Note: Descriptions are shown in the official language in which they were submitted.
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PAROXET1NE MALEATE
The present invention relates to a novel compound, to processes for preparing
it and to its
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)-pipetidine. 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.
Example 2 of US 4007196 describes the preparation of paroxetine by
demethylation of the
N-methyl derivative. Paroxetine free base is isolated as an oil by evaporation
of a benzene
solution. T'he free base is dissolved in ether and treated with a solution of
malefic acid in
ethyl ether to form a crystalline product, which is recrystallised from 99%
ethanol-ether to
give a maleate salt melting 136-8°C. Apart from the melting point,
there is no
characterizing data that allows an unambiguous assignment of structure.
Further, neither benzene nor ether are desirable as solvents for commercial
manufacture,
since high flammability, potentially explosive residues, and toxic residues
would require
expensive control measures. Also the process described in Example 2 of US
4007196 is
unsuitable for commercial use since it results in a heavy sticky gum.
We have now surprisingly discovered novel maleate 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, and novel methods of preparation which are
suitable for
commercial use.
In one aspect of the present invention there is provided paroxetine maleate in
which the
ratio of paroxetine to malefic acid (by mole) is 1:1. In another aspect of the
present
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invention there is provided paroxetine maleate in which the ratio of
paroxetine to malefic
acid (by mole) is 2:1.
In the 1:1 salt, the maleate anion may be associated with a proton (hydrogen
atom) in
addition to paroxetine or may be associated with another cation, for example
an alkali
metal or ammonium canon. In the former case the 1:1 salt may be described as
paroxetine
hydrogen maleate, while in the latter case the salt may be described as a
mixed salt.
In one aspect the novel salts of this invention are provided in non-
crystalline form, which
may 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.
We have discovered that crystalline paroxetine maleate in which the ratio of
paroxetine to
malefic acid (by mole) is 1:1 exists in at least two polymorphic forms.
Accordingly a further aspect of the invention provides
paroxetine (l:l) maleate Form A having a melting point of 139-141°C and
having an IR or
XRD spectrum substantially as disclosed in Example 1 below; and
paroxetine (1:1) maleate Form B having a melting point of 136-138°C and
having an IR or
XRD spectrum substantially as disclosed in Example 2 below.
The above-mentioned paroxetine maleates may be prepared by contacting
appropriate
stoichiometric amounts of the acid and paroxetine free base. Preferably the
base is in
solution, more preferably both are in solution. Mixed salts may be prepared by
forming the
precursor 1:1 salt in situ or using it pre-formed; and contacting it in
solution with a solution
containing the metal or ammonium ion.
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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 malefic acid may be
added as a
solid, but is preferably added as a solution in an organic solvent such as
ethanol or ethyl
acetate, or water, methanol, propan-2-ol, or acetone. The malefic acid may
also be added in
the form of a soluble salt, for example ammonium maleate, or the malefic acid
salt of an
amine, for example ethylamine or diethylamine.
The concentration of paroxetine base is preferably in the range 5 to 50%
weight/volume,
more preferably in the range 10 to 30%. The concentration of malefic acid when
used in
solution is preferably in the range 0.1 to 5, preferably 0.5 to 2 molar.
Elevated temperatures
may be used to increase solubility.
The salt may be isolated in solid form by conventional means from a solution
thereof
obtained as above. For example, a non-crystalline salt may be prepared by
precipitation
from solution, spray drying and freeze drying of solutions, evaporating a
solution to a
glass, or vacuum drying of oils, or solidification of melts obtained from
reaction of the free
base and the acid.
A crystalline salt 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. For example, paroxetine maleate may be recrystallised from a variety of
organic
solvents, such as acetonitrile, butanone, sec-butanol, dichloromethane,
ethanol, 3-
pentanone, propan-2-of and toluene. 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 reproducibility of the
production
process and the particle size distribution and form of the product. 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 carried
out.
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Thus paroxetine ( 1:1 ) maleate Form A may be prepared by crystallisation from
a solution
of paroxetine maleate, which may be prepared, for example, by mixing together
a solution
of paroxetine free base and a solution of malefic acid. Advantageously an
excess of malefic
is used, for example a molar ratio between 1:1 and 1:1.5, preferably between
1.1 and 1.3.
Suitable solvents include ethyl acetate, methanol, ethanol, propan-2-ol,
propan-1-ol, sec-
butanol, butan-1-ol, methyl isobutylketone, acetone and acetonitrile, or a
mixture of
solvents, including mixtures with toluene.
The maleate Form B may be prepared by recrystallisation of Form A (or vice
versa). More
preferably, and advantageously, Form B is prepared directly by crystallisation
in a similar
manner to Form A, that is directly from a solution of paroxetine maleate,
which may be
prepared by mixing together a solution of paroxetine free base, typically as
the final stage
of a manufacturing process, and a solution of malefic acid. A wide range of
solvents may
be used, particularly if seeding is also used to ensure formation of the
desired polymorph,
but preferred solvents include toluene, butanone, acetone and dichloromethane.
Propan-2-
of may also be used.
Seeding with the desired polymorph may be incorporated into the process to
ensure
reliability of polymorph formation and to control crystal size distribution.
It has been found that toluene or mixtures containing toluene are among the
most suitable
solvents for the preparation of paroxetine maleate Form B.
The processing properties of Form B are generally superior to those of Form A,
since this
polymorph is more granular and easier to filter, wash and dry. Consequently,
this
invention provides a particularly convenient manufacturing process for
paroxetine ( 1:1 )
maleate, in which unsuitable solvents are avoided and a solution of paroxetine
free base is
prepared in toluene and converted directly to the maleate salt. Known
processes for the
preparation of paroxetine utilize toluene as the solvent of choice. Before the
invention of
paroxetine maleate Form B disclosed herein, there was no process available
which had the
convenience of using toluene solutions of free base as starting material,
since treatment of
such solutions generated paroxetine maleate in the form of an oil or gum.
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An alternative method of preparing paroxetine maleate is to start with a salt
of paroxetine
with an organic acid, such as acetic acid, rather than using paroxetine free
base. 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).
The salt may obtained as a solvate, when during isolation from solution it
becomes
associated with the solvent in which it is dissolved. Any such solvate 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.
Prior to the isolation of the paroxetine maleate, water may be removed from
the solution
containing the salt 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 and propan-2-ol. It
should also
be appreciated that mixtures of solvents can also be used to aid the
azeotropic removal of
water.
Paroxetine free base may be prepared according to the procedures generally
outlined in US
Patent No 4,007,196 and EP-B-0 223403. Malefic acid is 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
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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.
The present invention also provides the use of a salt of the invention for
treating and/or
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.
Compositions containing the salt of this invention may be formulated for
administration by
any route, and examples are oral, sub-lingual, rectal, topical, parenteral,
intravenous or
intramuscular administration. Preparations may, if desired, be designed to
give slow
release of the paroxetine salt.
The medicaments may, for example, be in the form of tablets, capsules,
sachets, vials,
powders, granules, lozenges, reconstitutable powders, or liquid preparations,
for example
solutions or suspensions, or suppositories.
The composition is usually presented as a unit dose composition containing
from 1 to
200mg of active ingredient calculated on a free base basis, more usually from
5 to 100mg,
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for example 10 to SOmg such as 10, 12.5, 1 S, 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-
0-
223403, 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:
Example 1
Preparation of Paroxetine (1:1) Maleate Form A
Malefic acid [14.8g,0.128 mol] was stirred in ethyl acetate [100m1] and the
solution
warmed gently. Paroxetine free base [42.7g] in ethyl acetate was then added
rapidly with
stirring and the suspension briefly became clear then immediately solidified.
Warming was
continued until the solution was at reflux and the mixture was then stirrable.
The reaction
mixture was allowed to cool with stirring and the cold solution filtered and
washed with
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ethyl acetate [25m1] and dried in a vacuum oven at 40 C for 3 hours to give
paroxetine
maleate Form A. NMR showed a ratio of 1:1 for paroxetine : malefic acid.
m.pt. 139-141 °C
IR 1674, 1360, 1306, 1269, 1248, 1190, 1137, 1101, 1026, 863, 834, 783, 706,
597.
XRD
Angle d-value Peak Int.
[2q] a [A] counts
5.10 17.30 8649
8.04 10.99 106
8.78 10.10 64
10.26 8.62 692
11.98 7.38 77
13.91 6.36 829
15.43 5.74 15500
15.88 5.58 5242
16.13 5.49 586
17.71 5.00 745
18.67 4.75 635
19.37 4.59 475
20.29 4.37 1544
20.52 4.32 1945
20.90 4.25 493
21.32 4.16 384
23.18 3.83 376
24.30 3.66 2663
25.00 3.56 912
25.80 3.45 566
26.52 3.36 1640
27.96 3.19 1616
_g_
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28.76 3.10 671
30.00 2.98 1030
30.34 2.94 552
31.10 2.87 1980
32.10 2.79 1005
32.77 2.74 342
33.36 2.69 529
Example 2
Paroxetine (1:1) Maleate Form B by recrystallization of Form A from butanone.
A suspension of paroxetine maleate Form A (0.5g) in butanone (4 ml) was
stirred
vigorously and heated to reflux. The solution was allowed to cool slowly to
room
temperature to give a paroxetine maleate Form B as a granular white
crystalline solid
which was collected by filtration and dried in vacuo over phosphorous
pentoxide. NMR
showed a ratio of 1:1 for paroxetine : malefic acid, butanone content was
approximately
0.1 % by weight.
m.pt. 136-138°C
IR {nujol mull), 1709, 1385, 1280, 1247, 1195, 1134, 1045, 931, 904, 876, 862,
838, 816,
805, 779, 714, 595, 543.
XRD
Angle d-value Peak Int.
[2q] a [A] counts
5.11 17.28 79
8.35 10.58 19
10.47 8.44 292
12.90 6.86 420
13.64 6.49 339
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13.97 6.34 196
14.41 6.14 428
15.51 5.71 724
16.32 5.43 1624
16.60 5.34 973
17.78 4.98 1332
19.75 4.49 3102
20.21 4.39 5868
20.68 4.29 729
21.25 4.18 420
21.95 4.04 1197
22.13 4.01 876
22.80 3.89 581
23.65 3.76 576
24.46 3.64 1747
24.97 3.56 5227
25.88 3.44 955
27.69 3.22 454
28.23 3.16 566
29.26 3.05 2470
29.94 2.98 1866
30.76 2.90 552
31.26 2.86 697
32.02 2.79 605
32.44 2.75 557
33.01 2.71 571
33.88 2.64 458
Example 3
Paroxetine (1:1) Maleate Form A by recrystallization from propan-2-of
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A suspension of paroxetine maleate Form A (O.Sg) in propan-2-of (4 ml) was
stirred
vigorously and heated to reflux. The solution was allowed to cool to room
temperature to
give a paroxetine maleate Form A as white plate-like crystals which were
collected by
filtration and dried in vacuo over phosphorous pentoxide. The infra-red
spectrum was the
same as for the product of Example 1.
Example 4
Paroxetine (1:1) Maleate Form A by recrystallization from acetonitrile.
A suspension of paroxetine maleate Form A (O.Sg) in acetonitrile (4 ml) was
stirred
vigorously and heated to reflux to dissolve. The solution was allowed to cool
to room
temperature to give paroxetine maleate Form A as large plate-like crystals.
The crystalline
solid was isolated by filtration and dried in vacuo over phosphorous
pentoxide. The infra-
red spectrum was the same as for the product of Example 1.
Example 5
Paroxetine (1:1) Maleate Form B by recrystailization of Form A from toluene.
A suspension of paroxetine maleate Form A (O.Sg) in toluene (8 ml) was stirred
vigorously
with heating and approximately half the solvent was distilled off. A further 3
ml toluene
was added and the reaction mixture cooled to room temperature. After 2 hours,
the white
solid which had formed was collected by filtration and dried, to afford
paroxetine maleate
Form B as a granular solid. The infra-red spectrum was the same as for the
product of
Example 2.
Example 6
Paroxetine (1:1) Maleate Form A by recrystallization from sec-butanol
A suspension of paroxetine maleate Form A (O.Sg) in sec-butanol (4 ml) was
stirred
vigorously and heated to reflux. The solution was allowed to cool to room
temperature to
produce paroxetine maleate Form A as a white crystalline solid, which was
collected by
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filtration and dried in vacuo over phosphorous pentoxide. The infra-red
spectrum was the
same as for the product of Example 1.
Example 7
Paroxetine Maleate Form B by recrystallization of Form A from dichloromethane
A suspension of paroxetine maleate Form A (O.Sg) in dichloromethane (3 ml) was
stirred
vigorously and heated to reflux. The solution was allowed to cool to room
temperature for
hours to produce paroxetine maleate form B as a white granular solid. The
product was
collected by filtration and dried in vacuo over phosphorous pentoxide.
The infra-red spectrum was the same as for the product of Example 2.
Example 8
Paroxetine (1:1) Maleate Form A by recrystallization from ethanol.
A suspension of paroxetine maleate Form A (O.Sg) in ethanol (3 ml) was stirred
vigorously
and heated to reflux. The solution was allowed to cool to room temperature to
give
paroxetine maleate Form A as a white crystalline solid which was collected by
filtration
and dried in vacuo over phosphorous pentoxide. The infra-red spectrum was the
same as
for the product of Example 1.
Example 9
Paroxetine {l:l) Maleate Form B by recrystallization of Form A from 3-
pentanone.
A suspension of paroxetine maleate Form A (O.Sg) in 3-pentanone (4 ml) was
stirred
vigorously and heated to reflux. The solution was allowed to cool to room
temperature to
give a paroxetine maleate Form B as a crystalline solid. The product was
collected by
filtration and dried in vacuo over phosphorous pentoxide. The infra-red
spectrum was the
same as for the product of Example 2.
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Example 10
Preparation of Paroxetine (1:1) Maleate Form A
To a solution of paroxetine free base (15.16 g) in toluene (75 ml) was added a
solution of
malefic acid (5.34 g) in ethyl acetate (37.Sm1) with vigorous stirring. A
solid product
crystallized out quickly and after 20 minutes was collected by filtration and
dried in vacuo
at 40°C. The infra-red spectrum was the same as for the product of
Example 1.
Yield: [18.60g, 41mmo1, 90.7%]
Example 11
Preparation of Paroxetine (1:1) Maleate Form B
N-phenyloxycarbonyl paroxetine (5.00 kg ), potassium hydroxide flake (4.50 kg)
and
toluene (75.0 litres) was heated to reflux under a nitrogen atmosphere with
good stirring
over a period of 40 minutes. After stirnng for 4 hr, 45 min at reflux the
contents of the
reactor was allowed to cool to room temperature. Water (SO litres) was added
and the
mixture stirred for 30 minutes and then allowed to settle for 30 minutes. The
lower aqueous
layer was drained from the reactor and the remaining toluene solution was
heated to reflux.
Water was removed by heating to reflux with Dean and Stark apparatus. Toluene
(11.5
litres) was added and a similar quantity of the reaction solvent removed by
distillation.
The remaining mixture was cooled to approximately 100°C, stirred
vigorously, and a
mixture of malefic acid (1.04 kg) and paroxetine maleate Form B (40 g) seed
crystals
added in four portions via a solids charging hopper. The temperature was
reduced in stages
whereupon crystallization commenced between 60°C and 50°C. The
temperature was held
at 40°C for two hours for the bulk of the crystallization to occur.
Finally the temperature
was reduced to approximately 15°C and the product Form B paroxetine
maleate collected
in a centrifuge, washed with toluene and dried in a vacuum oven at
50°C. Yield 3.1 kg.
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Example 12
Preparation of Paroxetine (2:1) Maleate
A solution of malefic acid [0.74g] in ethanol [100m1] was added to a solution
of paroxetine
in toluene [IOmI of a 0.42g/ml solution] and the solution stirred for 30
minutes at ambient
temperature. The solvent was removed by evaporation in vacuo to give a viscous
oil,
which was redissolved in chloroform. The chloroform solution was evaporated to
dryness
to give a white solid.
NMR indicated a molar ratio 2:1 paroxetine to malefic acid.
Example 13
INGREDIENTS 20 mg Tablet 30mg Tablet
Paroxetine maleate ( 1:1 20.00 mg based 30.0 mg based
or 2:1 )
on free base on free base
Dicalcium Phosphate (DCP)83.34 mg 125.0 mg
Microcrystalline Cellulose50.67 mg 76.0 mg
Sodium Starch Glycollate 8.34 mg 12.5 mg
Magnesium Stearate 1.67 mg 2.5 mg
Commercial source of the ingredients
Dicalcium Phosphate Dihydrate - Emcompress or Ditab*
Microcrystalline Cellulose - Avicel PH 102*
Sodium Starch Glycollate - Explotab.*
* Tradenames
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Method
1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine to the bowl.
3. Add 20 mesh Avicel and Explotab and mix ail 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
The tablets are made satisfactorily on a single punch or a Rotary press.
15 Example 14
INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet
Paroxetine maleate
(1:1 or 2:1) 10 mg based 20 mg based 30 mg based
on on on
free base free base free 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
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Method
Paroxetine, 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.
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