form A such as a mixture of polymorph forms A and B by
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dissolving the polymorph fonn A or the mixture of polymorph forms A and B,
preferably
as the hydrochloride salt, utilizing anhydrous conditions. In accordance with
a preferred
embodiment of the invention, this solid is in crystalline form and is re-
crystallized by
utilizing an anhydrous organic solvent. Any of the organic solvents mentioned
hereinbefore can be utilized in their anhydrous form to produce polymorph form
B. As set
forth above, it is important that the re-crystallization take place under
anhydrous
conditions. In addition it is preferred that the removal of solvent to produce
the crystalline
form of polymorph B take place at elevated temperatures, i.e. from about 50 C
to 80 C,
under anhydrous conditions. After crystallization of polymorph B from the
solvent
mixture, the solvent can be removed by filtering or decanting to leave
polymorph form B
substantially free of other polymorph forms. In preparing the crystallizing
medium prior
to removal of the solvent, the formation of the crystallizing medium
containing the
mixture of forms A and B for re-crystallization can take place at elevated
temperatures, if
desired, i.e. from 50 C to 80 C.
Polymorph form C can be prepared from either polymorph form A or polymorph
foi-m B or mixtures thereof. Polymorph form C is prepared by extensive heating
of either
polymorph form A or polymorph form B, or mixtures thereof, at temperatures of
at least
50 C, preferably from 60 C to 80 C. Heating can be continued until polymorph
form C
substantially free of other polymorph forms is formed. This heating can, if
desired, take
place over long periods of time i.e. from 12 hours to 4 days of longer, until
the polymorph
forms of the starting material are converted to polymorph form C substantially
free of
other polymorph forms. The acid addition salt having the crystalline structure
of
polymorph form C substantially free of other polymorph forms is produced by
extensive
heating, usually not in the presence of a solvent, of the acid addition salts
of polymorph
forms A and B. The preferred acid addition salt in this preparation is the
hydrochloride
acid addition salt fonn.
The techniques set forth above also allow for the preparation of mixtures of
the
individual polymorph forms of the acid addition salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane containing specific amounts of each of the polymorphs.
In
particular, mixtures of polymorph form A and either polymorph form B or
polymorph
form C, polymorph form B and polymorph form C, and polymorph form A, polymorph
form B and polymorph form C can be readily prepared with the desired amounts
of each
of the polymorphs. By way of example and not of limitation, a mixture of
polymorph
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foim A and polymorph form B containing the desired amount of each polymorph
can be
prepared by subjecting polymorph form A substantially free of other polymorph
forms and
prepared as described above to the procedure for preparation of polymorph form
B
described above for the period of time needed to produce the desired amount of
polymorph form B. By way of further example, a mixture of polymorph form A and
polymorph form C containing the desired amount of each polymorph can be
prepared by
subjecting polymorph form A substantially free of other polymorph forms and
prepared as
described above to the procedure for preparation of polymorph form C described
above for
the period of time needed to produce the desired amount of polymorph form C.
By way of
additional example, a mixture of polymorph form B and polymorph form C
containing the
desired amount of each polymorph can be prepared by subjecting polymorph form
B
substantially free of other polymorph forms and prepared as described above to
the
procedure for preparation of polymorph form C described above for the period
of time
needed to produce the desired amount of polymorph form C. By way of further
example,
mixtures of polymorph form A and either polymorph form B or polymorph form C,
polymorph form B and polymorph form C, and polymorph form A, polymorph form B
and
polymorph form C containing the desired amount of each polymorph can be
prepared by
combining the desired polymorphs substantially free of other polymorph forms
and
prepared as described above so that the desired mixture is obtained.
Using the techniques set forth above, mixtures containing specific percentages
of
the individual polymorphic forms of the acid addition salt of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane can be obtained. For example, mixtures containing from
about
10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99%
or
greater (by weight) of polymorph form A, with the remainder of the mixture
being either
or both polymorph form B and polymorph form C, can be prepared. As another
example,
mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-
85%, 85-95% and up to 95-99% or greater (by weight) of polymorph form B, with
the
reinainder of the mixture being either or both polymorph form A and polymorph
form C,
can be prepared. As a further example, mixtures containing from about 10% to
about 10-
20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% or greater (by
weight) of polymorph form C, with the remainder of the mixture being either or
both
polymorph form A and polymorph form B, can be prepared.
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Additionally, many pharmacologically active organic compounds regularly
crystallize incorporating second, foreign molecules, especially solvent
molecules, into the
crystal structure of the principal pharmacologically active compound to form
pseudopolymorphs. When the second molecule is a solvent molecule, the
pseudopolymorphs can also be referred to as solvates. All of these additional
forms of
(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are likewise contemplated
by the
present invention.
The polymorph forms A, B and C of the present invention can be prepared as
acid addition salts formed froni an acid and the basic nitrogen group of (+)-1-
(3,4-
dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Suitable acid addition salts are
formed from
acids, which form non-toxic salts, examples of which are hydrochloride,
hydrobromide,
hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen
phosphate.
Examples of pharmaceutically acceptable addition salts include inorganic and
organic acid
addition salts. The pharmaceutically acceptable salts include, but are not
limited to, metal
salts such as sodium salt, potassium salt, cesium salt and the like; alkaline
earth metals
such as calcium salt, magnesium salt and the like; organic amine salts such as
triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,
triethanolamine salt,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like;
organic acid salts
such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate,
mandelate, acetate,
dichloroacetate, trifl uoroacetate, oxalate, formate and the like; sulfonates
such as
methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino
acid salts
such as arginate, asparginate, glutamate, tartrate, gluconate and the like.
The
hydrochloride salt formed with hydrochloric acid is an exemplary useful salt.
The above individual polymorph forms and mixtures of polymorph forms of the
acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane can
be
administered to human patients in the same manner as the previously known
forms of (+)-
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. Suitable routes of
administration for
the above individual polymorph forms and mixtures of polymorph forms of an
acid
addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane include,
but are not
limited to, oral, buccal, nasal, pulmonary, aerosol, topical, transdermal,
mucosal,
injectable, slow release and controlled release delivery, although various
other known
delivery routes, devices and methods can likewise be employed. Useful
parenteral
delivery methods include, but are not limited to, intravenous, intramuscular,
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intraperitoneal, intraspinal, intrathecal, intracerebroventricular,
intraarterial, and
subcutaneous injection.
Suitable effective unit dosage amounts for the above individual polymorphic
forms
and mixtures of polyinorphic forms of an acid addition salt of (+)-1-(3,4-
dichlorophenyl)-
3-azabicyclo[3.1.0]hexane for matnmalian subjects may range from about 1 to
1200 mg, 50 to
1000 mg, 75 to 900 mg, 100 to 800 mg, or 150 to 600 mg. In certain
embodiments, the effective
unit dosage will be selected within narrower ranges of, for example, about 10
to 25 mg, 30 to 50
mg, 75 to 100mg, 100 to 150 mg, 150 to 250 mg or 250 to 500 mg. These and
other effective
unit dosage amounts may be administered in a single dose, or in the form of
multiple daily,
weekly or monthly doses, for example in a dosing regimen comprising from about
1 to 5, or 2-3,
doses administered per day, per week, or per month. In exemplary embodiments,
dosages of
about 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 200 (anticipated dosage
strength) mg, or
250 to 500 mg, are adininistered one, two, three, or four times per day. In
more detailed
enibodiments, dosages of about 50-75 mg, 100-150 mg, 150-200 mg, 250-400 mg,
or 400-600
mg are administered once, twice daily or three times daily. In alternate
embodiments, dosages
are calculated based on body weight, and may be administered, for example, in
amounts from
about 0.5mg/kg to about 30mg/kg per day, 1mg/kg to about 15mg/kg per day,
lmg/kg to about
10mg/kg per day, 2mg/kg to about 20mg/kg per day, 2mg/kg to about 10mg/kg per
day or
3nig/kg to about 15mg/kg per day.
Using the routes and methods of administration and dosage amounts described
hereinabove and the dosage forms described hereinbelow, the individual
polymorph forms
and mixtures of polyrnorph forms of the present invention can be used for the
prevention
and treatment of various diseases and conditions in humans. By way of example
and not
of limitation, in the case of depression, this is accomplished by
administering to a patient
in need of said treatnient who is suffering from depression a composition
containing one
of the above polymocph forms substantially free of other polymorph forms or
mixtures of
polymorphs and an inert carrier or diluent, said composition being
administered in an
effective amount to prevent or treat said depression. In accordance with this
invention,
(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, either as a polymorph
form
substantially free of other polymorph forms or as a mixture of polymorph
forms, is
administered in an effective amount to prevent or treat depression. Any
effective amount
of such polymorph form substantially free of other polymorph forms or mixtures
of
polymorph forms needed to prevent or treat depression can be utilized in this
composition.
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In general, in the case oral dosage forms, dosages of from about 0.5 mg/kg to
about 5.0
mg/kg of body weight per day are used. However the amount of such polymorph
form
substantially free of other polyniorph forms or mixtures of polymorph forms in
the oral
unit dose to be admiilistered will depend to a large extent on the condition
of depression
and the weight of the patient and of course be subject to the physician's
judgment. In
accordance with this invention, the oral unit dosage form containing the given
polymorph
form substantially free of other polymorph forms or mixtures of polymorph
forms can be
preferably administered at a dosage of from about 30 mg to 300 mg per day,
more
preferably from about 50 mg to about 200 mg per day, administered once or
twice during
the day or as needed.
The present invention includes pharmaceutical dosage forms for the above
individual polymorph forms and mixtures of polymorph forms of an acid addition
salt of
(+)-1-(3,4-dichloropllenyl)-3-azabicyclo[3.1.0]hexane. Such pharmaceutical
dosage forms
may include one or more excipients or additives, including, without
limitation, binders,
fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings,
preservatives,
buffers, wetting agents, disintegrants, effervescent agents and other
conventional
excipients and additives. The compositions of the present invention can thus
include any
one or a combinatioil of the following: a pharmaceutically acceptable carrier
or excipient;
other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers;
preservatives;
diluents; and various other pharmaceutical additives and agents known to those
skilled in
the art. These additional formulation additives and agents will often be
biologically
inactive and can be administered to patients without causing deleterious side
effects or
interactions with the active agent.
As previously noted, polymorph form A is a thermodynamically stable polymorph
of an
acid addition salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
Therefore, it is
preferred that polymolph form A be used in pharmaceutical dosage forms without
the presence
of other geometrical, optical and polymorphic isomers of (+)-1-(3,4-
dichlorophenyl)-3-
azabicyclo[3.1.0]hexane. However, polymorph forms B and C can also be included
in
pharmaceutical product formulations with less positive results concerning
formulation and
stability.
If desired, the individual polymorph forms or mixtures of polymorph forms of
the
present invention can be administered in a controlled release form by use of a
slow release
carrier, such as a hycirophilic, slow release polymer. Exemplary controlled
release agents
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WO 2006/023659 PCT/US2005/029420
in this context include, but are not limited to, hydroxypropyl methyl
cellulose, having a
viscosity in the range of about 100 cps to about 100,000 cps.
The individual polymorph forms or mixtures of polymorph forms of the present
invention can be formulated and administered in oral dosage form, optionally
in
combination with a carrier or other additive(s). Suitable carriers common to
pharmaceutical formulation technology include, but are not limited to,
microcrystalline
cellulose, lactose, sucrose, fructose, glucose, dextrose, other sugars, di-
basic calcium
phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives,
kaolin,
mannitol, lactitol, maltitol, xylitol, sorbitol, other sugar alcohols, dry
starch, dextrin,
maltodextrin, other polysaccharides, or mixtures thereof.
Exemplary oral unit dosage forms for use in the present invention include
tablets,
capsules, powders, solutions, syrups, suspensions and lozenges, which may be
prepared by
any conventional method of preparing pharmaceutical oral unit dosage forms.
Oral unit
dosage forms, such as tablets, may contain one or more of the conventional,
pharmaceutically acceptable additional formulation ingredients, including but
not limited
to, release modifying agents, glidants, compression aides, disintegrants,
effervescent
agents, lubricants, binders, diluents, flavors, flavor enhancers, sweeteners
and
preservatives. These ingredients are selected from a wide variety of
excipients known in
the pharmaceutical formulation art. Depending on the desired properties of the
oral unit
dosage form, any number of ingredients may be selected alone or in combination
for their
known use in preparing such dosage forms as tablets.
Suitable lubricants include stearic acid, magnesium stearate, talc, calcium
stearate,
hydrogenated vegetable oils, sodium benzoate, leucine carbowax, magnesium
lauryl
sulfate, colloidal silicon dioxide and glyceryl monostearate. Suitable
glidants include
colloidal silica, fumed silicon dioxide, silica, talc, fumed silica, gypsum
and glyceryl
monostearate. Substances which may be used for coating include hydroxypropyl
cellulose, titanium oxide, talc, sweeteners and colorants. The aforementioned
effervescent
agents and disintegrants are useftil in the formulation of rapidly
disintegrating tablets
known to those skilled in the art. These typically disintegrate in the mouth
in less than one
minute, and often in less than thirty seconds. By effervescent agent is meant
a couple,
typically an organic acid and a carbonate or bicarbonate.
The following examples illustrate certain embodiments of the present
invention,
and are not to be construed as limiting the present disclosure.
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EXAMPLES
Example 1
This example is directed to preparing the hydrochloride salt of (+)-1-(3,4
dichlorophenyl)-3-azabicyc lo[3. 1.0] hexane from the free base of (+)-1-
(3,4dichlorophenyl)-3-azabicyclo[3.1:0] hexane and to demonstrate that this
method
produced a mixture of polymorph form A and polymorph form B.
Approximately 250 mg of the free base of (+)-1-(3, 4-dichlorophenyl)-3-
azabicyclo[3.1.0] hexane was dissolved in 400 mL 95:5 (v/v) hexane/isopropanol
(with
0.05% diethylamine). The solution was evaporated under a nitrogen stream on a
stir plate
set at approximately 70 C, concentrating the sample to a clear gel. This gel
was dissolved
in 50 mL ethyl acetate and dried under a nitrogen stream, yielding a thin,
clear to off-white
(tint of yellow), milky residue. This residue was dissolved in 7 mL diethyl
ether, and 7
mL HCI saturated di ethyl ether was added; chunks of white solid were
precipitated
immediately. This solid was recovered through vacuum filtration and washed
with 19 mL
diethyl ether. The filtered solid appeared dry. The (+)-l-(3,4-dichlorophoyl)-
3-
azabicyclo[3.1.0] hexane hydrochloride salt was recovered (162.5 mg),
resulting in a yield
of 55.7%.
XRPD analysis and Raman spectroscopy performed as described above indicated
that both the startiilg material (free base) and end product (hydrochloride
salt) constituted
a mixture of polyniorph form A and polymorph form B. Both the starting
material and
end product were observed to contain approximately 50% (by weight) of each
polymorph.
There was only a niinor difference in the % of these polymorphs in the
starting material
and in the final product.
Example 2
Stability Studies on the End Product of Example 1
Duplicate samples of the hydrochloride salt of (+)-1-(3,4dichlorophenyl)-3-
azabicyclo[3.1.0] hexane produced in Example 1 and containing a 50% (by
weight)
mixture of polymoiph form A and polymorph form B were placed on informal
stability to
test storage in desiccators placed at ambient temperature and at 50 C in a
programmable
heating bloc. The samples were examined after 1 week and while both samples
contained
mixtures of polymorph form A and polymorph form B, the ratios observed showed
some
conversion of forms. The mixture subjected to ambient temperature was observed
to
contain 40% (by weigh) of polymorph form A and 60% (by weight) of polymorph
form B
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(as determined by XPRD analysis?). This result was confirmed by Raman
spectroscopy.
Subsequent XRPD analysis of the sample stored in a 50 C programmable heating
block
showed about 50% (by weight) of polymorph form A and 50% (by weight) of
polymorph
form C after 17 days of storage.
Example 3
Method of Manufacture of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.01 hexane
hydrochloride
Step 1: Sytithesis of a-bromo-3.4-dichlorophenylacetic acid meth ester
100 kg 3,4-dichlorophenylacetonitrile was added in portions over 1.25 hours to
a
mixture of 12 kg water and 140 kg 98% sulfuric acid. Exotherm was allowed to
65 C
maximum, and the reaction mix was maintained at 60-65 C for 30 minutes. After
cooling
to 50 C, 80 kg methanol was slowly added over 25-30 minutes. The mixture was
warmed
to 92-98 C, and maintained at this temperature for an additional three hours.
After
cooling to 35 C, the reaction mixture was quenched into an agitated mixture
(precooled to
0-5 C) of 150 L ethylene dichloride and 250 L water. The reactor and lines
were washed
with water into the quench mix, which was agitated 5 minutes and allowed to
stratify. The
lower organic phase was separated, and the aqueous phase washed with 2 x 150 L
ethylene
dichloride. The coinbined organic phases were washed with 100 L water and then
with
aqueous sodium carbonate (3 kg sodium carbonate in 100 L water). The solution
of crude
ester was azeotropically "dried" in vacuo at 60-620C, resulting in the
collection of 100 L
ethylene dichloride. A theoretical yield was assumed without isolation and the
solution
was used "as is" in the following bromination reaction.
A mixture of the solution (line-filtered) of crude methyl 3,4-
dichlorophenylacetate
(from above) and 88 kg 1,3-dibromo-1,3-dlmethylhydantoin (DBDMH) was warmed to
80 C, and a solution of 2.5 kg VAZO 52 in 15 L ethylene dichloride was added
portion
wise over a 5 hour period, maintaining 85-90 C (under reflux). An additional
8.8 kg
DBDMH was then added, and a solution of 0.5 kg VAZO 52 in 4 L ethylene
dichloride
was added portion wise over a 2.5 hour period, maintaining 85-90 C (under
reflux).
Heating was then discontinued, and 350 L water was added with agitation. The
mixture
was allowed to stratify, the lower organic phase was separated and the aqueous
phase was
washed with 50 L ethylene dichloride. The combined organic phases were washed
with
aqueous thiosulfate (5.0 kg sodium thiosulfate in 150 L water), aqueous sodium
carbonate
(2.5 kg sodium cai-bonate in 150 L water), and dilute hydrochloric acid (5.4 L
32% HCI in
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WO 2006/023659 PCT/US2005/029420
100 L water). The organic phase was line-filtered and distilled in vacuo to
"dryness" (full
vacuum to 83 C). Residual ethylene dichloride was chased with 20 kg toluene
(full
vacuum at 83 C). The crude a-bromo-3,4-dichlorophenylacetic acid methyl ester
was
taken up in 82 kg toluene, cooled to 40 C, and discharged to steel drums. The
product was
not isolated, and was used "as is" in Step 2. A theoretical yield was assuined
for
calculation purposes.
Step 2: Synthesis of 1-(3,4-dlchlorophenyl-1,2-cyclopropane-dicarboxylic
acid dimeth. l~ester
The crude a-bromo-3,4-dichlorophenylacetic acid methyl ester from Step 1 was
mixed well with 55.6 kg methyl acrylate, and then the mixture was added to a
precooled (-
2 C) mixture of 54.4 kg potassium methoxide in 500 L toluene (argon blanket)
over 5.5
hours with good agitation and maintained at <+10 C. After standing overnight
(5 psig
argon) with brine cooling (-5 C), the cold reaction mixtu're was quenched into
a mix of
250 L water and 30 kg 32% hydrochloric acid with good agitation. 200 L water
and 2.5
kg potassium carbonate were added to the mixture with good agitation for an
additional 30
minutes. After stratification, the lower aqueous phase was separated, and 150
L water and
1.0 kg potassium carbonate were added to the organic phase. The mixture was
agitated 5
minutes and stratified. The lower aqueous phase was separated and discarded,
as well as
the interfacial emulsion, and the organic phase was washed with 100 L water
containing 1
L 32% hydrochloric acid. After stratification and separation of the lower
aqueous phase,
the organic phase was line-filtered and distilled in vacuo to "dryness" (full
vacuum at
65 C). To the hot residue was added 70 kg methanol with agitation. The mix was
cooled
(seeding at +10 C) to -5 C and maintained at this temperature overnight. The
cold thick
suspension was suction-filtered (Nutsche), and the cake of 1-(3,4-
dichlorophenyl)-1,2-
cyclopropane-dicarboxylic acid dimethyl ester was suction dried, washed with 2
x 20 L
hexane, suction dried for 30 minutes and air-dried on paper (racks) for 2 days
at ambient
conditions.
To the nletlianolic liquors was added 50 kg caustic soda flake portion wise
over 8
hours with good agitation. After gassing and the slow exotherm (60 C maximum)
ceased,
the heavy suspension was held at 50 C for 1 hour. 100 L isopropanol was slowly
added
over 10 minutes, and then the mixture was agitated slowly overnight at ambient
conditions. The solids were suction-filtered (Nutsche) and reslurried with 80
L methanol.
The resulting 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid
disodium salt
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was suctioned-filtered (Nutsche), washed with methanol (40 L), suction dried
for 1 hour
and air-dried on paper (racks).
Step 3: Synthesis of 1-(3.4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid
A suspension of 42.0 kg 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic
acid disodium salt (from Step 2) and 120 L deionized water was warmed to 30-35
C, and
the solution was line-filtered and neutralized with 30 kg 32% hydrochloric
acid to
precipitate the free dicarboxylic acid. 120 kg ethyl acetate was added, and
the mix
warmed to 40-50 C to effect solution. The lower aqueous phase was separated
and
washed with 20 kg ethyl acetate. The combined organic extracts were washed
with
saturated sodium chloride (3 kg in 30 L water) and then distilled in vacuo to
"dryness"
(full vacuum to 70 C). 60 kg ethylene dichloride was added to the warm
residue, and the
solution cooled with slow agitation at-5 C overnight. Residual ethyl acetate
was distilled
(full vacuum to 43 C) to yield a thick suspension, which was then cooled with
full vacuum
to -5 C over a 2.5 hour period and then suction-filtered (Nutsche). The 1-(3,4-
dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid cake was washed with cold
ethylene
dichloride (2 x 5 L), followed by ambient ethylene dichloride (4 x 5 L). The
dicarboxylic
acid product was suction dried for 15 minutes and air-dried on paper (racks).
A mixture of 31.0 kg 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid
dimethyl ester (fi-om Step 2), 40 L water, 35 kg methanol and 18.0 kg 50%
caustic soda
was warmed to 70-75 C (under reflux) and maintained at 70-75 C for 1.5 hours.
10 L
water was then adcled, and the mixture was kept at 75-77 C for an additional 2
hours.
Methanol was slowly distilled off in vacuo to 70 C to give a heavy suspension,
which was
then mixed with 80 L water to effect solution. The free dicarboxylic acid was
precipitated
with 31 kg of 32% hydrochloric acid and extracted with 100 kg ethyl acetate.
The lower
aqueous phase was separated and washed with 20 kg ethyl acetate. The combined
organic
phases were washed with 50 L water, and then saturated aqueous sodium
chloride.
Distillation in vacuo to 80 C with full vacuum yielded a concentrate of 1-(3,4-
dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid, which was used "as is" for
the next
step, cyclization to the imide. A quantitative yield from the diester was
assumed for
calculation purposes.
Step 4: Synthesis and Recrystallization of 1 -(3 4-dichlorophenyl)-3-
azabicyclof3 1.01
hexane-2,4-dione
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WO 2006/023659 PCT/US2005/029420
The slurry of 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid (from
Step 3) was added to 45.6 kg warm (68 C) formamide, and residual ethyl acetate
was
distilled with full vacuum at 68-73 C. An additional 14.4 kg formamide was
added to the
mixture, followed by 11.2 kg of the dicarboxylic acid (derived from the
disodium salt,
Step 3). An argon blanket on the mixture was maintained for the following
operation.
The mixture was agitated 15 minutes at 73-75 C to effect a complete solution,
and then
heated over a 1 hour period to 140-145 C and maintained at this temperature
for an
additional 2.25 hours. Heating was discontinued, and the mixture was cooled to
70 C and
L water contaiiling 20 ml 32% HCI was slowly added over 30 minutes. The
mixture
10 was seeded and ci-ystallization commenced. An additional 20 L water was
slowly added to
the heavy suspension over a 2 hour period. After standing overnight at ambient
conditions, the mixture was agitated for 1.25 hours at ambient temperature and
then
suction-filtered (Nutsche). The cake of crude 1-(3,4-dichlorophenyl)-3-
azabicyclo-
[3.1.0]hexane-2,4-dione was washed with water (3 x 20 L), suction dried for 30
minutes
and air-dried on paper (racks) for 2 days under ambient conditions.
A mixture of 37 kg crude, damp 1-(3,4-dichlorophenyl)-3-azabicyclo-
[3.1.0]hexane-2,4-dione (from Step 4, above) and 120 L toluene was warmed to
75-80 C
to effect solution. After stratification and separation of the residual water
(3.3 kg), 1 kg
Darco G-60 activated carbon (American Norit Co.) (suspended in 5 L toluene)
was added.
The mixture was agitated at 80 C for 30 minutes and then pressure filtered
through a
preheated Sparklei- (precoated with filteraid), polishing with a 10 m in-line
filter. The
clear light yellow solution was concentrated in vacuo at 75-80 C to 100 L
final volume
and slowly cooled, with seeding at 70 C. The heavy crystalline suspension was
cooled to
-5 C, held 30 minutes at this temperature and suction-filtered (Nutsche). The
cake of
purified 1-(3,4-diclzlorophenyl)-3-azabicyclo-[3.1.0]hexane-2,4-dione was
washed with 2
x 10 L cold (-10 C) toluene, and then 2 x 20 L hexane. After suction drying
for 30
minutes, the 2,4-dione product was dried in vacuo (< 62 C).
Step 5: Synthesis and Purification of ( )-1-(3.4-Dichloroohenvl)-3-azabicvclo
j3.1.0]hexane hydrochloride
BH3-THF complex is charged into a 2 L addition funnel (9 x 2 L, then 1 x 1.5
L)
and drained into a 50 L flask.
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WO 2006/023659 PCT/US2005/029420
1000 g of ( )-1-(3,4 dichlorophenyl)-3-azabicyclo[3.1.0]-hexane-2,4-dione is
dissolved in 2 L of THF and added to the BH3-THF dropwise over a period of 2
hours.
The reaction mixture is heated to reflux and held at this temperature
overnight. The
mixture is then cooled to <10 C, adjusted to pH 2 with the addition of 1200 mL
of 6N
HCI dropwise at <20 C, and stirred for a minimum of 1 hour.
The reaction mixture is then transferred to a 10 L Buchi flask, concentrated
to a
milky white paste, and transferred again to a 5-gallon container. The mixture
is diluted
with 4 L of cold water and adjusted to pH 10 with 2000 mL of a 25% sodium
hydroxide
solution. A temperature of <20 C is maintained. Following this, 4.5 L of ethyl
acetate is
added and the mixture is stirred for 15 minutes. The solution is then filtered
through a 10
inch funnel with a filter cloth and washed with ethyl acetate (2 x 250 mL).
The filtrate is then transferred into a 40 L separatory funnel and the phases
are
allowed to separate. Each phase is then drained into separate 5-gallon
containers. The
aqueous layer is returned to the 40 L separatory funnel and extracted with
ethyl acetate (2
x 2 L). The organic phases are combined. The aqueous layer is discarded.
250 g of magnesium sulfate and 250 g of charcoal are added to the combined
organics and the mixture is stirred well. The solution is then filtered
through an 18.5 cm
funnel using a filter pad and washed with ethyl acetate (2 x 250 mL). The
filtrate is then
transferred to a 10 L Buchi flask and concentrated to dryness. The resulting
yellowish oil
is diluted with ethyl acetate (2.25 mL/g).
HCI gas is bubbled through a 12 L flask containing 10 L of ethyl acetate to
make
an approximately 2.3 M solution of HCUethyl acetate. This HCUethyl acetate
solution is
added to the oil dropwise at a rate that maintains a temperature of <20 C
using an
ice/water bath. The solution is then stirred at <10 C for a minimum of 2 hours
in the
ice/water bath. The material is chilled in a cold room overnight.
The resulting solids are then filtered through a 10 inch funnel utilizing a
filter cloth
and washed with ethyl acetate (2 x 200 mL) and ethyl ether (3 x 500 mL). The
product,
crude (t)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]-hexane hydrochloride, is
then
transferred to Pyrex drying trays and dried for 4 hours.
1900 g of crude (f)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
hydrochloride from above, and 15.2 L of isopropyl alcohol are charged to a 22
L flask.
The mixture is heated to dissolve all material.
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WO 2006/023659 PCT/US2005/029420
The material is then filtered through a 18.5 cm funnel utilizing a filter pad
and
transferred to a 22 L flask. The solution is then stirred at room temperature
for 1 hour.
The solution is then chilled to 4 C with an ice/water bath and stirred for
3.75 hours. The
product is then placed in a cold room overnight.
The solids are then filtered through a 13 inch filter using a filter cloth and
washed
with ethyl ether (3 x 633 mL). The product is then air dried for 2 hours.
The product, pure (f)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
hydrochloride, is transferred to clean Pyrex drying trays and dried to
constant weight.
Step 6: Resolution of ( )- I -(S3,4-dichlorophenyI)-3-azabicyclor[3.1.0]hexane
hvdrochloride into (+)-1-(3,4-dichlorophenvl -3-azablcyclo[3.1.0]hexane
hvdrochloride
In a 50 gallon reactor containing 60 L of 15% NaOH, 13.6 kg of pure (t)-1-
(3,4dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride (from Step 5,
above) is
added while keeping the temperature constant at approximately 20 C. Once the
addition
of ( )-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride is
complete, the
reaction mixture is allowed to stir at room temperature for a minimum of 8
hours.
40 L of ethyl acetate is added to the reactor and the two phase mixture is
stirred
until a clear solution is obtained (approximately 2 hours). The phases are
allowed to
separate and the organic layer is transferred to another 50 gallon reactor.
The remaining
aqueous layer is extracted with ethyl acetate (6 x 6 L). All organic phases
are combined
into the 50-gallon reactor. The organic phase is dried and decolorized by the
addition of
4000 g magnesium sulfate and 250 g of charcoal. The mixture is then filtered
through an
in-line filter. The filtrate is transferred via in-line filter to a 50-gallon
reactor.
In a separate 50-gallon reactor, 23,230 g of L-(-)-dibenzoyl tartaric acid is
dissolved with stirring (approximately 30 minutes) in 71 L of methanol. The
dissolution is
assisted with heating if necessary.
The L-(-)-dibenzoyl tartaric acid solution in methanol is added via addition
funnel
to the reactor containing the filtrate, over a period of approximately 1 hour,
maintaining
the temperature at 15-25 C. After the addition is complete the mixture is
stirred for
approximately 16 hours at 15-25 C. Following stirring, 50 L of methanol is
added to the
mixture and it is stirred again for 30 additional minutes. The resulting
solids are filtered
onto a plate filter. The solids are then washed with methanol (3 x 5 L) and
pressed dry.
The crude solids are weighed and transferred to a 50-gallon reactor to which
80 L of
methanol is added. The mixture is heated to reflux and stirred at reflux for
approximately
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WO 2006/023659 PCT/US2005/029420
30 minutes. The mixture is then cooled to 15-20 C and stirred at this
temperature for
approximately 2 hours. The resulting solids are filtered onto a plate filter
using a
polypropylene filter cloth. The cake is washed with methanol (3 x 5 L) and
pressed dry.
The solids are transferred to a tarred 5-gallon container and weighed (yield -
20 kg).
The solids are then added (over a period of approximately 1 hour) to a 50
gallon
reactor vessel containing 60 L of 15% NaOH while maintaining the temperature
at
approximately 20 C. Once the addition of the solids is complete 'the reaction
mixture is
stirred for approximately 19 hours.
40 L of ethyl acetate is charged to the reactor, while maintaining the
temperature
at < 35 C and the two phase mixture is stirred until a clear solution is
obtained
(approximately 2 hours). The phases are allowed to separate and the organic
layer is
transferred to another 50 gallon reactor. The remaining aqueous layer is
extracted with
ethyl acetate (6 x 6 L). All organic phases are combined into the 50-gallon
reactor. 5000
g of magnesium sulfate is then added to the organic phase. The mixture is then
filtered
through an in-line filter. The filtrate is transferred via in-line filter to a
50-gallon reactor.
The filtrate is concentrated to a total volume of 20-30 L.
In a 22 L three neck round bottom flask, HCl gas is bubbled through 12 L of
ethyl
acetate to make an approximately 2.3 M solution of HCUethyl acetate. After
titration
assay, the solution is adjusted to exactly 2.3 M by adding either ethyl
acetate or HCI gas.
8.2 L of the 2.3 M solution of HCI/ethyl acetate is added (over a period of
approx.
1.5 hours) to the filtrate (above), maintaining the temperature at < 20 C and
ensuring that
a pH of 2 is obtained. Once the addition is complete, the mixture is stirred
at 0 to -5 C for
a period of 16 hours.
The resulting solids, crude (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane
hydrochloride, are filtered onto a plate filter using a polypropylene filter
cloth. The solids
are then washed with ethyl acetate (2 x 2 L), acetone (2 x 2 L) and ethyl
ether (2 x 2 L)
and dried under vacuum. The material is transferred to a tarred 5-gallon
polyethylene
container and weighed.
Step 6a: Recrystallization of (+)-1-(3.4-dichloroPhenvl)-3-azabicvclor3 1
0lhexane
hydrochloride from isopropanol
The solids (from Step 6, above) are transferred to a 50-gallon reactor and
isopropanol is added (8-10 mL/g of solid). The mixture is heated to reflux.
The solution
is filtered through an in-line filter into another 50 gallon reactor. The
solution is cooled to
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WO 2006/023659 PCT/US2005/029420
0 to -5 C and maintained at this temperature with stirring for approximately 2
hours. The
resulting solids are filtered onto a plate filter using a polypropylene filter
cloth. The solids
are then washed with ethyl acetate (2 x 2 L), acetone (2 x 2 L) and ethyl
ether (2 x 2 L).
The solids are dried under vacuum.
The product, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
hydrochloride,
is transferred into clean, tarred drying tray(s). The tray(s) are placed in a
clean, vacuum
drying oven. The product is dried at 50 C to constant weight. The material is
dried for a
minimum of 12 hours at < 10mm Hg. This product was a mixture of polymorph form
A
and polymorph form B, with each polymorph present in the mixture in an amount
of about
50% by weight. This product was used as the starting material for Examples 4
through 8
below.
Example 4
The 50% by weight mixture of polymorph form A and polymorph form B of the
hydrochloricle salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
(54 mg) was
dissolved in 12 ml of acetonitrile and water. Approximately half of this stock
solution was
then filtered through a 0.2:m nylon syringe filter into a clean vial. The vial
was covered
with aluminum foil punctured with a pinhole and left in a fume hood under
ambient
conditions for slow evaporation. After allowing the solvent in the vial to
evaporate, which
occurred in about four days, a crystal residue was obtained which was the pure
polymorph
form A fonn of the hydrochloride salt of (+)-1-(3, 4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane as demonstrated by Raman spectroscopy and XRPD
analysis as
described above
The same pure crystalline form was also obtained with other solvents prepared
using the same method, such as acetone, 2-butanol, dichloromethane, ethanol,
methanol,
nitromethane, isopropanol and tetrahydrofuran. These solvents also contained
water.
Example 5
68 m,; of the 50% by weight mixture of polymorph form A and polymorph form B
of the hydrocliloride salt of (+)-1- (3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane was
dissolved in 3.4 ml of ethyl ether:ethanol (1:1 ratio) solvent mixture. The
resulted solution
was filtered tlirough a 0.2:m nylon syringe filter into a clean vial. Solid
samples were
collected by rotary evaporation of the solvents under vacuum. The solids were
than dried
under vacuuni at ambient temperature to produce pure polymorph form B crystals
of the
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WO 2006/023659 PCT/US2005/029420
hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as
demonstrated by Raman spectroscopy and XRPD analysis as described above.
Example 6
51 mg of the 50% by weight mixture of polymorph form A and polymorph form B
of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane was
weighed into a vial. The vial was covered with aluminum foil perforated with
pinholes and
placed in an oven at 80 C for 4 days to produce the pure polymorph C crystals
of the
hydrochloride salt of (+)-1-(3, 4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as
demonstrated by Raman spectroscopy and XR.PD analysis as described above.
Example 7
Preparation of Polymorph Form B
40 mg samples of the 50% by weight mixture of polymorph form A and
polymorph foi-m B of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane were mixed with 0.5 mL of anhydrous acetonitrile to
produce a
concentration of about 80-100 mg/mL and the resulting samples were stirred at
various
temperatures between 50 C and 80 C for various periods of time (some for 4
days and 6
days at about 50 C and some for 1 day at about 80 C). The resulting samples
were each
mixtures of a clear liquid and some solid. The clear liquid was decanted off,
and the
remaining solid was vacuum dried at ambient temperature for 1 hour to 2 days
(50 C
sample), or 6 days (80 C sample) to afford pure crystalline polymorph form B.
All
samples produced the pure polymorph form B crystals of the hydrochloride salt
of (+)-1-
(3, 4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as demonstrated by Raman
spectroscopy
and XRPD analysis as described above.
Example 8
Preparation of Polymorph Form A
20 nig samples of the 50% by weight mixture of polymorph form A and
polymorpli form B of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane were dissolved in 0.5 ml of aqueous ethanol. Other
samples were
prepared by dissolving 20 mg of this mixture in 0.5 mL of water. Both
solutions were
filtered through a 0.2 micron nylon filter. Both filtered solutions were then
allowed to
evaporate uncier ambient conditions, some samples partially covered and other
samples
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WO 2006/023659 PCT/US2005/029420
completely uncovered. After 6 days, both the uncovered and partially covered
ethanol
solution samples evaporated. After 7 days, the uncovered water solutions
evaporated.
After 15 days, the partially covered water solutions evaporated. For each
sample, after
the solvent (either aqueous ethanol or water) evaporated completely, 20 mg of
dry solid
residue was left. The solid in all samples thus produced was the pure
polymorph form A
crystals of the hydrochloride salt of (+)-1-(3,4-dichlorophenyl)-3-
azabicyclo[3.1.0]hexane
as demonstrated by Raman spectroscopy and XRPD analysis as described above.
