Note: Descriptions are shown in the official language in which they were submitted.
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WO 99/40084 PCT/GB99/00380
SALTS OF PAROXETBVE
The present invention relates to novel compounds, to processes for preparing
them
and to their use in treating medical disorders.
Pharmaceutical products with antidepressant and anti-Parkinson properties are
described in US-A-3912743 and US-A-4007196. An especially important compound
among those disclosed is paroxetine, the (-)traps isomer of 4-{4'-
fluorophenyl)-3-(3 ;4'-
methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as
the
hydrochloride salt for the treatment and prophylaxis of inter alia depression,
obsessive
compulsive disorder (OCD) and panic.
We have now surprisingly discovered novel salts of paroxetine which may be
used
as an alternative to the currently marketed hydrochloride, or as an
intermediate in the
preparation of the hydrochloride.
According to the present invention there is provided a novel salt of
paroxetine with
an acid selected from the group consisting of sulphuric, tartaric, oxalic,
fumaric, propionic,
formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-
methylbenzenesulphonic,
hypophosphorous, lactic, and mandelin acids and glycine.
Tartaric, glutamic, lactic and mandelic acids exist in enantiomeric forms and
this
invention includes salts with both the D and L-acids and racemic mixtures
thereof, as well
as with the symmetric meso-tartaric acid.
Sulphuric, tartaric, oxalic, fumaric, glutamic, and succinic acids are dibasic
and the
invention therefore includes both salts in which the ratio of paroxetine to
acid (by mole) is
1:1 and salts in which the ratio of paroxetine to acid (by mole) is 2:1, as
well as mixed salts
with, for example, an alkali metal or ammonium cation.
Citric and phosphoric acids are tribasic and the invention therefore includes
salts in
which the ratio of paroxetine to acid (by mole) is 1:1, 2:1, and 3:1
respectively, as well as
mixed salts with, for example, an alkali metal or ammonium cation.
In one aspect the novel salts of this invention are provided in non-
crystalline form,
which may take the form of a solid or an oil. The oil is preferably absorbed
on a solid
carrier, especially a carrier that is usable as a component of a
pharmaceutical composition.
In another aspect the novel salts of this invention are provided in
crystalline form.
When the crystalline form exists as more than one polymorph, each polymorph
forms
another aspect of this invention.
-1-
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Paroxetine salts may be prepared by contacting stoichiometric amounts of the
acid
(enantiomer or racemic mixture) and paroxetine free base. Preferably the base
and/or the
acid is in solution, more preferably both~are in solution. Mixed salts can be
prepared by
forming the precursor 1:1 or hydrogen salt (of paroxetine with the acid, or
the metal or
ammonium ion with the acid) in situ or using it preformed in solution.
Most commonly used solvents are suitable for mobilising paroxetine free base,
for
example toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such
as ethyl
acetate, ketones such as acetone and butanone, halogenated hydrocarbons such
as
dichloromethane, and ethers such as tetrahydrofuran and diethyl ether. The
concentration
of paroxetine base is preferably in the range 5 to 50% weight/volume, more
preferably in
the range 10 to 30%.
Suitable solvents for the acids used in accordance with the present invention
include water, lower alcohols such as methanol, ethanol and isopropanol,
ethers such as
diethyl ether and tetrahydrofuran, hydrocarbons such as toluene and benzene,
esters such as
ethyl acetate, ketones such as acetone, butanone and isobutyl methyl ketone,
and
halogenated hydrocarbons such as chloroform. The concentration of the acid
(other than
glutamic acid) is preferably in the range 0.1 to 6.0 molar, for example 0.5 to
4.0 molar, in
particular 1.0 to 3.0 molar. Elevated temperatures may be used to enhance
solubility. The
concentration of glutamic acid is preferably in the range 0.01 to 1.0 molar,
in particular 0.1
to 0.5 molar. The acids may also be used in the form of a soluble salt such as
the
ammonium salt or a salt of an amine, for example ethylamine or diethylamine.
The paroxetine salts may be isolated in solid form by conventional means from
a
solution thereof obtained as above. For example, the non-crystalline salts may
be prepared
by precipitation, spray drying, and freeze drying of solutions, or vacuum
drying of oils, or
solidification of melts obtained from reaction of the free base and the acid.
The crystalline salts may be prepared by directly crystallising from a solvent
in
which the product has limited solubility, or by triturating or otherwise
crystallising a non-
crystalline salt. An improved yield of the salt is obtained by evaporation of
some or all of
the solvent or by crystallisation at elevated temperature followed by
controlled cooling,
preferably in stages. Careful control of precipitation temperature and seeding
may be used
to improve the reproducibity of the production process and the particle size
distribution and
form of the product.
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An alternative method of preparing paroxetine salts is to start with a salt of
paroxetine with an organic acid, such as acetic acid or malefic acid. Use of
another salt of
paroxetine as a starting material is suitable for preparation of the
crystalline salt or, if a
volatile acid such as acetic acid is used, non-crystalline salts by methods
that involve
evaporation (such as freeze-drying and spray-drying).
Prior to the isolation of the paroxetine salt, water may be removed by
azeotropic
distillation to avoid the formation of hydrates or to obtain the product in
anhydrous form.
In that case, suitable solvents for the solution of the salt are those which
form an azeotrope
with water, such as toluene, pyridine, isopropanol, isobutyl methyl ketone and
xylene. It
should also be appreciated that mixtures of solvents can also be used to aid
the azeotropic
removal of water.
More generally, crystallization may be carried out from any solvent which
allows
formation of the desired crystal structure, using seeds of the desired
structure where
necessary or desirable. When polymorphs exist, individual polymorphs are
preferably
crystallized directly from a solution of the salt, although recrystallizing a
solution of one
polymorph using seeds of another polymorph may also be cairied out.
Suitable solvent systems for crystallising/recrystallising salts of the
present
invention are set out below:
Sulphate: water, butan-1-ol, butan-2-ol.
Tartrates: ethanol, methanol, isopropanol, toluene.
Oxalates: ethanol, methanol, acetone, tetrahydrofuran.
Fumarates: methanol, butanol, tetrahydrofuran.
Propionate: hexane, cyclohexane, chloroform.
Formate: diethyl ether, water, alcohols, toluene, ethyl acetate.
Glutamates: water, methanol, toluene/hexane.
Succinates: toluene, acetone, or lower alcohols followed by precipitation with
ethyl
acetate, ether, or hexane. Paroxetine succinate may be recrystallised by
cooling and
optionally seeding hot solutions in suitable solvents such as butan-1-of or
acetonitrile.
Benzoate: As used for salt formation.
Citrate: As used for salt formation.
Nitrate: toluene, toluenelcyclohexane, isopropanol.
Phosphate: toluene, ehtanol, tetrahydrofuran, isopropanol.
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4-Methylbenzenesulphonate: toluene or lower alcohols followed by precipitation
with
ether or hexane.
Hypophosphite: toluene or lower alcohols followed by precipitation with ether
or
hexane.
Lactate: As used for salt formation.
Mandeiate: isopropanol, toluene.
Glycinate: As used for salt formation.
The salt may obtained as a solvate or hydrate, when during isolation from
solution
it becomes associated with the solvent in which it is dissolved. Any such
solvate or
hydrate forms a further aspect of this invention. Solvates may be returned to
the
unsolvated salt by heating, for example by oven-drying, or by treatment with a
displacement solvent which does not form a solvate.
Paroxetine free base may be prepared according to the procedures generally
outlined in US Patent No 4,007,196 and EP-B-0223403. The acids are
commercially
available.
The compounds of this invention may be used to treat and prevent the following
disorders:
Alcoholism Anxiety
Depression Obsessive Compulsive Disorder
Panic Disorder Chronic Pain
Obesity Senile Dementia
Migraine Bulimia
Anorexia Social Phobia
Pre-Menstrual Syndrome (PMS) Adolescent Depression
Trichotillomania Dysthymia
Substance Abuse
These disorders are herein after referred to as "the Disorders".
The present invention further provides a method for treating and/or preventing
any
one or more of the Disorders by administering an effective and/or prophylactic
amount of a
salt of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in
the
treatment and/or prevention of the Disorders which comprises an admixture of a
salt of the
invention with a pharmaceutically acceptable carrier.
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The present invention also provides the use of a salt of the invention for
treating
andlor preventing the Disorders.
The present invention also provides the use of a salt of the invention in the
manufacture of a medicament for treating and/or preventing the Disorders.
Most suitably the present invention is applied to the treatment of depression,
OCD
and panic.
The compositions of this invention are usually adapted for oral
administration, but
formulations for dissolution for parental administration are also within the
scope of this
invention.
The composition is usually presented. as a unit dose composition containing
from 1
to 200 mg of active ingredient calculated on a free base basis, more usually
from 5 to
100mg, for example 10 to SOmg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a
human
patient. Most preferably unit doses contain 20mg of active ingredient
calculated on a free
base basis. Such a composition is normally taken from 1 to 6 times daily, for
example 2, 3
or 4 times daily so that the total amount of active agent administered is
within the range 5
to 400mg of active ingredient calculated on a free base basis. Most preferably
the unit dose
is taken once a day.
Preferred unit dosage forms include tablets or capsules.
The compositions of this invention may be formulated by conventional methods
of
admixture such as blending, filling and compressing.
Suitable Garners for use in this invention include a diluent, a binder, a
disintegrant,
a colouring agent, a flavouring agent and/or preservative. These agents may be
utilized in
conventional manner, for example in a manner similar to that already used for
marketed
anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B-
0223403, and US 4,007,196 in which the products of the present invention may
be used as
the active ingredients.
The following Examples illustrate the present invention:
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Example 1: preparation of tablets
INGREDIENTS 20 mg Tablet 30mg Tablet
Paroxetine salt 20.00 mg 30.0 mg
(calc. as free base)(calc. as free base)
Dicalcium Phosphate (DCP)83.34 mg 125.0 mg
Microcrystalline Cellulose50.67 mg 76.0 mg
Sodium Starch Glycollate8.34 mg . . 12.5 mg
Magnesium Stearate 1.67 mg 2.5 mg
!"~~.~.~....._-.-I-t
_ r .,
.....aaaaaavavacaa ovuW .G Vl L11G lllb'1Gt11G1115
Dicalcium Phosphate Dihydrate - Emcompress or Ditab*
Microcrystalline Cellulose - Avicel PH 102*
Sodium Starch Glycollate - Explotab.*
* Trade names
Method
1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine salt to the bowl.
3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes.
4. Add magnesium stearate and mix for 5 minutes.
Tablet into Pentagonal Tablets using the following punches:
30 mg Tablet 9.5 mm Circumcircle
mg Tablet 8.25 mm Circumcircle
15 The tablets are made satisfactorily on a single punch or a Rotary press.
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Example 2 : preparation of tablets
INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet
Paroxetine salt 10 mg 20 mg 30 mg
(calc.as free (calc.as free(calc.as free
base) base) base)
Sodium Starch Glycollate2.98 mg 5.95 mg 8.93 mg
Granular Dicalcium
Phosphate 158.88 mg 317.75 mg 476.63 mg
(DITAB) or Dicafos
Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg
w d..aL _ ~
1. Paroxetine salt, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate
are
screened and mixed together in a suitable mixer.
(Planetary, Cuble or High Energy Shear mixer.)
2. Add Magnesium Stearate and compress it into a tablet using a single punch
or
Rotary Tablet machine.
Example 3 : Paroxetine sulphate 1:1 salt.
Aqueous sulphuric acid ( 1.5 ml , 2 molar) was added to a solution of
paroxetine free base
( 1.0 g) in propan-2-of ( 10 ml) and the mixture stirred at ambient
temperature for three
hours. The solvent was removed by evaporation and the residue was stirred in a
mixture of
hexane (10 ml) and butan-1-of (10 ml) until the product crystallised. Finally,
the crystals
were filtered, washed with hexane and dried in vacuo.
m.pt 128-130oC
IR nujol mull:
Bands at 1632, 1500, 1324, 1114, 1065, 1005, 925, 884, 844, 761, 672, 614, 578
cm-1.
X-ray powder diffractogram (Cu K2~:
Angle [028] Rel. Int
9.3 10.1
14.3 26.4
14.8 13.5
_7_
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WO 99/40084 PCT/GB99/00380
15.3 19.0
16.9 33.3
17.7 22.6
18.7 44.4
19.2 100.0
20.3 65.4
20.9 27.3
21.5 11.5
22.3 15.6
23.415 10.8
23.720 16.9
24.325 25.9
24.475 26.8
25.640 62.5
26.950 40.2
28.340 36.5
30.335 20.4
Example 4 : Paroxetine sulphate 2:1 salt.
Aqueous sulphuric acid ( 1.5 ml , 2 molar) was added to a solution of
paroxetine free base
(2.1 g) in toluene (20 ml) with vigorous stirring. Almost immediately a solid
began to
separate out. The mixture was diluted with hexane {40 ml) and butanol (20 ml)
and stirred
rapidly, as a result the form of the crystalline solid improved. After
stirring for i hour the
crystals were filtered, washed with hexane and dried in vacuo.
m.pt 247-250oC
IR nujol mull:
Bands at 1627, 1511, 1230, 1161, 1040, 958, 825, 779, 613, 593 cm-1.
X-ray powder diffractogram (Cu K2a):
Angle [~28] Rel. Int [ %
]
5.300 25.3
13.215 9.6
15.185 27.3
_g_
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WO 99/40084 PCT/GB99100380
17.595 46.7
18.290 1 ~.0
18.980 35.0
19.465 ~,3
20.755 39.2
21.420 53.0
21.635 64.3
22.305 21.8
24.875 54.7
26.075 28.2
26.615 59. I
30.355 26.5
31.710 16.3
Example 5 - Paroxetine sulphate 2:1 salt
Paroxetine base (54.9 g) was dissolved in a mixture of propan-2-of (500 ml)
and water (20
ml). To the stirred, clear solution was added slowly a mixture of sulphuric
acid (8.3 g,
98%), water (20 ml), and propan-2-of (200 ml); during the course of the
addition seeds of
paroxetine sulphate (2:1 ) were added to induce crystallisation. After
stirring for 2 hours,
the mixture was stored overnight at 4°C, then filtered, washed with
propan-2-of (1()D ml)
and dried in an air oven.
Yield 54.8 g.
Example 6 - Preparation of non-crystalline paroxetine sulphate (2: i )
Concentrated sulphuric acid ( I.6 g) was diluted to 10 ml with water, and the
solution added
slowly to a stirred mixture of paroxetine base ( 11.0 g) and water (20 ml).
The clear
solution was evaporated at reduced pressure to form a white, crisp glassy
solid.
Example 7 - Preparation of paroxetine sulphate (2:1)
Concentrated sulphuric acid ( 16 g) was diluted to 100 ml with water, and the
solution
added slowly to a stirred mixture of paroxetine base ( 109.8 g) and water (200
ml). The
clear solution was cooled overnight, then stirred and seeded until
crystallisation was
complete. The product was collected by filtration, washed with propan-2-ol,
and dried
under vacuum.
Yield 96.7 g.
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Example 8 - crystallisation of non-crystalline paroxetine sulphate (2:1 )
The non-crystalline paroxetine sulphate prepared in Example 6 was suspended in
propan-2-
ol (200 ml), stirred vigorously, and gradually heated to reflux. After 2 hours
the paroxetine
sulphate could be seen to have changed form, so the mixture was cooled,
filtered, washed
with cold propan-2-ol, and dried under vacuum to give crystalline paroxetine
sulphate
(2:1 ).
Yield 8.5 g.
Example 9 : Paroxetine L(+) tartrate 1:1 salt.
L(+)-tartaric acid ( 1.25 g) was dissolved in propan-2-of ( 10 ml) with
heating, and mixed
with a stirred solution of paroxetine base (2 g) in toluene {20 ml). A
crystalline
suspension formed which was stirred for a further 1 hour at room temperature.
Finally, the
product was filtered, washed with acetone and dried under reduced pressure.
Yield 2.65 g.
Example 10 : Paroxetine L(+) tartrate 1:1 salt.
A solution of L(+)-tartaric acid ( 1.0 g) in methanol ( 10 ml) was mixed with
a solution of
paroxetine base ( 1.75 g) in methanol ( 1 Sml) and the mixture stirred at
ambient
temperature. Crystals separated within a few minutes and the suspension was
stirred for a
further 1 hour at ambient temperature: Finally the crystals were filtered,
washed with
acetone and dried under reduced pressure. Yield 2.01 g.
Example 11 : Larger scale preparation of paroxetine L(+) tartrate 1:1 salt.
L(+) tartaric acid (25 g) was dissolved in propan-2-of (200 ml) with heating
and mixed
with a solution of paroxetine base {42 g) in toluene (400 ml). A crystalline
precipitate
formed, which was stirred for 1 hour at ambient temperature then at OoC for a
further 1
hour. Finally the crystals were filtered, washed with acetone and dried under
reduced
pressure. Yield 59.88g.
m.pt 176-178oC.
IR nujol mull:
Bands at 1718, 1602, 1504, 1490, 1465, 1242, 1190, 1106, 833, 780, 650 cm-!
X-ray powder diffractogram (CuK2~
Angle [029] Rel. Int [
% ]
6.1 12.8
14.2 44.7
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PCT/GB99/00380
16.2 2
17.3 42.6
17.9 100.0
20.1 24.0
20.4 30.6
21.9 34.5
22.3 48.6
22.6 48.6
23.0 33.0
24.0 42.2
25.1 36.9
25.7 52.5
26.1 59.5
27.3 27.8
28.6 21.3
34.3 24.2
Example 12 : Paroxetine D(-) tartrate 1:1 salt.
D(-)-tartaric acid (1.25 g) was dissolved in propan-2-of (10 ml) with heating,
and mixed
with a stirred solution of paroxetine base (2.1 g) in toluene (20 ml). A
crystalline
suspension soon formed which was stirred~for another hour at room temperature.
The
product was then filtered, washed with acetone and dried under reduced
pressure. Yield
2.70 g.
Example 13 : Larger scale preparation of paroxetine D(-)-tartrate 1:1 salt.
D(-) tartaric acid (25 g) was dissolved in propan-2-of (200 ml) by heating and
added
rapidly to a solution of paroxetine base (42 g) in toluene (400 ml). A
crystalline
precipitate soon formed, and was stirred for 1 hour at ambient temperature
then at OoC for
a further 1 hour. The crystals were then filtered, washed with toluene and
dried under
reduced pressure. Yield 57.59g.
m. pt 174-176oC.
IR nujol mull:
Bands at 3489, 3354, 1726, 1616, 1462, 1184, 1097, 936, 831, 794, 694 cm-l.
X-ray powder diffractogram major peaks (CuK2~:
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WO 99/40084 PGT/GB99/00380
Angle [029) Rel. Int [ %'o
)
4.4 100.0
16.5 11.6
16.8 27.7
17.3 70.9
17.6 52.9
20.5 15.1
24.3 13.3
25.2 10.6
25.9 10.4
26.3 18.5
26.4 15.4
28.5 12.7
28.8 15.9
Example 14 : Preparation of non-crystalline.2:1 salt with L(+)-tartaric acid.
L(+) tartaric acid ( 1.0 g) was heated in propan-2-of ( 10 ml) to form a
solution, and mixed
with a solution of paroxetine base (5.0 g) in toluene (20 ml). The resulting
solution was
stirred at ambient temperature and then hexane (50 ml) vvas added.and a white
solid
precipitated. The suspension was stirred for a further 1 hour then the solid
was filtered,
washed with hexane and dried under reduced pressure. This solid was shown by X-
ray
diffraction to be non-crystalline.
Yield 4.32g.
Example 15 : Preparation of crystalline 2:1 salt with D(-)-tartaric acid.
D(-) tartaric acid ( 1 g) was heated in propan-2-of to form a solution. This
solution was
mixed with a stirred solution of paroxetine base (5.0 g) in toluene (20 ml).
Crystallization
commenced within two minutes, and the suspension was stirred at ambient
temperature for
a further 1 hour. Finally the product was filtered, washed with toluene and
dried under
reduced pressure. Yield 5.69 g.
Example 16 : Larger scale preparation of crystalline 2:1 salt with D(-)-
tartaric acid.
D(-) tartaric acid ( 10 g) was dissolved in propan-2-of ( 100 ml) by heating
and then mixed
with a stirred solution of paroxetine base (50.4 g) in toluene (200 ml).
Within 5 minutes
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crystals had precipitated, and the suspension was stirred at ambient
temperature for an hour
then a further hour in an ice/water bath. Finally, the crystals were filtered,
washed with
toluene and dried under reduced pressure. Yield 57.12g.
m.pt 190-192oC.
IR nujol mull:
Bands at 3436, 1650, 1556, 1491, 1221, 1120, 1035, 931, 832, 783, 631, 538 cm-
I
X-ray powder diffractogram major peaks (CuK2~:
Angle [029] Rel. Int [ % ]
' 3.6 35.1
5.5 33.8
15.6 20.6
16.5 24.4
16.9 53.0
17.1 51.5
17.6 67.7
18.0 57.6
18.7 100.0
19.2 65.2
19.5 74.4
20.1 55.5
21.1 76.1
21.6 38,g
22.9 70.5
23.2 59.7
23.5 53.3
24.3 40.1
27.2 35.3
27.8 27.6
28.7 38.0
28.9 33.6
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31.8 27.6
Example 17 : Preparation of crystalline 2:1 salt with L(+)-tartaric acid.
L(+)-potassium hydrogen tartrate ( 1.0 g) was heated in a mixtwe of ethanol (
120 ml) and
water (40 ml) to form a solution. Paroxetine base (4.2 g) in toluene ( 10 ml)
was added and
the mixture stirred at ambient temperature for several hours but remained
clear. The
solvent was therefore removed by evaporation and the residue redissolved in
toluene. The
evaporation procedure was repeated and the residue stirred with fresh toluene
for 30
minutes to form a crystalline product, which was filtered, washed in toluene
and dried
under reduced pressure. Yield 2.18 g.
IR nujol mull:
Bands at 1572, 1463, 1226, 1187, 1098, 1035, 943, 835, 781, 721, 598, 542 cm-1
X-ray powder diffractogram major peaks:
Angle [028] Rel. Int [%]
6.0 41.9
13.0 29.7
15.6 7$,g
15.9 40.5 '
16.7 49.9
17.8 69.3
18.0 61.3
19.1 37.6
20.7 63.4
21.2 57.5
21.9 53.2
22.4 80.1
23.1 39.0
24.7 55.5
24.9 59.2
25.5 49.4
26.0 32.7
26.6 57.2
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27.6 38.1
28.0 30.9
28.9 25.3
33.1 23.6
Example 18 : Preparation of paroxetine 1:1 meso-tartrate
A solution of meso-tartaric acid (2.14 g) in water ( 19 ml) was prepared by
heating to
reflux temperature. Propan-2-of {20 m1) and paroxetine base (4.2 g) in toluene
(20 ml)
were added and the mixture stirred, then the solvents were removed by
distillation at
S reduced pressure. Toluene (20 ml) was added and the distillation repeated to
yield the 1:1
meso-tartrate as a non-crystalline solid. Trituration with heptane caused the
solid to
crystallise, and the white powdery product was filtered, washed with heptane
and dried
under reduced pressure.
Yield 3.52 g
Melting point I68-1710C
IR nujol mull:
Bands at 1725,1622,1463,1378,1267,1104, 944, 824, 779, 677 cm-1.
X-ray powder diffractogram (Cu K2a):
Angle [028]Rel. Int
(%]
4.7 71.2
9.4 20.6
11.1 2.1
12.8 2.6
14.6 25.9
15.2 16.9
15.7 15.1
16.6 44,5
17.4 70.0
17.9 44.0
16.7 55.8
19.1 100.0
19.7 49.4
20.7 34.7
-IS-
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WO 99/40084 PCT/GB99/00380
21.0 47.3
21.6 3.1
22.4 37.6
23.0 45.3
23.4 56.1
23.7 52.5
24.8 45.3
25.3 50.7
25.8 36.7
26.1 16.3
- 27.0 5.1
27.5 14.5
28.1 30.1
29.4 7.2
29.9 29.5
30.2 21.1
31.0 7.9
31.5 15.2
31.9 13.8
32.4 13.1
33.2 4.0
33.6 10.9
Example 19 : Preparation of paroxetine oxalate ( 1:1 )
Oxalic acid (1.15 g) was dissolved in methanol (50 ml) with heating. A
solution of
paroxetine base in toluene (4.2 g in 20 ml) was added and the reaction mixture
stirred at
room temperature. The solvents were removed in vacuo to afford a white glassy
solid of
non-crystalline paroxetine oxalate. Trituration with heptane caused the
produce to
crystallise to a white powdery solid, which was filtered, washed with heptane
and dried at
reduced pressure.
Yield 2.93g
Melting point 122-134oC
IR nujol mull:
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Bands at 1732,1634,1505,1376,1038, 930, 835, 720, 538 cm-1.
X-ray powder diffractogram (Cu K2a):
Angle [026]Rel. Int
(%]
8.1 3.1
10.6 2.7
12.9 9.2
13.8 18.8
15.7 30.1
16.3 34.4
19.1 100.0
19.7 77.1
20.1 63.1
21.4 65.2
22.6 54.9
23.1 44.1
24.8 38.4
26.1 44.3
26.7 47.0
27.3 38.9
28.9 31.3
30.5 24.8
32.1 27.3
33.0 27.7
34.6 54.6
Example 20 : Preparation of paroxetine oxalate (2: I )
Oxalic acid ( 1.15 g) was added to methanol (40 ml) and the mixture heated to
achieve total
dissolution of the acid. Paroxetine base in toluene (8.4 g in 40 ml) was added
and the
solution stirred at room temperature. White crystals separated rapidly. The
product was
filtered, washed with heptane and dried at reduced pressure.
Yield 7.34 g.
Melting point 207-21 l0C
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IR nujol mull:
Bands at 1585,1509, 1377,1286,1081, 926, 831, 761, 604, 574 cm-1
X-ray powder diffractogram (Cu K2a):
Angle [028]Rel. Int
[%]
5.4 3.9
6.3 2.8
8.4 7.3
11.1 8.1
12.6 11.3
13.4 7.1
14.2 27.8
14.9 23.3
16.0 54.4
16.4 59.6
16.7 86.3
17.2 38.8
18.4 81.8
18.6 77.4
19.4 51.2
19.9 53.0
20.5 63.1
21.6 100.0
22.2 40.6
22.7 40.3
23.1 37.5
23.4 29.3
25.4 95.6
26.9 55.2
27.8 41.2
30.1 34.6
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31.8 2?.3
32.6 25.5
34.0 23.1
Example 21: Preparation of 1:1 salt.
Fumaric acid (0.3 g) was heated in a mixture of toluene (5 ml) and propan-2-of
(5 ml) to
form a solution. This solution was mixed with a solution of paroxetine free
base ( 1 g) in
toluene (10 ml) while stirring. Crystals separated within 2 minutes and the
suspension was
stirred at ambient temperature for a further 1 hour. Finally the product was
filtered, washed
in toluene and dried at reduced pressure.
Molar ratio of paroxetine to fumaric acid = 1:1.
Example 22: Larger scale preparation of 1:1 salt.
Fumaric acid {30 g) was heated in propan-2-of until the solid dissolved and
the warm
solution was mixed with a solution of paroxetine free base (84 g) in toluene
(500 ml) with
stirring. Crystals separated rapidly and the suspension was stirred for 1 hour
at ambient
temperature then 1 hour at OoC (ice/water bath). Finally the crystals were
filtered. washed
in toluene and dried at reduced pressure.
Yield 102.31g.
Molar ratio of paroxetine to fumaric acid = 1:1.
Paroxetine Fumarate 1:1 salt characterising data:
m. pt 180-182oC.
IR nujol mull:
Bands at 1706, 1659, 1504, 1487, 1466, 1295, 1184, 1032, 833, 792, 636cm-I
X-ray diffractogram major peaks (CuK2a):
Angle [029] Rel. Int [ % ]
4.8 1 I .8
14.4 58.0
16.4 53.7
16.9 ~ 16.7 __
17.9 100.0
19.0 20.1 _
19.2 24.9
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20.0 55.8
20.2 25.2
21.6 27.1
24.0 62.6
24.3 60.4
26.6 46.5
28.3 58.2
29.0 40.5
32.9 19.4
Example 23: Preparation of 2:1 salt.
Fumaric acid (0.3 g) was heated in propan-2-of ( 10 ml) until the solid
dissolved and this
solution was mixed with paroxetine free base (2.1 g) in toluene (20 ml). The
mixture was
stirred for 1 hour at room temperature and a gel began to separate. Diethyl
ether (20 ml)
was added and the product crystallised. The suspension was stirred for a
further 1 hour.
Finally the crystals were filtered, washed in diethyl ether and dried at
reduced pressure.
Yield 1.79g.
Molar ratio of paroxetine to fumaric acid = 2:1.
Example 24: Larger scale preparation of 2:1 salt.
Fumaric acid (9 g) was heated in propan-2-of (200 ml) until the solid
dissolved, and the
warm solution was added to a solution of paroxetine free base (63 g) in
toluene (600 ml).
The mixture was stirred at ambient temperature and the product crystallised.
After 1 hour it
was necessary to add more toluene to enable the crystals to be collected by
filtration. The
prouct waswashed in toluene and dried at reduced pressure.
Yield 58.86g.
Molar ratio of paroxetine to fumaric acid = 2:1.
Example 25: Preparation of non-crystalline salt.
Paroxetine fumarate (2 g) (prepared as Example 22) was heated in methanol (50
ml) to
form a solution. The solvent was removed by evaporation at a water bath
temperature of
between 70 and 80oC. The product was a glassy solid which was shown by X-ray
diffraction to be non-crystalline.
Paroxetine Fumarate 2:1 salt characterising data:
m. pt 164-165oC.
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IR nujol mull:
Bands at 1644,1508, 1464, 1246, 1205, 1138, 1044, 934, 836, 835, 722, 674 cm-1
X-ray diffractogram major peaks (CuK2a):
Angle [a29] Rel. Int [ % ]
11.4 3.8
12.4 9.4
12.9 3.9
15.3 5.4
15.8 6.9
16.5 11.8
18.2 25.8
19.4 100.0
19.8 41.9
21.7 32.6
22.6 31.4
23.0 39.2
27.8 38.2
28.4 14.3
33.4 12.1
Example 26.
Propionic acid (0.5 ml) was added to a solution of paroxetine free base (2 g)
in toluene (20
ml). No crystals separated until the solution was diluted with hexane (40 ml)
when an oiI
formed which crystallised within 1 hour. The suspension was stirred for a
further 1 hour at
ambient temperature. Finally the crystals were filtered, washed with hexane
and dried at
reduced pressure.
Yield 0.60g.
Example 27.
Propionic acid ( 15 ml) was added to a solution of paroxetine free base (63 g)
in toluene
( 150 ml). The mixture was diluted with hexane ( 1500 ml) and an oil formed
which began
to crystallise within a few minutes. The suspension was stirred for 1 hour at
ambient
temperature then 1 hour at OoC (icelwater bath). The product was filtered,
washed with
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hexane and dried at reduced pressure. Since some of the oil had not
crystallised, more
hexane was added and the mixture was stirred overnight at ambient temperature.
Finally
the product was filtered, washed with hexane and dried at reduced pressure.
Yield 60.Og.
Paroxetine Propionate characterising data:
m. pt 89-9loC.
IR nujol mull:
Bands at 1634, 1604, 1464, 1289, 1249, 1223, 1193, 1036, 979, 870, 808, 721,
671 cm-1.
X-ray diffractogram major peaks (CuK2~:
Angle [028) Rel. Int. [ %
)
5.7 37.8
8.1 29.2
i 6.2 40.6
16.6 69.8
17.1 100.0
18.9 83.0
19.2 24.1
19.7 23.6
21.7 98.5
22.2 20.7
22.5 42.3
22.6 38.4
22.9 21.6
23.3 45.3
23.7 70.0
25.2 54.2
27.3 20.6
27.8 46.2
28.1 44.4
29.5 29.0
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32.0 21.1
Example 28: Preparation of crystalline paroxetine formate
A solution of paroxetine base in toluene (2 ml, 2.55 mmol) was added to a
solution of
formic acid (U.12g, 2.50 mmol) in toluene ( 10 ml). The solvent was removed at
reduced
pressure to yield a white solid. Trituration with diethyl ether (c. 10 ml) and
filtration
S under nitrogen gave a white solid which was washed with diethyl ether (2 x
10 ml) and
dried.
Yield 0.84g.
Example 29: Larger scale preparation of crystalline salt.
A solution of paroxetine base in toluene ( 120 ml, 153.0 mmol) was added to a
solution of
formic acid (7.2g, 156.0 mmol) in toluene (300 ml). The solvent was removed at
reduced
pressure to yield a white solid. Trituration with diethyl ether (c. 400 ml)
and filtration gave
a white solid which was washed with diethyl ether (2 x 100 ml) and dried at
reduced
pressure. Yield 56.1Og.
1H NMR (CDCIg) showed a ratio between fornuc acid and paroxetine of 1:1.
m.p. 100 - 103°C.
IR nujol mull:
Bands at 1638, 1574, 1508, 1490, 1462, 1377, 1342, 1279, 1246, 1204, 1136,
1090, 1044,
934, 913, 836, 826, 804, 786, 762, 722, 674, 603, 577, 542 cm-1
X-ray diffractogram major peaks (CuK2a):
Angle [28] Rel. Int [
12.6 16.3
16.3 11.4
16.8 29.8
16.9 29.8
18.6 10.1
19.5 100.0
20.2 20.9
20.4 16.9
21.0 13.5
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21.5 ~ 11.8
22.1 32.8
22.7 30.4
23.1 42.3
25.8 13.6
27.8 41.6 _.
28.7 11.3
29.0 14.2
29.7 10.6
32.6 11.4 _
34.0 12.1
Example 30 : Preparation of non-crystalline paroxetine L-glutamate
A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a
suspension of L-
glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 ml). The mixture was
heated at
reflux for 1 hour, allowed to cool, filtered and the solvent was removed at
reduced
pressure. The residual oil was diluted with toluene ( 15 ml) and the solvent
removed at
reduced pressure. Trituration with diethyl ether (c. 20 ml) and filtration
under nitrogen
gave a white powder which was washed with diethyl ether (2 x 10 ml) and dried
(yield
2.64 g, 87%).
1H NMR (DMSO) shows a ratio between L-glutamic acid and paroxetine of 1:1.
IR nujol mull:
Bands at 1465, 1377, 1223, 1186, 1037, 931, 831, 721, 541.
Example 31 : Preparation of non-crystalline paroxetine D-glutamate
A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a
suspension of
D-glutamic acid (0.94 g, 6.38 mmol) in hot methanol (45 ml). The mixture was
heated at
reflux for 1 hour, allowed to cool, filtered and the solvent removed at
reduced pressure.
The residual oil was diluted with toluene (30 ml) and the solvent removed at
reduced
pressure. Trituration with diethyl ether (c. 20 ml) and filtration under
nitrogen gave a pale
brown solid which was washed with diethyl ether (2 x 10 ml) and vacuum dried.
Yield
2.b5g.
1H NMR (DMSO) shows a ratio between D-glutamic acid and paroxetine of 1:1.
IR nujol mull:
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Bands at 1558, 1465, 1377, 1224, 1187, 1038, 931, 832, 722, 541.
Example 32 : Preparation of crystalline 1:1 salt with L-glutamic acid.
Paroxetine free base (2.1 g) in toluene (5 ml) was added to a suspension of L-
glutamic acid
(0.8 g) in propan-2-of (90 ml) and water ( 15 ml), stirred, and diluted
further with toluene
( 100 ml). The mixture was gently heated to dissolve the acid, and the
solution evaporated.
The residue from evaporation was stirred at ambient temperature with a mixture
of toluene
(50 ml) and n-hexane (50 ml) until the product appeared to-have crystallised
and then for
another hour. Finally, the crystals were collected by filtration; washed with
hexane and
dried at reduced pressure.
m.pt 92-98oC.
IR nujol mull:
Bands at 1650, 1598, 1573, 1507, 1207, 1043, 933, 826, 804, 648, 540cm-1
X-ray powder diffractogram (CuK2a):
Angle [o26J Rel. Int
[ lo ]
13.4 11.9
15.7 18.4 0
17.4 38.9
17.5 33.1
19.1 100.0
19.7 55.0
20.2 31.6
20.8 32.9
21.5 44,1
22.5 66.5
22.7 60.0
24.0 38.0
24.4 24.1
27.3 35.9
29.2 20.6
30.5 14.6
32.2 15.2
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33.2 15.7
34.0 23.5
Example 33: Preparation of crystalline paroxetine D-glutamate 1:1 salt
A solution of paroxetine base (4.2 g) in toluene ( 10 ml) was added to a
suspension of D-
glutamic acid (1.88 g, 12.76 mmoles) in water (35 ml) and toluene (40 ml). The
reaction
mixture was stirred and brought to reflux temperature and all of the water was
removed
using a Dean and Stark apparatus. Almost immediately a solid separated. The
mixture
was cooled to OOC, and the reaction mixture was diluted with propan-2-of (80
ml) with
stirring, to afford paroxetine D-glutamate 1:1 salt as a white crystalline
solid. The product
was filtered off under a nitrogen atmosphere, and dried at reduced pressure.
Melting point = 1950C
Molar ratio by 1 H NMR of paroxetine to D-glutamic acid = 1:1
IR Nujol Mull:
Bands at 2741, 1642, 1584, 1510, 1315, 1150, 1078, 947, 867, 675 538 cm-1.
X-rav diffractoerm (Cu K~n):
An le [029]Relative intensit
[%]
3.8 44.3
6.2 3.1
6.9 2.8
9.7 10.9
11.5 35.7
11.9 17.8
12.5 5.5
13.2 11.1
14.2 22.8
14.7 3.7
15.3 12.8
16.0 28.9
16.3 12.4
16.8 9.2
17.6 9.0
18.3 78.5
18.6 37.8
19.3 74.8
19.9 51.8
20.3 36.2
20.8 27.3
22.3 27.9
22.7 100.0
23.5 66.6
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23.9 41.2
24.4 33.9
25.0 19.4
26.1 13.9
26.6 10.8
27.1 19.6
27.9 48.2
28.7 30.4
31.0 14.4
31.6 15.7
32.2 16.3
33.3 24.1
34.4 22.6
Example 34 : Preparation of crystalline 1:1 paroxetine succinate
Succinic acid (0.35 g) was dissolved in propan-2-of (5 ml) with heating and
mixed with a
solution of paroxetine base ( 1 g) in toluene ( 10 ml). The solution was
diluted with ethyl
acetate (15 ml) and hexane (20 ml). An oil formed initially, but this
crystallised within 15
S minutes following scratching and ultrasonication. The suspension was stirred
at
approximately 20°C for a further hour then the crystals were filtered,
washed with ethyl
acetate and dried at reduced pressure. .
Yield 0.92 g.
Example 35 : Larger scale preparation of crystalline 1:1 paroxetine succinate.
Succinic acid (20 g) was dissolved in propan-2-of (300 ml) with heating and
then mixed
witht a solution of paroxetine base (60 g) in toluene 500 ml. The warm
solution was
diluted with ethyl acetate (500 ml) and hexane (800 ml) and stirred
vigorously. Crystals
began to separate out within a few minutes, and stirring at approximately
20°C was
continues for an hour, and then at OoC for a further hour. Finally the
crystals were filtered,
washed with ethyl acetate and dried at reduced pressure.
Yield 66.24g.
m. pt 116-117oC.
IR nujol mull:
Bands at 1713, 1573, 1488, 1464, 1272, 1185, 1032, 833, 793, 721, 627 cm-1
X-ray powder diffractogram major peaks (CuK2~:
Angte [~28] Rel. Int [ % ]
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4.8 6.0
11.3 15.8
14.4 33.7
16.3 60.1
17.8 99.3
19.2 25.1
19.9 61.4
21.6 20.5
21.8 26.8
23.9 72.8
24.1 100.0
24.5 25.9
25.5 34.6
26.4 72.6
27.1 28.4
27.3 26.7
28.2 32.4
28.6 21.9
29.0 27.4
29.4 35.8.
32.8 17.5
Example 36 : Alternative preparation of crystalline 1:1 paroxetine succinate.
Succinic acid (0.7 g) was heated in propan-2-of (10 ml) to form a solution,
which was then
added to a solution of paroxetine free base (4.2 g) in toluene ( 10 ml). The
mixture was
diluted with diethyl ether (30 ml) and hexane (30 ml) and the resulting oil
was scratched
and ultrasonicated until it crystallised. The suspension was stirred for a
further 1 hour,
filtered, washed with diethyl ether and dried at reduced pressure.
Yield 0.99g.
Example 37 : Preparation of crystalline 1:1 paroxetine succinate.
A solution of succinic acid (0.35 g) in hot propan-2-of was mixed with a
solution of
paroxetine base ( 1 g) in toluene ( IO ml). The mixture was stirred at
approximately 20°C
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and then diluted with hexane ( 15 ml) when an oil formed which crystallised on
standing.
The solid was filtered, washed with hexane and dried at reduced pressure.
Yield 0.6g.
Example 38 : Preparation of 2:1 paroxetine succinate.
A solution of succinic acid (0.35 g) in methanol ( 10 ml) was added to a
solution of
paroxetine free base (2.1 g) in toluene ( 10 ml). The solvent was removed by
evaporation
under reduced pressure to yield a white crisp foam. Diethyl ether (25 ml) and
hexane (25
ml) were added and the solid triturated to give a solid, easily stirrable
product. After
stirring for 30 minutes, the product was filtered, washed in diethyl ether and
dried at
reduced pressure.
Example 39 : Preparation of paroxetine benzoate
Paroxetine base (2.1 g) in toluene (5 ml) was added to a suspension of benzoic
acid (0.78 g,
6.38 mmol) in toluene ( 15 ml) and stirred vigorously. The solvent was removed
from the
resulting clear solution by evaporation under high vacuum to afford paroxetine
benzoate.
Yield 2.9g
Molar ratio of paroxetine to benzoic acid = 1:1
IR nujol mull:
Bands at 2879,1627,1509,1376,1037, 932, 830, 799, 695 cm-1.
Example 40: Preparation of paroxetine citrate ( 1:1 )
A solution of paroxetine base (4.2 g) in toluene (25 ml) was added to a
suspension of citric
acid (2.45 g) in water (4 ml), and the mixture was heated to reflux to form a
clear solution.
The water was removed by heating at reflux in a Dean and Stark apparatus, then
the
mixture was cooled and the solvent decanted. Fresh toluene (20 ml) was added
to the solid
residue, and the mixture heated once again at reflux in a Dean and Stark
apparatus. Finally
the toluene was removed at reduced pressure and the residue stirred with
heptane
overnight, filtered and dried to produce paroxetine citrate 1:1 salt as a
yellowish powder.
Example 41: Preparation of paroxetine citrate (2:1 )
A solution of paroxetine base (4.2 g) in toluene (30 ml) was added to a
suspension of citric
acid (1.23 g) in water (2 ml), and the mixture was heated to reflux to form a
clear solution.
The water was removed by heating at reflux in a Dean and Stark apparatus, then
the
mixture was cooled and the solvent decanted. Propan-2-of (30 ml) was added to
the solid
residue and the mixture stirred and heated to reflux temperature for 30
minutes, then cooled
to room temperature (approximately 22°C), whereupon a yellowish
precipitate was
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produced. The produce, paroxetine citrate 2:1, was collected by filtration
under an
atmosphere of nitrogen and dried under vacuum.
Yield 3.1 g
IR spectrum (nujoi mull):
Bands at 2970, 2360, 1738, 1622, 1487, 1134, 929, 830, 668 cm-l.
Example 42: Preparation of paroxetine citrate (3:1 )
A solution of paroxetine base (6.3 g) in toluene (25 ml) was added to a
suspension of citric
acid ( 1.23 g) in water (2.5 ml), and the mixture was heated to reflux to form
a clear
solution. The water was removed by heating at reflux in a Dean and Stark
apparatus, then
the mixture was cooled and the solvent decanted. Residual toluene was removed
at
reduced pressure and the solid product stirred with heptane overnight,
filtered and dried at
reduced pressure to give paroxetine citrate 3:1 salt as a yellowish powder.
Yield 5.1 g
IR spectrum (nujol mull):
Bands at 2970, 2359, 1738, 1558, 1487, 1366, 1035, 929, 720 cm-1.
Example 43. Preparation of paroxetine nitrate
Concentrated nitric acid ( 1.7 g, 1.2 ml, 19.14 mmol) was diluted with water
(28 ml), and
the solution mixed with a solution of paroxetine base (6.3 g) in toluene ( 15
ml). The
mixture was heated at reflux in a Dean and Stark apparatus under nitrogen
until all the
water had been removed, and the resulting solution cooled to room temperature
and
evaporated to an oil. On diluting the oil with toluene ( 10 ml), the product
crystallised;
heptane ( 100 ml) was added to the crystals and the suspension was stirred at
ambient
temperature. Finally, the crystals were collected by filtration, washed with
heptane and
dried in vacuo.
Yield 6.1 g.
Melting point 95-990C
IR nujol mull:
Bands at 1630, 1504, 1458, 1321, 1037, 930, 834, 719, 574cm-l.
X-ray powder diffractogram (Cu K2a):
Angle [028)Rel. Int
[%]
6.5 1.3
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8.1 0.3
9.7 1.3
11.5 1.0
13.0 19.5
13.7 12.9
14.0 7.8
14.5 4.6
15.8 11.8
16.7 17.1
18.0 52.4
19.1 76.9
19.4 100.0
21.0 17.2
23.1 39.3
23.9 27.4
24.2 32.3
24.7 17.5
25.9 14.7
26.9 40.3
27.2 38.4
28.1 23.1
28.8 26.6
29.7 15.7
31.0 11.8
32.0 17.5
33.5 10.4
Example 44 : Paroxetine phosphate 1:1 salt.
A solution of paroxetine base (2.1 g) in toluene (20 ml) was diluted with
acetone (20 ml).
Orthophosphoric acid in propan-2-of ( 1.5 ml, 3.675molar) was added and the
mixture
diluted further with propan-2-of (20 ml) and stirred for 1 hour at ambient
temperature. The
product crystallised and was filtered, washed with propan-2-of and dried in
vacuo. Yield
1.92 g.
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Example 45 : Larger scale preparation of paroxetine phosphate 1:1 salt.
Orthophosphoric acid in propan-2-of (45 ml, 3.675 molar) was added to a
solution of
paroxetine base (63 g) in toluene (600 ml). The mixture was stirred for 1
hour, and then
diluted with acetone (600 ml). Crystallisation began within a few minutes, and
the
suspension was stirred for 1 hour at ambient temperature and for a further 1
hour in an
ice/water bath. The crystalline product was filtered, washed with propan-2-of
and dried in
vacuo. Yield 74.53 g.
m. pt 207-210oC.
IR nujol mull:
1606, ISl2, 1466, 1225, 1190, 1079, 1040, 953, 831, 722, 608, 577cm-1.
X-ray powder diffractogram major peaks (CuK2~:
Angle [~29] Rel. Int. [%]
14.0 48.6
17.4 80.1
19.8 _ 71.4
21.4 96.3
23.6 65.3
24.8 100.0
26.2 48.6
Example 46 : Preparation of paroxedne phosphate 2:1 salt.
A solution of paroxetine base (4.2 g) in toluene (20 ml) was treated with a
solution of
orthophosphoric acid in propan-2-of ( 1.5 ml, 3.675 molar). Propan-2-of (20
ml) was added
and a white solid precipitated. The suspension was stirred for 1 hour at
ambient
temperature, and then the product was filtered, washed with propan-2-of and
dried in
vacuo. Yield 3.40 g.
IR nujol mull:
Bands at 1573, 1466, 1225, 1189, 1039, 876, 834, 782, 720, 547 cm-1.
Example 47: Preparation of non-crystalline paroxetine phosphate 2:1 salt.
Paroxetine base (4.2 g) in toluene (10 ml) was added to a suspension of
aqueous
orthophosphoric acid (0.37 ml, 14.6 molar, 85%) in methanol (50 ml), with
stirring to form
a clear solution. The solvents were removed by distillation in vacuo to
produce an oil,
which was dissolved in toluene (30 ml) and the solvent removed once more. The
resulting
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glassy solid was triturated with heptane (50 ml) to give a white powdery non-
crystalline
solid, which was filtered, washed with heptane and dried in vacuo.
field = 2.51 g.
Example 48: Crystallisation of paroxetine phosphate 2:1 salt.
The non-crystalline paroxetine phosphate prepared in Example 47 ( 1 g) was
suspended in a
mixture of ethanol (18 ml) and propan-2-of (20 ml) and heated to reflux
temperature with
stirnng. After 30 minutes the mixture was allowed to cool, then was collected
by filtration
and dried in vacuo. The product was found to be crystalline paroxetine
phosphate 2:1 salt.
Yield = 0.89 g.
Molar ratio of paroxetine to phosphoric acid = 2:1
IR nujoll mull:
Bands at 1606,1468,1377,1225,1040, 952, 783, 609, 578 cm-1.
X-ray powder diffracto~ram (Cu K~nl:
An le [029]Relative Intensit
[%]
4.6 70.2
8.3 2.3
11.3 8.9
12.5 10.7
14.0 100.0
14.5 ~ 16.5
15.3 39.9
15.6 29.8
16.0 25.5
17.4 90.7
17.7 74.6
18.2 49.2
19.2 52.4
20.4 60.0
20.6 50.6
21.5 77.3
21.8 83.6
22.7 40.7
23.5 60.0
24.3 41.5
24.8 78.4
26.2 39.9
28.3 11.3
30.7 8.5
31.5 6.9
33.6 1.5
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Example 49 : Preparation of crystalline paroxetine 4-methylbenzenesulphonate
A solution of paroxetine base in toluene (2.1 g in 5 ml) was mixed with a
solution of 4-
methylbenzenesulphonic acid monohydrate {1.21g) in methanol (15 ml). The
solvent was
removed in vacuo, replaced with fresh toluene ( 10 ml), and evaporated again.
The residue
S was triturated with diethyl ether ( 15 ml) to produce a white crystalline
solid, which was
filtered, washed with diethyl ether (2 x 10 ml) and dried in a vacuum
desiccator.
Yield 3.09g.
Example 50 : Preparation of crystalline paroxetine 4-methylbenzenesulphonate
A solution of paroxetine base in toluene (42 g in 100 ml) was added to a
solution of 4-
methylbenzenesulphonic acid (24.2 g) in methanol (300 ml}. The solvent was
removed in
vacuo, the residue diluted with toluene (200 ml) and the solvent again removed
in vacuo.
Trituration with diethyl ether (c. 300 ml) gave a white crystalline solid
which was filtered,
washed with diethyl ether (2 x SO ml) and dried in a vacuum desiccator.
Yield 61.13g.
m. p. 105 - 109°C.
IR nujol mull:
Bands at 1603, 1504, 1465, 1377, 1224, 1188, 1159, 1119, 1030, 999, 930, 830,
779, 722,
684, 564 cm-1.
X-ray powder diffractogram major peaks (CuK2~:
Angle [26] Rel. Int [ %
J
4.9 32.8
7.3 21.6
9.9 14.6
12.9 22.3
14.9 22.8
15.9 18.2
16.3 28.0
17.0 17.2
17.3 23.3
17.8 21.1
18.5 34.7
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19.0 19.0
19.4 31.2
19.8 45.0
20.5 28.6
20.8 15.7
22.1 100.00
28.0 15.1
Example 51: Preparation of paroxetine hypophosphite
Paroxetine base (4.2 g) in toluene ( 10 ml) was added to a 50% aqueous
solution of
hypophosphorous acid { 1.32 ml, 9.7 molar) and the mixture stirred at
approximately 20°C.
The solvents were then removed by distillation at reduced pressure to produce
non-
crystalline paroxetine hypophosphite as a crisp glassy solid. This solid was
triturated with
heptane to form the crystalline salt as a white solid, which was filtered
under nitrogen and
dried in vacuo.
Yield 5.1 g.
Molar ratio of paroxetlne to hypophosphorous acid = 1:1
IR nujol mull:
Bands at 2352,1602, 1466,1377,11 SI ,1975, 836, 722, 539 cm-1.
X-ray diffractogram (CuK~_n)
An le [028]Rel. Int
[%]
8.2 6.2
9.9 1.1
12.9 1.7
15.6 30.3
16.4 46.1
17.5 17.8
18.6 22.9
19.2 67.1
19.5 36.4
21.2 100.0
21.8 41.0
22.5 24.2
22.6 21.3
23.5 11.6
24.2 73.6
24.9 70.3
25.5 17.7
26.1 9.0
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27.6 35.7
28.8 40.0
29.3 11.7
29.9 15.4
31.5 13.5
32.7 14.2
33.1 19.0
34.3 8.6
Example 52 Preparation of paroxetine L-(+)-lactate
Paroxetine base (2.1 g) in toluene (5 ml) was added to a suspension of L-(+)-
lactic acid
(0.63 g, 6.38 mmoles) in methanol (10 ml) and stirred at approximately
20°C until a clear
solution formed. The solvents were then removed by evaporation in vacuo to
afford a
white glassy non-crystalline salt of paroxetine L-(+)-lactate. This solid was
triturated with
heptane and the white powdery solid of crystalline paroxetine L-(+)-lactate
was filtered,
washed with heptane and dried in vacuo.
Melting point = 98-1030C.
IR nujol mull: Bands at 1647,1588,1464,1377,1195,1038, 930, 785, 721cm-l.
X-ray diffractogram (CuK2~:
An le [028]Rel. Int
[%)
5.4 6.2
7.8 50.7
8.4 1.2
9.4 0.1
10.4 3.6
11.9 1.3
15.6 39.6
16.3 100.0
16.5 95.2
17.4 61.8
17.7 58.3
18.7 37.4
18.9 14.3
19.6 19.0
20.0 4.5
20.9 8.4
21.4 38.g
21.9 93.4
22.1 b 1.5
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22.9 48.2
23.6 45.7
2~.0 28.2
24.8 9.1
25.1 11.8
25.6 7.9
26.2 9.4
26.8 18.2
27.8 40.5
28.4 40.7
29.3 11.0
29.6 15.1
30.1 13.2
31.2 8.0
31.6 10.6
32.2 30.2
32.6 15.7
33.0 10.1
33.7 12.1
_ 12.1
34.4
Example 53 - Preparation of paroxetine R-(-)-mandelate
Paroxetine base (4.2 g) in toluene ( 10 ml) was added to a suspension of R-(-)-
mandelic
acid ( 1.94 g, 12.76 mmoles) in methanol (20 ml), and stirred at approximately
20°C until a
clear solution was formed. The solvents were removed by low pressure
evaporation to
produce an off white glassy solid of non-crystalline paroxetine mandelate.
This solid was
triturated with heptane (50 ml) and the white powdery crystalline solid was
filtered,
washed with heptane and dried in vacuo. Yield 3.9 g
melting point = 78-83oC
IR nujol mull: Bands at 1617,1463,1267,1183,1015, 984, 870, 735, 539, 516 cm-
1.
X-ray diffractogram major peaks (Cu K2a):
An le [o2A]Rel. Int
[%]
3.6 8.7
9.1 8.2
9.5 29.1
10.5 2.7
13.5 7.9
15.5 10.6
18.2 27.3
.
1 28.9
18.4
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19.1 100.0
19.5 40.5
24.4 66.4
21.6 30.5
23.0 24.9
23.6 24.7
25.3 18.5
27.2 32.1
27.7 24.9
28.0 20.7
28.8 22.0
29.3 19.9
31.9 15.9
34.1 11.3
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