Note: Descriptions are shown in the official language in which they were submitted.
CA 02353693 2001-07-24
Pltarrnaceatical composition containing Citalopram
The present invention relates to a novel pharmaceutical composition containing
citalopram, 1-(3-(dimethylamino)propyl]-1-(4-fluoropbenyl)-1,3-dihydro-
S~isobenzo
furancarbonitrile.
Bsclrground of the Ynvention.
Citalopram is a well-knoww antidepressant drug that has the following
structure:
N
~ H3
H
~ CH3
Tt is a selective, centrally active serotonin (S-hydroxytryptamine; 5-H~
reuptake
inhibitor, accordingly having antidepressant activities.
Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193.
This
patent publication describes the preparation of citalopram by one method and
outlines
a further method, which may be uscd for preparing citaloprani. The citalopram
2o prepared was isolated in crystalline fonni as the oxalate, the hydrobmmide
and the
hydrochloride salt, respectively. Furthermore, the citalopratn base was
obtained as an
oil (B.P. 175 CI0.03 nunHg). The publication also outlines the manufacture of
tablets
containing salts of citalopram. Citaloprarn is marketed as the hydrobromide
and the
hydrochloride, respectively.
Manufacture of crystalline citaloprara base is disclosed in co-pending DK 2000
00402. This patent publication describes the preparation of crystalline
citalopram base
and the use of crystalline citalopram base as an intermediate in the
purification of
crude citalopram hydrobromide into pure citalopratm hydrobmmide. The
publication
3o also outlines the manufacture of tablets containing citalopram base.
CA 02353693 2001-07-24
2
Citalopram is marketed in a number of countries as a tablet prtpared by
compression
of granulated citalopram hydrobromide, lactose and other excipients.
Yt is well recognised that preparation of tablets with a reproducible
composition
s requires that all the dry ingredients have good flow properties. In cases,
where the
active ingredient has good flow properties, tablets can be prepared by direct
compression of the ingredients. However, in many casts the particle size of
the activo
substance is small, the active substance is cohesive or has poor flow
properties.
to Further, active substances with a small particle size mixed with excipients
having a
larger particle size will typically segregate or de-mix during the tabletting
process.
The problem of small particle size and poor flowability, is conventionally
solved by
enlarging the particle size of the active substance, usually by granulation of
the active
15 iagaredient either alone or in combination with a filler andlor other
conventional tablet
ingredients.
One such granulation method is the "wet" granula'on pmcess. Using this method,
the
dry solids (active ingredients, filler, binder etc.) are blended and moistened
with water
24 or another wetting agent (e.g. an alcohol) and agglomerates or granules are
built up of
the moistened solids. Wet massing is continued until a desired homogenous
particle
size has been achieved whereupon the granulated product is dried.
An alternative to the "wet" granulation method is the "melt" granulation,
which is also
25 known as the "thermal plastic" granulation process, where a low melting
solid is used
as the granulation agent. Tnitially, the dry solids are blended and heated
until the
binder melts. As the binder is liquefied and spreads over the surface of the
particles,
the particles will adhere to each other and form granules. The binder
solidifies upon
cooling fornvng a dry granular product.
Wet granulation as well as melt granulation are energy intensive unit
operations
requiring complicated and expensive equipment as well as technical skill.
CA 02353693 2002-11-20
3
The pmcess used for the preparation of citalop~ratn hydrobromide results in a
product
with a very small particle sire around 2-20 pm that, as many other particulate
products with a small particle sixe, hae very poor flow properties. Thus, in
order to
achieve appropriate dosing of the citalopram during tahletting, it was
cotrsiderat
s necessary to make a gratrulate of citalopram with larger particle size and
improved
flow properties.
The citalopram tablet that is marketed is a tablet made from granulated
citatopram
hydmbromide with various excipiants.
to
1n view of the fact that direct compression is much simpler and cheaper than
the
processes involving granulation there is a desire for.a process for direct
compression
of citaloprsm hydrobmmide.
15 The obataclos that hitherto have hindered direct compression of citaloptam
tablets
have now been circunnvented after extensive laboratory research.
rt has boon found that largo particles, i.e. particles of a size eotaparable
to the size of
the filler, may be propared by a new and inven've cxyetallisation process ~d
that
20 these particles are useful for the manufacture of directly compressed
tablets. Accurate
dosing in cagsulas may also be with such large particles.
It has also been found, that tablets with surprisingly small variation i>1 the
content of
citalopram may be preparai by direct cotrrpiession of citalopram hydrobrornido
25 having a significantly smaller particle size than the filler. Arxurate
dosing in capsules
may also be achieved despite iho small particle size of citalopram.
Objects olthe Iaverition
3o It is the object of the present invention to provide a novel pharmaceutical
unit dosage
form containing citalopram with a suitable large particle size, wherein said
unit
dosage form may be prepared by direct compression.
A second object of the invention ( not claimed) is to provide
a capsule containing citalopram.
CA 02353693 2001-07-24
4
A third object of the invention is to provide large crystals of a
pharmaceutically
acceptable salt of eitalopram suitable for use in direct compression.
s A fourth object of the invention is to provide a method for manufacture of
large
crystals of a pharmaceutically acceptable salt of citaloprara.
Summary of the lrnveation
1o The invention then, inter alia, comprises the following alone or in
combination:
A solid unit dosage form comprising eitalopratn prepared by direct compression
of a
mixture of eitalopram base or a pharmaceutically acceptable salt thereof and
pharmaceutically acceptable excipients, or by filling of said mixture in a
hard gelatine
15 capsule_
Crystals of a pharmaceutically acceptable salt of citalopram suitable for use
in a solid
unit dosage form with a median particle site of at least 40 Nra.
2o A method for the manufacture of crystals of a pharmaceutically acceptable
salt of
citalopram having a median particle size of at least 40 lrm and suitable for
use itt a
solid unit dosage form wherein a solution of a pharmaceutically acceptable
salt of
citalapram in a suitable solvent system at a first temperature is first cooled
down to a
second temperature then seeded by addition of crystals of said citalopram salt
25 followed by a holding time at said second temperature and a controlled
cooling down
to a third temperature whereupon said crystals are isolated by conventional
solidlliquid separation techniques.
The direct compression of citalopram, a filler and other pharmaceutically
acceptable
30 excipients into tablets has the great advantage, that the granulation and a
drying step is
avoided. Further, as the granulation step is avoided, it is no Longer
necessary to add a
binding agent.
CA 02353693 2002-11-20
As used herein, "direct compression" means that the solid
unit dosage form is prepared by compression of a simple
mixture of the active ingredient and excipients, without
the active ingredient having been subjected to an
intermediate granulation process in order to embed it in a
larger particle and improve its fluidity properties.
As used herein, "binder" means an agent, which is used in
wet or melt granulation processes and acts as a binder in
the granulated product.
As used herein, "particle size distribution" means the
distribution of equivalent spherical diameters as
determined by laser diffraction at Z bar dispersive
pressure in a Sympatec Helos* equipment. "Median particle
size", correspondingly, means the median of said particle
size distribution.
As used herein, "refluxing temperature" means the tempera-
ture at which the solvent or is solvent system refluxes or
boils at atmospheric pressure.
Thus in one embodiment of the invention, the present
invention relates to a tablet prepared by direct
compression of a mixture of citalopram base or a
pharmaceutically acceptable salt thereof in the form of
crystals with a medium particle size of at least 40~,m and
pharmaceutically acceptable excipients.
* (trademarks)
CA 02353693 2002-11-20
5a
In another embodiment not claimed, the present invention
relates to a capsule prepared by filling a mixture of
citalopram base or a pharmaceutically acceptable salt
thereof and pharmaceutically acceptable excipients in a
hard gelatine capsule.
In a further embodiments not claimed, the present invention
relates to a solid unit dosage form comprising citalopram
in crystals with a median particle size below 20 ,um.
In another embodiment, the present invention relates to a
solid unit dosage form comprising citalopram in crystals
with a median particle size of at least 40 ~.m, preferably
in the range of 40 - 200 ~Cm, even more preferred 45 - 150
~m and most preferred 50 - 100 ~.m.
CA 02353693 2002-O1-29
6
Flow, segregation and demixing properties and, hence, the suitability of the
citalopram crystals for direct compression depend, besides the median particle
size, on
the particle side distribution.
s Preferably, the solid unit dosage forms according to the invention do not
contain a
binder.
The solid unit dosage form according to the invention may contain 2-60 % w/w
active
ingredient calculated as citalopram base, preferably 10-40 % w/w active
ingredient
calculated as citalopram base, and more preferred 15-25 % w/w active
ingredient
calculated as citalopram base. Suitably, the solid unit dosage form of the
invention
contains 20 % w/w active ingredient calculated as citalopram base.
In particular, the present invention relates to a solid unit dosage form
wherein the
active ingredient is citalopram hydrobromide, or citalopram hydrochloride.
Preferably the active ingredient contained in the solid unit dosage form of
the
invention is citalopram hydrobromide.
The solid unit dosage form according to the invention may contain a filler
selected
2o from lactose, or other sugars e.g. sorbitol, mannitol, dextrose and
sucrose, calcium
phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified
starches,
microcrystalline cellulose, calcium sulphate and/or calcium carbonate. In a
preferred
embodiment, the solid unit dosage form of the invention does not contain
lactose.
Suitably the filler is a microcrystalline cellulose such as ProSolv SMCC90*
manufactured by Penwest Pharmaceuticals or Avicel PH 200 manufactured by FMC
Corporation.
Besides the active ingredient and filler, the solid pharmaceutical unit dosage
forms
may include various other conventional excipients such as disintegrants, and
optionally minor amounts of lubricants, colorants, and sweeteners.
* (trademarks)
CA 02353693 2001-07-24
7
Lubricants used according to the invention may suitably be one or more of the
follovcring metallic stearates (magnesium, calcium, sodium), stearic acid,
wax,
hydrogenated vegetable oil, talc and colloidal silica.
Suitably the lubricant ie magnesium stearate or calcium stearate
Disintegrants include sodium starch glycolate, croscarmellose, crospovidone,
lover
substituted hydmxypropylccllulose, modified cornstarch, pregelatizined starch
and
natural starch.
to
The solid, pharmaceutical unit dosage form of the invention may be prepared by
conventional methods using a tablet press with forced feed capability.
?he filled, hard gelatine capsule of the invention may be prepared by
conventional
~ s methods using a capsule filler suitable for powder filling.
In one embodiment of the present invention the crystals of a pharmaceutically
acceptable salt of citalopram have a median particle size in the range of 40 -
200 p.m,
preferably 45 -150 pro and even more preferred 50 -120 pro.
In a preferred embodiment of the present invention the crystals are of
citalopram
hydrobromide or citalopram hydrochloride, preferably citalopram hydrobmmide.
xn yet another embodiment of the present invention crystals of a
pharmaceutically
acceptable salt of citalopram having a median particle size of at least 40 itm
and
suitable for use in a solid unit dosage form are crystallised from a solution
of a
pharmaceutically acceptable salt of citalopram in a suitable solvent system.
Said
solvent system may comprise one or more alcohols and optionally water,
preferably
the solvent system is a mixture of methanol and water, wherein the
methanol:water
3o weight ratio preferably is in the range of S:1 to 50:1; even more preferred
10:1 to 30:1
and most preferred 15:1 to 25:1. Said pharmaceutically acceptable salt of
citaloprarn
is preferably dissolved in the solvent system at a temperature in the range
between 50
°C and the refluxing temperattue of the solvent system, preferably
between 60 °C and
CA 02353693 2001-07-24
B
the refluxing temperature and more preferred between 64 °C and the
refluxiirg
temperature. The amounts of pharmaccudcally acceptable salt of citaloprarn and
solvent used are preferably corresponding to a sol~rentaolute weight ratio in
the range
of 0.5:1 to 5:1, more preferred 0.7:1 to 2:1 arid most preferred 0.9:1 to
1.5:1. The
solution of a pharmaceutically acceptable salt of citalopram is cooled down to
a
temperature, the seeding temperature, in the range of 20-40 °C,
preferably 25-35 °C,
whereupon it is seeded with citalopraJn crystals and kept at said seeding
temperature
for a holding time for crystal grnwth in the range of 30 minutes to 7 days,
prefcrebly 1
hour to 4 days and more preferred 12 to 36 hours. After said holding time, the
to crystallisation batch is gradually cooled down in a controlled way from the
seeding
temperature to the temperature at which the crystals will be isolated from the
mother
liquor wherein said gradual cooling down is done over a time span in the range
of 5
minutes to 6 hours, preferably 1 S minutes to 4 hours aad more preferred 30
minutes to
2 hours_ 'Ihe crystals of said pharmaceutically acceptable salt of citalopram
are
preferably isolated from the mother liquor at a temperature in the range of 0-
20 °C,
more preferred 5-15 °C, using conventional separation techniques, e.g.
filtration.
The small crystals of a pharmaceutically acceptable salt of citalopram used ip
one
embodiment of the invention may be produced according to methods described in
US
4,136,193.
The crystals of citalopram base used in one embodiment of the invention may be
producod according to metbods described in NL patent No. 1016435.
xn the following, the invention is illustrated by way of examples. However,
the
examples are merely intended to illustrate the invention and should not be
constnred
as limiting.
CA 02353693 2001-07-24
Example 1
Crystallisation of citalopram hydrobromide into large crystals
Citalopram hydrobromide (200 g) is dissolved in a mixture of methanol (200 g)
and
water (20 g) at 69 °C. The solution is cooled down to 30 °C,
seeded with citalopram
hydrobromide crystals and kept at 30 °C for 24 hours, whereupon it is
cooled down to
°C within 1 hour. The cry. stals are isolated by filtration, washed
with cold methanol
and dried. The particle size distribution for the resulting crystals is listed
in table 1.
io
Ezamplc 2
Crystallisation of citalopram hydrobromide into large crystals
1s CitaJopram hydrobromide (12.0 kg) is dissolved in a mixture of methanol
(12.5 kg)
and water (1.2 kg) at reflux. The solution is cooled down to 30 °C,
seeded with
citalopram hydrobromide crystals (27 g) and kept at 30 °C for 16 hours,
whereupon it
is cooled down to 10 °C within 1 hour. The crystals are isolated by
filtration, washed
with cold (10 °C) methanol (3.5 kg) and dried. The particle size
distribution for the
2o resulting crystals is listed in table 1.
Example 3
Crystallisation of citalopram Lydrobromide Into small crystals
Citalopram hydrobromide (Z00 kg) is dissolved in a mixture of methanol (170 L)
and
acetone (680 L) at 56 °C. The solutioa is cooled down to 1 S °C,
seeded with
citalopram hydrobromide crystals (50 g), hexane (1600 L) is gradually added
within
60 minutes, whereupan the suspension is left standing with moderate stirring
and
3o cooling for 8 boors. The crystals are isolated by filtration, washed fast
with a cold (10
°C) mixture of acetone (s0 L) and hexane then with cold (10 °C)
hexane (220 L) and
dried. The particle size distribution far the resulting crystals is listed in
table 1
CA 02353693 2002-O1-29
to
Example 4
Crystallisation of citalopram as the free base.
Citalopram hydrobromide (101 g) is suspended in water (500 mL) and toluene
(500
mL). NaOH (60 mL, 5 N (aq)) is added and the mixture (pH>10) is stirred for 15
min
before the phases are separated. The organic phase is washed with water (2
x100 mL)
and filtered through a pad of filter help. The volatiles are removed in vacuo
and the
title compound is obtained as an oil. n-Heptane (400 mL) is added and the
mixture is
heated to 70 °C. On cooling, crystals forms. The white crystals of
citalopram base are
f ltered off and dried at ambient temperature over night in vacuo.
Table 1: Particle size distribution (Sympatec Helos) for citalopram
hydrobromide crystals and ProSolv SCMC90*
Quartile Example 1 Example Example ProSolv SCMC90
(%) (um) 2 3 (wm)
(um) (!gym)
95 465.43 549.42 96.96 279.94
90 342.89 352.23 72.27 231.66
50 96.87 52.70 14.04 114.17
10 16.54 11.97 1.19 32.10
5 8.23 6.67 0.82 20.56
Example 5
Tablet prepared by direct compression of small citalopram hydrobromide
crystals.
Tablet ingredients:
Citalopram, HBr 58_ 00 g (20 % w/w)
ProSolv SMCC90* 23055 g (79.5 % w/w)
Magnesium stearate 145 g (0.5 % w/w)
* (trademarks)
CA 02353693 2002-O1-29
11
Citalopram hydrobromide crystals from example 3 and ProSolv SMCC90 Were
blended at 7 rpm for 10 min in a 100 litre Bohle PTM 200 mixer. Magnesium
stearate
was added and blending continued for 3 min.
25 kg of the resulting mixture was tabletted (125.000 tablets/hour) on a 30
station
Fette P 1200/IC# tablet press fitted with oblong, embossed, scored 5,5 x 8 mm
punches. Tablet core weight was set to 125 mg. The nominal yield was 200.000
tablets. The tablet press was run until the mixture level was just above the
forced
feeder, i.e. the tabletting was continued as long as possible in order to
identify
1o possible segregation tendencies in the last quantities of mixture.
Tablet properties:
Diametrical crushing strength: 70 N
Disintegration time: 30 seconds
Friability: NA
Weight variation: 0.84% relative standard deviation (measured on 20 tablets)
Punch adhesion: None observed
Citalopram content in the composition during compression.
Tablets were sampled throughout the compression in order to measure
segregation
tendency. Since there is a significant size difference between the active
ingredient,
citalopram hydrobromide, and the inert filler, ProSolv SMCC90, as seen in
table 1, it
would be expected that the unequally sized components would segregate; i.e. de-
mix,
during transfer from blending vessel to tablet press hopper or sitting in the
tablet press
hopper during tabletting.
Sampling was performed 50 times at regular intervals during tabletting,
corresponding
to sampling at every 4000 tablets produced. Two tablets were withdrawn for
each
sample.
* (trademarks)
CA 02353693 2002-O1-29
12
The tablets were assayed by a validated method using UV-absorption in an
aqueous
solution, thus analysing in total 100 tablets. The relative standard deviation
in
citalopram content was 1.6%
The variability in tablet strength is surprisingly low in view of the small
particle size
of citalopram hydrobromide as compared to the inert filler.
One possible explanation for this surprising and beneficial result may be that
the
tendency to segregation between small citalopram crystals and larger filler
particles is
to uniquely balanced by the poor flow properties of the small crystals.
Example 6
Tablet prepared by direct compression of large citalopram hydrobromide
1s crystals.
Tablet ingredients:
Citalopram, HBr (20 % w/w)
2o ProSolv SMCC90* (79.5 % w/w)
Magnesium stearate (0.S % w/w)
Citalopram hydrobromide crystals from example 2 and ProSolv SMCC90 were
blended. Magnesium stearate was added and blending continued.
2S
Tablets (12S mg nominel weight) were produced.
The tablets had satisfactory technical properties.
* (trademarks)
CA 02353693 2002-O1-29
13
Example 6
Tablet prepared by direct compression of citalopram crystals.
Tablet ingredients:
Citalopram base (16 % w/w)
ProSolv SMCC90* . (83.3 % w/w)
Magnesium stearate (0.7 % w/w)
to
Citalopram base crystals from example 4 were sieved through sieve aperture of
0.3
mm and mixed with ProSolv SMCC90*for 3 minutes in a Turbula mixer. Magnesium
stearate was added and blending continued for 30 seconds.
Tablets were produced on a single punch tabletting machine Korsch EKO*
Tablet properties:
Tablet strength, mg: 20
Nominel tablet weight, mg: 125
2o Tablet diameter, mm: 7
Tablet shape: Film coating, special doomed
Diametrical crushing strength: 61.6 N
Disintegration time, min: < 1
Friability: 0.1
Mean tablet weight: 125.4
Weight variation: 0.22 % relative standard deviation
The tablets produced had satisfactory technical properties.
* (trademarks)
