Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02330055 2000-10-23
WO 99/55698 PCT/GB99/01244
PAROXETINE ASCORBATE
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)-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 a novel salt 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 paroxetine ascorbate.
In one aspect the novel salt of this invention is 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 salt of this invention is provided in crystalline
form. When the
crystalline form exists as more than one polymorph, each polymorph forms
another aspect
of this invention.
Paroxetine ascorbate may be prepared by contacting stoichiometric amounts of
ascorbic
acid and paroxetine free base. Preferably either the acid or base is in
solution, more
preferably both are in solution. filevated temperature may be used to bring
the acid into
solution, but good yields of the salt are obtained by evaporation of some or
all of the
solvent or by controlled cooling, preferably in stages. Most commonly used
solvents are
suitable for mobilizing paroxetine free base, for example toluene, alcohols
such as
-1-
CA 02330055 2000-10-23
WO 99/55698 PC'T/G899/01244
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, but solvents in which ascorbic acid is very
insoluble are
preferably avoided. Suitable solvents for ascorbic acid include water and
lower alcohols.
The salt may be isolated in solid form by conventional means from a solution
thereof
obtained as above. For example, the non-crystalline salt 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
salt may be
prepared by crystallization or recrystallization from appropriate solvents.
When the salt is obtained as a solvate, by association with the solvent in
which it is
dissolved, 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 paroxedne 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 and propan-2-ol. 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 carned out.
Paroxetine free base may be prepared according to the procedures generally
outlined in US
Patent No 4,007,196 and EP-B-0 223403. Ascorbic acid is commercially
available.
The compounds of this invention may be used to treat and prevent the following
disorders:
-2-
CA 02330055 2000-10-23
WO 99/55698 PCT/GB99/01244
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 Garner.
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.
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.
-3-
CA 02330055 2000-10-23
WO 99/55698 PCTlGB99/01144
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,
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 400rng
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 carriers 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 ascorbate
A 1.28 mol solution of paroxetine base in toluene (5 mI, 6.38 mmol) was added
to a
solution of ascorbic acid (1.128, 6.38 mmol) in methanol (15 ml). The solvent
was
removed in vacuo, the residual oil was diluted with toluene (15 ml) and the
solvent
removed in vacuo. Trituration with diethyl ether (c. 15 ml) and filtration
under nitrogen
-4-
CA 02330055 2000-10-23
WO 99/55698 PCT/GB99/01244
gave a pale yellow solid which was washed with diethyl ether (2 x 10 ml),
dried in a
vacuum desiccator for 3 hours.
Yield 2.998.
IR nujol mull:
Bands at 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722,
540 cm-I
Example 2: preparation of tablets
INGREDIENTS 20 mg Tablet 30mg Tablet
Paroxetine ascorbate 20.00 mg 30.0 mg
(based on free base)(based on free base)
Dicalcium Phosphate 83.34 mg 125.0 mg
(DCP)
Microcrystalline Cellulose50.67 mg 76.0 mg
Sodium Starch Glycollate8.34 mg 12.5 mg
Magnesium Stearate 1.67 mg 2.5 mg
Commercial source of the ingredients
i 5 Dicalcium Phosphate Dihydrate - Emcompress or Ditab*
Microcrystalline Cellulose - Avicel PH 102*
Sodium Starch Glycollate - Explotab.*
* Tradenames
Method
-5-
CA 02330055 2000-10-23
WO 99/55698 PCT/GB99/01244
1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine Ascorbate 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
20 mg Tablet 8.25 mm Circumcircle
The tablets are made satisfactorily on a single punch or a Rotary press.
Example 3: preparation of tablets
INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet
Paroxetine ascorbate10 mg 20 mg 30 mg
(as on free (as on free (as on 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
Method
1. Paroxetine ascorbate, Sodium Starch Glycollate and Dicalcium Phosphate
Dihydrate are screened and mixed together in a suitable mixer.
-6-
CA 02330055 2000-10-23
WO 99/55698 PCT/GB99/01244
(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.
