Note: Descriptions are shown in the official language in which they were submitted.
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METHOD AND DEVICE FOR PRODUCING TABLETS
The present invention relates to a process and an apparatus for
producing tablets by melt extrusion.
European patent EP-B-0 240 906 discloses a process for producing
tablets by melt extrusion, in which an extrudable pharmaceutical
mixture is heated and extruded in the form of a continuous
product strip, the product strip which is still moldable is
compressed to a continuous tablet belt, the individual tablets in
the belt being connected together by product webs, the tablet
belt is allowed to cool, and the tablets are finally singulated
and deflashed.
In contrast to conventional processes which are based on the
compression of powders or granules, in the melt extrusion process
an active ingredient-containing melt of a thermoplastic,
water-soluble or water-swellable polymer is processed.
For this purpose, the individual components are first mixed and
then melted in an extruder. The mixing of the components may also
take place in the extruder. Suitable extruders are, for example,
single screw machines, intermeshing screw machines, multiscrew
extruders, especially twin screw extruders, which may be designed
to be corotating or counter-rotating and, where appropriate, may
be equipped with kneading disks. Suitable extruders are included,
for example, in the ZSK series from Werner & Pfleiderer.
The extruder may have a plurality of inlets. It is possible,
where appropriate, to provide separate addition of solid and
liquid ingredients of the mixture. It is additionally possible to
provide connectors for introducing inert gas and/or for
degassing. Since the mixing of the ingredients takes place. in the
extruder, it is normally possible to dispense with premixing. The
heated pharmaceutical mixture is expelled in the form of product
strips or belts through one or more dies, for example slit dies,
in the extruder head. The product strips or belts are then sent
to shaping means. Various means for shaping tablets from active
ingredient-containing melts are known. For example, the melt can
be compressed to tablets by a calendering process using
counter-rotating molding rolls. In this case, depressions
corresponding to the desired tablet shape are provided in one or
in both molding rolls. However, it is also possible to allow a
belt having depressions or apertures of the desired tablet shape
to pass through between two smooth calender rolls. The tablet
belt produced by calendering contains the shaped individual
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tablets, which are normally connected together by fine burrs or
product webs. These product webs may in fact be useful in the
shaping because they favor release of the tablet from the mold.
Concerning the procedure for the conventional melt extrusion
process, reference may be made not only to EP-B-0 240 906 but
also to EP-B-0 240 904, EP-B-0 337 256 and EP-B-0 358 105.
To produce single tablets from the tablet belt shaped in this
way, the belt is initially allowed to cool, and the cooled tablet
belts are put into a large vessel, which is made to rotate. The
mechanical stress arising thereby, which can be controlled within
certain limits by the quantity of tablets added, the size of the
vessel and its speed of rotation, leads to singulation of the
large, plate-like parts of the tablet belt stepwise to ever
smaller aggregates, until finally only a large proportion of
so-called "twins" still remains, which is singulated to
individual tablets as the process continues. Collision of the
tablets during rotation in the vessel abrades off the residues of
the burrs, so that the tablets are also deflashed simultaneously
with the singulation.
The known process for producing single tablets by melt extrusion
is, however, associated with disadvantages. Whereas the melt
extrusion process provides a continuous process for producing
tablets, the final singulation and deflashing process takes place
batchwise in vessels. Since the processing time in the vessel, in
particular for singulating the tablets from the tablet belt, is
relatively long, the possible productivity of a continuous tablet
production by melt extrusion is not exploited. In addition, it
has emerged that this simple singulation and deflashing process
in the vessel is not successful in all cases. In the particular
case of tablets having a score to facilitate dividing, the known
process leads to a high proportion of broken tablets, which must
be rejected mechanically and considerably reduce the yield.
Divisible tablets having a score have, however, in recent years
become increasingly frequently employed because it is possible
with them to adapt the dose, e.g. pediatric/adult dosage, with a
single tablet.
It is an object of the present invention to provide a process for
producing tablets by melt extrusion which firstly makes greater
productivity possible and, moreover, ensures production of
tablets which are easily broken, for example divisible tablets,
without unacceptably high loss rates. Another object of the
present invention is to provide an apparatus for carrying out the
process.
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We have found that this object is achieved by the process claimed
in the main claim herein.
The present invention accordingly relates to a process for
5 producing tablets by melt extension in which, in a manner known
per se, an extrudable, preferably pharmaceutical, mixture is
heated and extruded in the form of a continuous product strip,
the still deformable product strip is compressed to a continuous
tablet belt, the individual tablets in the belt being connected
10 together by product webs, the tablet belt is allowed to cool, and
the tablets are finally singulated and deflashed, wherein firstly
the tablets are mechanically singulated in a continuous process,
and then the singulated tablets are transported further and
subsequently deflashed.
Accordingly, the invention proposes that the combined singulation
and deflashing process which in known processes takes place in a
cylindrical vessel be carried out in two separate steps, with the
singulation process taking place continuously.
The process of the invention is associated with numerous
advantages. A continuous singulation of the tablet belt to single
tablets means that this step can take place at the same speed as
the shaping of the tablets by melt extrusion. The subsequent
deflashing step can take place in a vessel as in the process of
the invention. Preference is given to employment of coating
vessels known per se or machines used for film coating (for
example the Dria-Coater from Driam). Since it is no longer
necessary for singulation to take place in the vessel, the time
required for deflashing therein is distinctly reduced. The
overall result therefore is a saving in processing time compared
with the known process.
The separation, provided according to the invention, of
singulation and deflashing additionally allows the two processes
to be specifically adapted to particular requirements. Since it
is now necessary in the concluding deflashing step in the vessel
only to remove the residues of the burr present on the individual
tablets, the deflashing can be carried out under milder
conditions. In the prior art process, the energy input into the
vessel is considerably greater, because it is also necessary in
particular for the singulation of the larger tablet plates to
take place therein. The process of the invention can therefore be
employed with particular advantage in particular in the
production of tablets which break easily, such as, for example,
tablets with scores.
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For singulation of the tablet belt by the process of the
invention it is necessary to reduce the temperature of the
tablets until there is no bending or deformation of the tablets,
which may still be plastic, on exposure to a mechanical force.
In an advantageous embodiment of the process of the invention, a
force with a component perpendicular to the plane of the cooled
tablet belt is allowed to act on the belt to singulate the
tablets. This leads directly to a bending and subsequent breaking
of the tablet belt at the thin product webs which connect the
individual tablets together. The process functions very
efficiently in particular when the temperature of the tablet belt
is low enough for the thin product webs or burrs no longer to be
plastic, but to display a certain brittleness. However, it is
also possible to allow a force to act in the plane of the tablet
belt, so that the tablets are torn apart at the product webs.
This variant of the process of the invention can even be employed
when the temperature of the tablet belt is still high enough for
the product webs still to have a certain plasticity. However, a
particularly advantageous process is one in which there is both a
force acting perpendicular to the tablet belt and a force acting
in the plane of the tablet belt.
The perpendicular component of force is preferably generated by
diverting the solidified tablet belt out of its transport plane,
while the parallel component of force is generated by exerting a
traction force on the solidified tablet belt.
The present invention also relates to an apparatus for producing
tablets, in particular for carrying out the process of the
invention described above. The apparatus of the invention
comprises at least one extruder, means, downstream of the
extruder, for shaping a tablet belt, first transport means,
downstream of the shaping means, for the tablet belt and means
for singulating and deflashing the tablets. In the apparatus of
the invention, the means for singulating and deflashing the
tablets comprise at least one singulating means, arranged
downstream of the first transport means, and at least one
deflashing means, arranged downstream of the singulating means
and spatially separate therefrom. Suitable shaping means are
primarily two molding rolls which can be pressed against one
another, as described in the European patent EP-B-0 240 906
mentioned at the outset. The first transport means may be, for
example, a conveyor belt which serves primarily for cooling the
pharmaceutical melt which has been compressed to a tablet belt.
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The singulating means following the first transport means is
particularly advantageously designed as roller arrangement. In a
simple embodiment, the singulating means comprises at least one
rotatable roller for diverting the tablet belt out of a transport
5 plane of the first transport means. The melt, which is initially
still plastic, solidifies on the first transport means so that
the solidified tablet belt leaves the transport means in a plane
defined by the latter. It is possible to arrange a rotatable
roller immediately following the transport means, which roller
diverts the rigid belt for example downwards and thus exerts the
force, provided in the process of the invention, perpendicular to
the table belt. This diversion is associated with breakage of
the, now brittle, connecting webs between the tablets. In an
advantageous embodiment of the apparatus of the invention, the
singulating means is designed as two counter-rotating rollers
which can be pressed against one another. One of the rollers
rotates above and the other roller rotates beneath the tablet
belt. The rollers can be designed to be driveable. The speed of
rotation can be selected to be greater than the speed with which
the tablet belt is transported on the first transport means, so
that the rollers generate a traction force in the plane of the
tablet belt. The rollers can be arranged so that the tangential
plane of the slot through which the tablet belt passes forms an
angle with the plane of the tablet belt on the transport means,
so that once again diversion of the solidified belt is brought
about, leading to breakage of the tablet belt at the product
webs. The rollers or roller combinations used as singulating
means can easily be adapted to the different requirements of
specific tablet formulations. For example, it is possible to
employ rollers differing in surface structure. It is possible to
use, for example, smooth rollers, rollers with brushes or pins,
with bars or other structures. The force applied for the
singulation can be influenced by changing the arrangement of the
rollers, the diameter of the rollers and the contact pressure.
Other possibilities are different combinations of material, for
example foams, plastics, rubber or stainless steel. It is
possible in particular to influence the traction force in the
plane of the tablet belt through the speed of rotation of the
rollers.
In a preferred embodiment of the invention, the first transport
means has additional means for cooling the extruded and shaped
tablet belt. If the transport means is designed, for example, as
circulating conveyor belt it is possible to provide one or more
cooling plates underneath the upper part of the belt. The cooling
can be adapted to the specific requirements of the particular
tablet formulation through the length of the transport belt. With
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longer transport belts it is possible to divide the cooling
section into individual zones which are cooled separately, so
that a stepwise, easily controlled cooling process can be carried
out.
The cooling provided for the first transport means can, however,
also take place by air cooling. In this case, cooling from above
is possible, for example with cooling air being allowed to pass
over the shaped tablet belt. However, it is also possible to
design the transport belt with perforations and provide air
cooling from below. Cooling of the tablet belt can, however, also
take place, for example, by spraying with cooling water.
In a particularly preferred embodiment of the apparatus of the
invention, a second transport means is provided between the
singulation means and the deflashing means and comprises a
shaking or vibrating unit. The latter can be designed, for
example, as vibrating screen. After the singulation, the tablets
fall onto a vibrating screen and are transported thereon to the
deflashing means. Larger residues of the burrs are removed from
the tablets even on the vibrating screen, so that the processing
time for the deflashing is further reduced. It is also possible
for any "twins" still present after the singulation, that is to
say two tablets still connected by product webs, to be separated
on the vibrating second transport means.
The present invention is explained in more detail below with
reference to an example depicted in the drawings attached.
The drawings show:
Figure 1 a diagrammatic representation of an apparatus of the
invention for producing single tablets by melt extrusion;
Figure 2 a plan view of a tablet belt immediately after shaping
with the molding calender rolls; and
Figure 3 a section through the tablet belt of Fig. 2;
Figure 4 a plan view of a variant of the roller arrangement of the
singulating means;
Figure 5 a plan view of another embodiment of the breaking roller
of the singulating means.
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Figure 1 depicts an overall view of a preferred embodiment of the
apparatus of the invention. The extruder 10, which is depicted
diagrammatically, serves to mix and melt the pharmaceutical
mixture. An extruder head 11 of the extruder 10 has a slit die 12
out of which the plastic extrudate is expelled in belt form.
While still in the plastic state, the extrudate 13 reaches the
shaping means 20 which, in the present case, is formed by two
counter-rotating calender rolls 21, 23. Depressions 22 and 24,
whose shape in each case corresponds to one half of the tablet to
be produced, are formed in the surfaces of the rolls. The rolls
are mutually adjusted so that in each case two halves of the
shape coincide exactly in the contact region. In this contact
region the rolls form an intake slit 25, which extrudate 13
enters and is compressed to a tablet belt 14.
The tablet belt produced in this way is depicted in more detail
in Figures 2 and 3. The tablets 15 in the tablet belt 14 are
connected together by product webs 16. As is evident in
particular from the sectional depiction in Figure 3, the product
webs 16 are very thin compared with the tablets 15.
The tablet belt reaches, where appropriate via suitable
deflecting devices 17, a first transport means 30 which, in the
present case, is designed as belt conveyor unit. The conveyor
unit has a circulating conveyor belt 31 and two deflecting rolls
32, 33. In the example depicted there is also provision of
cooling means 70, with depiction by way of example of a
circulating air cooling 71 with a cooling unit 72 above the
tablet belt 14 and cooling plates 73 below the tablet belt 14.
The length of the conveyor belt 31 is chosen - depending on the
additional cooling means used - so that at the end of the
conveyor belt the product webs 16 have cooled so much that they
already have a certain brittleness. The substantially solidified
tablet belt on the transport means 30 defines a transport plane
34 - depicted by a broken line in Figure 1.
The singulating means 40 immediately follows the first transport
means 30 and consists in the present case of two rollers 41, 42
pressed against one another. The upper roller 41 is designed as
embossed roller, while the lower roller is designed as smooth
roller. The rollers are displaced slightly relative to one
another in the direction of transport of the belt and are,
moreover, arranged so that the slit 43 defined by the rollers is
located below the transport plane 34 of the solidified belt. It
is evident that the tangential plane 44 - depicted by a broken
line - of the slit 43 forms an angle with the transport plane 34,
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so that it is clear that the solidified band is diverted downward
on being guided through the slit 43. This diversion exerts a
force essentially perpendicular to the plane of the tablet belt
14, which causes the thin product webs 16 to break. In the
example depicted, there is also a guide device 45 provided for
the tablet belt between the two rollers 41 and 42 and the end of
the conveyor belt 31.
After passing through the singulating means, the tablets of the
belt are in the form of single tablets 18, some of which still
have residues of the product web on the periphery. The individual
tablets 18 fall onto a second transport means 16, which is
designed in this case as a shaking screen 61. The shaking screen
61 guides the individual tablets 18 into the deflashing means 50,
which consists of a rotating drum 52 with inlet opening 51.
During transport on the shaking screen 61, the residues of the
product webs are broken off the individual tablets 18 and enter a
collecting channel 62. The flash present on the tablets is
therefore now only very thin and is completely abraded off after
a short treatment time in the drum 52.
Figure 4 shows another variant of the roller combination of the
invention for the singulating means 40. The roller 46 rotating
above the tablet belt has longitudinal bars 47, while the lower
roller 48 has transverse bars 49 which are arranged essentially
perpendicular to the longitudinal bars 47.
Figure 5, finally, shows another variant of a breaking roller for
the singulating means 40'. The roller 46' has a plurality of
flexible thin plastic plates 47' oriented along the axis of the
roller 46'. The thin plates may be, for example, bonded or molded
onto the basic cylindrical element of the roller, or be secured
in slots formed therein. The thin plate roller 46' can be
employed as single breaking roller or together with a
counter-roller of similar construction or a smooth roller.
The term "tablet" is intended for the purpose of the present
invention to have the widest possible meaning. It is linked
neither to a particular shape nor to a particular application. It
therefore encompasses, for example, tablets for oral use, but
also tablets for example for rectal use in the form of
suppositories. In this connection, tablets also mean all dosage
forms suitable for use as pharmaceuticals, crop treatment
compositions, and human and animal foodstuffs, and for releasing
fragrances and perfume oils.
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Active pharmaceutical ingredients for the purpose of the
invention mean all substances with a pharmaceutical action and
minimal side effects as long as they do not decompose under the
processing conditions. The amount of active ingredient per dose
unit and the concentration may vary within wide limits depending
on the efficacy and rate of release. The only condition in this
connection is that they suffice to achieve their desired effect.
Thus, the active ingredient concentration can be in the range
from 0.1 to 95, preferably from 20 to 80, in particular from 30
to 70, percent by weight. The term active ingredient also
encompasses in the present connection any combinations of active
ingredients. Vitamins, for example, as also active ingredients
for a purpose of the invention. Particularly preferred active
ingredients are ibuprofen (as racemate, enantiomer or enriched
enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid,
verapamil, paracetamol, nifedipine and captopril.
The polymeric binder must soften or melt in the complete mixture
of all the components in the range from 50 to 180°C, preferably
60 to 130°C. The glass transition temperature of the mixture must
therefore be below 180°C, preferably below 130°C. If necessary,
it
is reduced by conventional, pharmacologically acceptable
plasticizing excipients. Suitable polymeric binders are
described, for example, in WO 97/15291.
Polymeric binders preferably employed for the melt extrusion of
active pharmaceutical ingredients are: polymers or copolymers of
N-vinylpyrrolidone, Eudragit types (acrylic resins) or
celluloses. Particular preference is given in this connection to:
polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and
vinyl esters such as vinyl acetate, poly(hydroxyalkyl acrylates),
poly(hydroxyalkyl methacrylates), polyacrylates, poly-
methacrylates, alkylcelluloses or hydroxyalkylcelluloses.
The extrudable mixture may, besides the polymeric binder and the
active ingredient(s), also contain conventional additives, for
example plasticizers, lubricants, flow regulators, dyes,
stabilizers or wetting agents, preservatives, disintegrants,
adsorbents, mold release agents and blowing agents. It is
likewise possible for conventional pharmaceutical excipients, for
example extenders and fillers, to be present. Suitable additives
and pharmaceutical excipients are described, for example, in
WO 97/15291.
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Examples
Comparative example 1
5 A mixture containing 48~ by weight of verapamil hydrochloride as
active ingredient and hydroxypropylcellulose, methylhydroxy-
propylcellulose and lecithin powder as excipients was processed
in a twin screw extruder (ZSK-58; Werner and Pfleiderer) to a
homogeneous melt. The melt throughput was 120 kg/h. The material
10 temperature shortly before the die of the extruder was about
120-130~C. The melt was discharged through a slot die in the form
of a sheet and shaped in a downstream molding roll calender to
elongate tablets (without score, about 20 mm long, about 5 mm
thick). The tablets left the calender in the form of a coherent
tablet belt. The tablet belts cooled on a transport belt with a
total length of about 4 m through radiation of heat to the
surrounding air.
At the end of the transport belt, 50 kg of the resulting tablet
belt were broken down manually into smaller pieces of belt which
were then introduced into a Driacoater pan (from Driam). The
singulation and deflashing took place with the drum rotating at
20 rpm. The entire process took about 40 minutes. It was possible
to singulate and deflash all the tablets.
Comparative example 2
The test took place as indicated in comparative example 1, but
the calendering resulted in elongate tablets (identical
length/width) with a score in the middle of the tablet. The
singulation and deflashing in the Driacoater resulted in about
10-30~ of the tablets being broken even during the rotation in
the Driacoater.
Example 1
The test took place as indicated in comparative example 1, but
with the following alterations:
- The transport belt contained at the end a brush roller
(diameter about 9 cm) which was driven by a separate driving
motor. The speed of rotation of the breaking rollers was
adjusted to suit the conveying speed of the transport belt.
- The calendering resulted in breakable tablets having a score
in the middle (score geometry as in comparative example 2).
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Satisfactory singulation of the tablet belts was possible with
the aid of the brush rollers. 50 kg of the singulated tablets
were then put in a Driacoater and deflashed with the drum
rotating at 5-10 rpm. Deflashing was complete after only
10 minutes. There was no detectable increase in the proportion of
broken tablets.
Example 2
The test took place as indicated in example 1, but in place of a
brush roller at the end of the transport belt there was a plastic
roller 450 mm long with 9 thin plates oriented in the long axis
of the roller (corresponding to the depiction in figure 5). The
basic element of the cylindrical roller, which consisted of POM,
had a diameter of 75 mm. The thin plates were made of flexible
PVC, were inserted about 15 mm deep into the roller element and
projected about 20 mm beyond the surface of the roller.
Satisfactory singulation of the belts of tablets with scores was
possible with the aid of the thin plate rollers. 400 kg of the
singulated tablets were then put in a Driacoater and deflashed
with the drum rotating at 5-10 rpm. Once again, there was no
detectable increase in the proportion of broken tablets.
30
40
