Process and apparatus for the production of divisible tablets

A process for the production of divisible tablets by melt calendering in which two molding rolls are combined together, at least one of which has depressions with at least one bar which extends up to the surface line of the molding roll and forms a score.

The present invention relates to a process for the production of divisible 
tablets by molding a melt which contains an active ingredient in a 
calender with counter-rotating molding rolls which have on their surface 
depressions for receiving and molding the tablet composition (melt 
calendering). 
The production of tablets by calendering a melt containing an active 
ingredient is disclosed in DE-A 1 766 546 and U.S. Pat. No. 4,880,585. The 
basis of this process is the embedding of an active ingredient in a melt 
of a carrier, eg. fatty substances or water-soluble thermoplastic 
polymers. The melt is produced by melting the mixture of active 
ingredient, polymer and, where appropriate, other ancillary substances, 
for example in an extruder, and molding the melt in a downstream molding 
calender to give tablets, which harden on cooling. The molding calender 
comprises a pair of counter-rotating molding rolls which have on their 
surface corresponding engravings (depressions) which correspond to the 
shape of one half of the required tablet. The tablet molding takes place 
in the region of contact of the two rolls by combination of the tablet 
composition in one depression on one roll with that in the opposite 
depression on the other roll. Calendering of the melt containing an active 
ingredient as disclosed in U.S. Pat. No. 4,880,585 took place using a pair 
of molding rolls with identical depressions. In this way each molding roll 
provides an identically shaped half of the tablet so that the resulting 
tablets are symmetrical. 
It is often desirable for tablets to be divisible in order to be able to 
alter the dosage without the need to produce individual tablets for each 
particular dosage. However, the production of divisible tablets by 
calendering has met with considerable difficulty. Attempts have been made 
to provide the molding rolls with depressions which afford tablets which 
are visually identical to the divisible tablets produced by conventional 
tableting techniques. This has been brought about by leaving, when cutting 
out the depressions, a small rib, often in the micrometer range, in the 
middle of the bottom of each depression, which leads to formation of what 
is called the score (on each half of the tablet, on both sides) in the 
finished tablets. However, the manufacture of such molding rolls entails a 
considerable increase in cost. This is because, after the depressions have 
been cut out, a polishing is necessary to smooth the surface. This is 
possible in such a case only manually and meets with considerable 
difficulties because of the ribs present in the depressions. 
It is an object of the present invention to provide a process for the 
production of divisible tablets by melt calendering which can be 
implemented in a simple and cost-saving manner. 
We have found that this object is achieved by combining two molding rolls 
together, at least one of which has depressions which are separated from 
one another by at least one bar which extends essentially as far as the 
surface line. 
The present invention therefore relates to a process for the production of 
divisible tablets by molding a melt containing an active ingredient in a 
calender with two counter-rotating molding rolls which have depressions 
for receiving and molding the melt to tablets, wherein at least one 
molding roll in which the depressions are divided by at least one bar 
which extends essentially as far as the surface line of the molding roll, 
and forms a score, is used. 
The tablets are formed by combination of the depressions on the first 
molding roll with the corresponding depressions on the second molding 
roll. The bar present in the depressions is relatively narrow and leads to 
formation of the score on molding of the tablets. 
In a preferred embodiment there is use of a first molding roll in which the 
depressions are divided by n bars, and a second molding roll with 
corresponding depressions divided by n' bars. In this case, n' is in the 
range from 0 to n-1. 
The number n of bars in the depressions on the first roll depends on the 
number of parts the tablets are to be divisible into. In the simplest and 
commonest case, this number will be one (n=1). If a tablet half obtained 
therewith is combined with a tablet half resulting from a depression with 
n'=n-1=0, ie. no bar, on the second roll, the result is a tablet which can 
be divided into two parts. Normally, the bar divides the depressions on 
the first roll into two equal parts (essentially mirror-image identical) 
so that the resulting tablet can be divided into two equal parts. The two 
parts of a depression on the first roll can, however, also be different, 
ie. the result in this case is a tablet which can be divided into two 
different parts, for example one part can comprise 1/3 and the other can 
comprise 2/3 of the tablet, so that it is also possible conveniently to 
administer 1/3 or 2/3 of the amount of active ingredient contained in the 
tablet. This embodiment with n=1 and n'=0 is particularly advantageous for 
producing divisible oblong tablets and lenticular tablets. 
The number of bars n' in a depression on the second molding roll is not 
more than n-1. This number can, however, also be lower and is therefore in 
the range from 0 to n-1. For example, depressions with two bars (n=2) on 
the first molding roll can be provided for combination with corresponding 
depressions without bar or with one bar on the second molding roll (n'=0 
or 1). The result in this case is a tablet which can be divided into 
three, or a tablet which can be both divided into three (n=2; n'=0) and 
halved (n=2; n'=1). 
Depending on the contact pressure of the molding rolls it is possible to 
produce a "chain" of two, three or more tablets, from which any required 
number can be taken off in order to alter the dosage, or (with a higher 
contact pressure) individual divisible tablets. 
In a particularly preferred embodiment, the second molding roll is a smooth 
roll, ie. it has no depressions. It is possible in this way to bring about 
a substantial alteration in the dosage at a given concentration of active 
ingredient in the melt by altering the number of bars in the depressions 
on the first roll. In order to obtain divisible tablets, either the bar 
terminates a short distance below the surface of the molding roll, or the 
contact pressure between the two molding rolls is relatively low, or there 
is in fact a small distance between the molding rolls (eg. 0.1-1 mm) when 
the bar extends up to the surface. 
The latter embodiment moreover has advantages compared with all the others 
based on a combination of two molding rolls with depressions. In the 
production of tablets by means of two molding rolls with depressions, the 
latter must in each case be exactly opposite to one another so that the 
tablet halves which are formed are not displaced with respect to one 
another, which makes great demands on the precision of production of the 
depressions and of rotation of the molding rolls. The displacement problem 
does not, by contrast, occur with a combination with one smooth molding 
roll because, in this case, there are not two tablet halves which might be 
displaced with respect to one another. This embodiment is therefore 
particularly suitable for smaller tablet forms in which even very small 
inaccuracies in managing the calendering molding rolls have very great 
effects on the appearance of the tablets. 
The tablets are produced starting from a mixture which contains one or more 
pharmaceutical active ingredients and one or more conventional ancillary 
substances and which becomes a paste or viscous liquid, and can therefore 
be extruded, by melting or softening of at least one component. 
These are, in particular, mixtures containing pharmacologically acceptable 
polymers (with the glass transition temperature of the mixture being below 
the decomposition temperature of all the components of the mixture), for 
example polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) 
and vinyl acetate, copolymers of vinyl acetate and crotonic acid, 
partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, ethylene/vinyl 
acetate copolymers, poly(hydroxyethyl methacrylate), copolymers of methyl 
methacrylate and acrylic acid, cellulose esters, cellulose ethers, 
polyethylene glycol or polyethylene, preferably NVP copolymers with vinyl 
acetate, hydroxypropylcellulose and polyethylene glycols/polyethylene 
oxides. The K values (H. Fikentscher, Cellulose-Chemie 13 (1932) 58-64 and 
71-74) of the polymers are in the range from 10 to 100, preferably 12 to 
70, in particular 12 to 35, for PVP preferably 12-35, in particular 12-17. 
The polymeric binder must soften or melt in the complete mixture of all the 
components in the range from 50 to 180, preferably 60 to 130.degree. C., 
so that the composition can be extruded. The glass transition temperature 
of the mixture must therefore always be below 180, preferably below 
130.degree. C. It is if necessary reduced by conventional 
pharmacologically acceptable plasticizing ancillary substances such as 
long-chain alcohols, ethylene glycol, propylene glycol, 
trimethylolpropane, triethylene glcyol, butanediols, pentanols, hexanols, 
polyethylene glycols, silicones, aromatic carboxylic esters (eg. dialkyl 
phthalates, trimellitic esters, benzoic esters, terephthalic esters) or 
aliphatic dicarboxylic esters (eg. dialkyl adipates, sebacic esters, 
azelaic esters, citric and tartaric esters) or fatty acid esters. 
Examples of conventional pharmaceutical ancillary substances, whose total 
amount can be up to 100% by weight based on the polymer, are extenders 
such as silicates or diatomaceous earth, stearic acid or salts thereof, 
eg. the magnesium or calcium salt, methylcellulose, sodium 
carboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch, 
potato flour, polyvinyl alcohol, also wetting agents, preservatives, 
disintegrants, absorbents, colorants, flavorings (cf., for example, H. 
Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978). 
Pharmaceutical active ingredients mean for the purpose of the invention all 
substances with a pharmaceutical effect 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 activity and rate of release. The only condition 
is that they suffice to achieve the desired effect. Thus, the 
concentration of active ingredient can be in the range from 0.1 to 95, 
preferably from 20 to 80, in particular 30 to 70, % by weight. It is also 
possible to use combinations of active ingredients. Active ingredients for 
the purpose of the invention are also vitamins and minerals, as well as 
crop treatment agents and insecticides. 
The process according to the invention is suitable, for example, for 
processing the following active ingredients: 
acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, 
alfacalcidol, allantoin, allopurinol, ambroxol, amikacin, amiloride, 
aminoacetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, 
ampicillin, ascorbic acid, aspartame, astemizole, atenolol, 
beclomethasone, benserazide, benzalkonium hydroxide, benzocaine, benzoic 
acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol, prazosin, 
bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, 
buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, 
carboplatin, carotenoids such as .beta.-carotene or canthaxanthin, 
cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, 
ceftazidime, ceftriaxone, cefuroxime, celedilin, chloramphenicol, 
chlorhexidine, chlorpheniramine, chlortalidone, choline, cyclosporin, 
cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, 
clarithromycin, clavulanic acid, clomipramine, clonazepam, clonidine, 
clotrimazole, codeine, cholestyramine, cromoglycic acid, cyanocobalamin, 
cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, 
dextropropoxiphene, diazepam, diclofenac, digoxin, dihydrocodeine, 
dihydroergotamine, diltiazem, diphenhydramine, dipyridamole, dipyrone, 
disopyramide, domperidone, dopamine, enalapril, ephedrine, epinephrine, 
ergocalciferol, ergotamine, erythromycin, estradiol, ethinylestradiol, 
etoposide, Eucalyptus globulus, famotidine, felodipine, fenofibrate, 
fenoterol, fentanyl, flavin mononucleotide, fluconazole, flunarizine, 
fluorouracil, fluoxetine, flurbiprofen, furosemide, gemfibrozil, 
gentamicin, Ginkgo biloba, glibenclamide, glipizide, clozapine, 
Glycyrrhiza glabra, guaifenesin, haloperidol, heparin, hyaluronic acid, 
hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone, 
ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol, 
iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, 
ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose, 
lecithin, levocarnitine, levodopa, levoglutamide, levonorgestrel, 
levothyroxine, lidocaine, lipase, lipoic acid, lisinopril, loperamide, 
lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate, 
methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole, 
midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin 
mixtures or combinations and mineral salts, N-methylephedrine, 
naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, 
nicotine, nicotinic acid, nifedipine, nimodipine, nitrendipine, 
nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, 
nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, 
pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, 
pentoxifylline, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, 
polymyxin B, povidone-iodine, pravastatin, prednisolone, bromocriptine, 
propafenone, propranolol, pseudoephedrine, pyridoxine, quinidine, 
ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, 
rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, 
somatropin, sotalol, spironolactone, sucralfate, sulbactam, 
sulfamethoxazole, sulpiride, tamoxifen, tegafur, teprenone, terazosin, 
terbutaline, terfenadine, theophylline, thiamine, ticlopidine, timolol, 
tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, 
trimethoprim, troxerutin, uracil, valproic acid, vancomycin, verapamil, 
vitamins B.sub.1, B.sub.2, B.sub.4, B.sub.6, B.sub.12, D.sub.3, E, K, 
folinic acid, zidovudine. 
In a few cases, solid solutions may form. The term "solid solutions" is 
familiar to the skilled person, for example from the literature cited at 
the outset. In solid solutions of pharmaceutically active ingredients in 
polymers, the active ingredient is present in a molecular dispersion in 
the polymer. 
The pharmaceutical mixture is then melted in a conventional way, preferably 
in an extruder, and fed to the molding calender as described, for example, 
in U.S. Pat. No. 4,880,585. If necessary, the tablets are cooled after the 
calendering, eg. in an air or cooling bath. 
In the case of sticky or highly viscous materials which are detached from 
the mold only with difficulty or not at all, it is expedient to use a mold 
release agent, for example a silicone oil, silicone paint, triglyceride or 
lecithin. 
The tablets can, if required, be provided with a covering, in particular to 
mask the taste or to make the tablets distinguishable by color or for 
packaging. For this purpose, the melt containing active ingredient is fed 
between two sheets of the covering material into the molding rolls. 
The covering material can be selected from a wide range of materials. The 
only requirement is that the material is pharmaceutically acceptable. 
Covering materials which are suitable for producing film-coated tablets and 
which rapidly dissolve in the acidic gastric fluid are sheets of, for 
example, gelatin, polyvinyl alcohol, alkylcelluloses such as 
methylcelluloses, hydroxyalkylcelluloses such as hydroxyethyl-, 
hydroxypropyl- or hydroxypropylmethylcellulose, polyvinylpyrrolidone, 
certain acrylic resins such as copolymers based on dimethylaminoethyl 
methacrylate and methacrylates (Eudragit E) etc. 
The covering material can, if required, contain a colorant or a pigment or 
else another active ingredient. 
In another embodiment, the sheets used are those suitable for packaging the 
tablets. These are, in particular, water-insoluble thermoforming sheets, 
the preferred material being polyethylene, polypropylene, polyvinyl 
chloride, polyethylene terephthalate, polystyrene, aluminum or coated 
aluminum. The tablets are in this way immediately sealed in a blister 
pack. The separate packaging step which is otherwise customary is thus 
unnecessary and, moreover, it is possible in this way to pack the tablets 
aseptically in an extremely simple manner, especially when care is taken 
that the outer edges of the tablet strip are sealed airtight. 
It has emerged that there is not, as expected, vigorous adhesion of the hot 
tablet composition to the water-insoluble thermoforming sheet so that 
later removal of the tablets from the pack would be impeded or even 
impossible. 
It has proven particularly advantageous for packaging the tablets to 
combine a molding roll with the depressions for receiving and molding the 
tablet composition with a smooth roll. This results in "half" tablets 
which are sealed in a blister pack which has on one side depressions for 
receiving the tablets and is closed on the other side with a smooth sheet 
which can be pulled off. In this case, an aluminum sheet or a sheet of 
coated aluminum has proven particularly expedient for closing the pack. 
It may also prove to be expedient not to allow the packaged tablets to cool 
in air, as otherwise usual, but to provide a separate cooling step. 
Suitable for this purpose is a water bath, stream of cold air etc. This 
prevents the tablets in the pack cooling too slowly, which may lead to 
subsequent deformation of the tablets. 
It is also possible to use the sheets for the film coating of the tablets 
and the sheets for the blister-packaging of the tablets simultaneously. In 
this case, the melt in the molding rolls is covered by the sheet for the 
film coating and simultaneously sealed in the packaging sheet. 
The shape of the depressions, and thus of the tablets obtainable according 
to the invention, can be chosen substantially as desired. Besides the 
oblong tablets already mentioned, lenticular tablets have proven to be 
particularly expedient. The molding rolls used to produce them have 
depressions in the shape of segments of an ellipsoid, in particular of a 
sphere. The angle between the tangential surface of the depressions at the 
upper edge and the tangential surface of the molding roll (at the 
intersection between the depression and the surface of the roll) is 
&lt;90.degree., preferably &lt;45.degree., in this case. The lenticular tablets 
have the advantage that deflashing thereof is particularly easy. 
The present invention also relates to an appliance (calender) for carrying 
out the process according to the invention with two counter-rotating 
molding rolls which are in contact where appropriate along a surface line 
and have depressions for receiving and molding the melt to tablets, 
wherein at least one molding roll has depressions which are divided by at 
least one bar which extends essentially up to the surface of the molding 
roll and forms a score. 
In general, said bar extends up to the surface of the molding roll. 
However, in some cases, it may be expedient for the bar not to extend 
completely to the surface line, i.e. it terminates a short distance below 
the surface line. This increases the stability of the resulting tablet. 
In a preferred embodiment, the first molding roll has depressions which are 
divided by n bars, while the corresponding depressions on the second 
molding roll are divided by n' bars, where n' is in the range from 0 to 
n-1. 
The depressions on the second molding roll are expediently deeper than 
those on the first molding roll. The result is then asymmetric tablets in 
which the "half" without score is larger than the "half" with score. The 
risk of breakage during packaging or on inappropriate handling is 
considerably less with tablets of this type. 
A first molding roll which has depressions with a bar is preferably 
combined with a second molding roll which has a corresponding depression 
without bar. 
In another embodiment, a first molding roll which has depressions with two 
bars (n=2) is combined with a second molding roll which has corresponding 
depressions without bar (n'=0) or with one bar (n'=1). 
In a particularly preferred embodiment, a first molding roll which has 
depressions with at least one bar is combined with a smooth roll. 
The invention is explained in detail hereinafter by means of the drawing 
and the examples.

FIG. 1 shows a prior art molding roll 1. It has depressions 2 for receiving 
and molding the molten tablet composition to tablets. At the bottom of 
these depressions there are ribs 3 which are perpendicular to the 
longitudinal axis of the molding rolls and which have been left on cutting 
out the depressions. Combining together two such prior art molding rolls 1 
and producing tablets by melt calendering results in elongate tablets 4, 
called oblong tablets of the type shown in FIG. 2. These tablets have a 
score 5 which allows the tablet to be broken into two equal parts. 
FIG. 3 shows a combination according to the invention of a first molding 
roll 6 with a second molding roll 8. The molding roll 6 has three 
identical, immediately adjacent depressions 2. These depressions are each 
divided by a bar 7 which extends to the surface of the molding roll 6. The 
second molding roll 8 likewise has three directly adjacent depressions 2 
of corresponding shape. In the case shown, all the depressions 2 are 
separated from one another only by a narrow flash 13 which, in the case 
shown, essentially corresponds to the bar 7. However, it is also possible 
for a larger space, ie. a wider flash 13, to lie between the depressions 2 
used to form a tablet. 
The peripheral line around the depressions 2 in the molding roll 6 (in the 
surface of the molding roll) corresponds to the peripheral line around the 
depressions in the molding roll 8, ie. the base areas of the resulting 
tablet halves correspond to one another, so that the two halves can be 
joined together to give a tablet. 
This results in divisible tablets 9 of the type shown in FIG. 4. They have 
a score 5 which makes it possible to divide the tablets into two equal 
halves. 
As mentioned above, the precision in the production and rotation of the 
molding rolls must be very great in order to avoid displacement between 
the upper and lower halves of the tablet. A displacement of this type 
between tablet halves 10 and 11 is shown in FIG. 5. Such a displacement 
between the tablet halves is avoided with the combination, shown in FIG. 
6, of a first molding roll 6 with five bars 7 with a second molding roll 8 
which is designed as smooth roll. The combination of molding rolls shown 
in FIG. 6 results, with a relatively low contact pressure or with a small 
distance between the molding rolls, in a "chain" of "half tablets" 12 of 
the type shown in FIG. 7. It is possible for this type of tablets in 
particular to be produced with very small dimensions so that the dosage 
can be varied within a wide range by the choice of the size of the 
depressions and the length of the "chain" of the tablets. 
EXAMPLE 1 
A mixture of 60.0% by weight of Kollidon VA-64 (BASF) (polyvinylpyrrolidone 
copolymer with vinyl acetate (60:40)) and 40.0% by weight of lactose 
monohydrate was extruded in a twin screw extruder (ZSK-40, 
Werner+Pfleiderer) under the following conditions: 
______________________________________ 
Temperatures: 
______________________________________ 
Shot 1: 80.degree. C. 
Shot 2: 100.degree. C. 
Shot 3: 130.degree. C. 
Shot 4: 130.degree. C. 
Dies: 135.degree. C. 
Material throughput: 
25 kg/h 
Screw speed: 160 rpm 
______________________________________ 
The melt was fed into a molding calender with two molding rolls of the type 
shown in FIG. 3. This resulted in tablets as depicted in FIG. 4. They 
could be easily and smoothly broken into two equal halves. 
Tablets were produced in a corresponding way using the combination of 
molding rolls shown in FIG. 6. This resulted in tablets as depicted in 
FIG. 7. 
The calender and molding rolls useful for the present invention can be 
cooled or heated in a manner known per se and the optimum surface 
temperature of the rolls for the relevant processing step can be adjusted 
in this way.