J. DRUG DEL. SCI. TECH.

, 17 (3) 199-203 2007

Formulation design and development to produce

orodispersible tablets by direct compression

L. Segale1, L. Maggi2*, E. Ochoa Machiste2, S. Conti2, U. Conte2, A. Grenier3, C. Besse3

1
Discaff, University of Piemonte Orientale, Via Bovio, 6, 28100 Novara, Italy
2
Department of Pharmaceutical Chemistry, University of Pavia, Viale Taramelli, 12, 27100 Pavia, Italy
3
Antares Pharma AG, Gewerbestrasse 18, Allschwil, 4123, Switzerland
*Correspondence: lauretta.maggi@unipv.it

Orodispersible tablets (OTs) are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed.
The object of the present work is to develop an OT formulation able to disintegrate in less than 30 s, characterized by acceptable technological
properties and suitable for an industrial production. We tested how the characteristics of different direct-compression excipients can influence
tablet disintegration and technological properties. The results show that mannitol guarantees the shortest disintegration time and the best tech-
nological and organoleptic properties. Starting from this excipient, to verify which is the effect of the tablets size and shape on the performance
and the technological properties of the dosage form, an OT formulation, containing a slightly soluble non-steroidal anti-inflammatory drug has
been scaled up preparing the tablets by direct compression and using punches of different size. The developed OT formulation maintains adequate
organoleptic, technological characteristics and disintegration ability, sizes ranging from 6.5 to 13 mm in diameter and it is possible to adapt this
formulation to different production needs.

Key words: Orodispersible tablets – Disintegration time – Direct-compression – Mannitol.

Orodispersible tablets (OTs) are uncoated tablets intended to be processing steps (drug-excipients blending and compression), reduced
placed in the mouth where they disperse rapidly before being swallowed process time and low application cost. It utilizes conventional tablet
[1]. These products combine the properties of solid dosage forms, such equipment and commonly available excipients; furthermore, it is
as stability, ease of manufacture and ease of handling (by patients) suitable for thermolabile and humidity-sensitive drugs. To produce
with the advantages of improved bioavailability, typical of liquid OTs by direct-compression with satisfactory technological, biophar-
preparations. After administration, the drug is immediately released maceutical and organoleptic characteristics, it is necessary to chose
from the dosage form and is readily available for absorption, improving appropriate excipients able to impart to the product the desired efficacy
its action onset. In some cases (soluble drugs), it is also possible to and a pleasant mouth-feel. An OT formulation should contain, together
achieve absorption of drugs across the oral mucosa directly into the with the active principle, bulking agents (the most widely used are
systemic circulation to some extent, avoiding first pass hepatic meta- sugar-based materials characterized by high water solubility, sweetness
bolism and related side effects. The product can be taken anyway and and good palatability), lubricants, disintegrants (to improve the tablet
at anytime: it does not require liquids to be swallowed and it is ready disintegration performance), sweeteners (to give pleasant taste), flavors
for use in emergency situations. These therapeutic systems have not to and taste-masking agents, which overcome the bad tastes of certain
be swallowed whole and this increases patient compliance, especially actives and allow maximal patient acceptability [16-18]. However,
for children, the elderly or patients with swallowing disorders [2-4]. the disintegration performance of this type of orodispersible tablets
Orodispersible tablets may be produced by various technological is affected, besides by their composition, by their size and hardness
processes (freeze-drying, molding, and direct-compression); there are (compression force applied).
advantages and limitations associated with each technology [5-7]. The Starting from this preamble, the object of the present work is to
freeze drying technique is able to guarantee the production of tablets design and develop a placebo OT formulation able to disintegrate in less
characterized by very porous structure ensuring rapid penetration of the than 30 s, much faster than the Pharmacopoeia limit [1], characterized
saliva into the pores and very rapid tablet disintegration, but lyophilized by acceptable technological properties (friability lower than 1% and
orodispersible tablets are very friable and highly sensitive to moisture acceptable crushing strength) and suitable for industrial production.
and reveal weak mechanical strength which does not allow standard In particular, the first aim of this study is to assess the influence of
packaging [8]. They require specific blisters (“peel-off” blisters): the various direct-compression excipients and the suitable compression
patients do not have to push the tablet through the foil film, but instead force applied on the performance and technological properties (fria-
peel the film back to release the tablet [9]. Molding technology is an bility, crushing strength, disintegration time) of these drug delivery
efficient method of OTs production, the tablets show good disintegra- systems. Different placebo formulations have been tested; they have
tion properties and mouth-feeling but they are not resistant to handling the same composition except for the type of the bulking agent used.
during manufacturing and packaging processes [10]. A good OT formulation should guarantee good technological,
Freeze-drying and molding technologies involve the use of specific biopharmaceutical and organoleptic properties of the products and
equipment which causes high production costs; therefore the develo- these characteristics should be as independent as possible of the
pment of a simple and cheap production method becomes a research compression force applied.
purpose. The second object of the work is to investigate the effect of the
Direct-compression is a good way to produce orodispersible ta- tablets mass, size and shape on the physical parameters of the dosage
blets; it is the right compromise among economical, manufacturing forms [19]. In this case, the best placebo formulation (able to satisfy
and technological needs [11-15]. In fact, it has a limited number of technological, biopharmaceutical and organoleptic needs at the same

199
J. DRUG DEL. SCI. TECH., 17 (3) 199-203 2007 Formulation design and development to produce
orodispersible tablets by direct compression
L. Segale, L. Maggi, E. Ochoa Machiste, S. Conti, U. Conte, A. Grenier, C. Besse

time) among those tested in the first part of the work, has been selec- for force compression measurements (Kistler, Winterthur, Switzerland)
ted and a model active, Meloxicam, has been included. Each batch and equipped with flat punches of 8 mm in diameter. OTs, 110 mg in
of orodispersible tablets has been prepared by direct compression, at weight, have been produced by applying suitable compression forces.
a suitable compression force, using a single punch tableting machine For all formulations prepared, the mass uniformity of the tablets has
equipped with punches having different diameters. Obviously, the been checked, all the batches obtained are in compliance with Phar-
tablet weight has been adjusted to the punch dimensions, maintaining macopoeia specifications and standard deviation is always lower than
the same proportions among the excipients except for drug dose which 2.65 %.
is fixed. In the second part of the work, starting from the best placebo for-
Moreover, an accelerated stability study has been conducted on mulation and adding the active molecule, Meloxicam, orodispersible
orodispersible tablets to verify whether they are able to maintain their tablets with different sizes have been prepared using an alternative
disintegration performance and their technological properties over single punch tableting machine (Korsch, Berlin, Germany) equipped
time. with various flat or convex punches to verify which tablet shape
influences the technological properties. In particular, flat punches of
I. MATERIALS AND METHODS 6.5, 7, 8, 10, 11, 12 and 13 mm in diameter and concave punches of
1. Materials 7, 8, 9, 10 and 12 mm have been employed.
Isomalt (Isomalt DC100, Tillmanns, Spain); maltitol, maltodextrin The composition has been kept constant for all the batches produced,
(Maltisorb P200, Glucidex IT19, Roquette, France); mannitol of two while the tablet weight has been adapted to the punch dimensions: the
different particle sizes Pearlitol 100SD and Pearlitol 200SD, Roquette, ratio tablet diameter/mass used 6.5, 7 mm/125 mg; 8-10 mm/235 mg;
France (coded mannitol 100SD and mannitol 200SD); microcrystal- 11-13 mm/455 mg.
line cellulose (Avicel PH101, FMC, Pennsylvania, USA); corn starch All batches have been tasted by six volunteers to verify their
(Carlo Erba, Italy); trehalose (C* Ascend Trehalose 16400, Cerestar, organoleptic properties and have been characterized for mass unifor-
Belgium) and xylitol (Xylitab 200, Xyrofin, Finland) have been used mity, porosity, hardness, friability, disintegration time in water and
as bulking agents; methacrylic acid copolymer (Eudragit L100-55, in simulated saliva. Placebo samples have been tested immediately
Rohm Pharma Polymers, Germany), generally used as pH-sensitive after production, while OTs containing the active principle have been
polymer [20-22] but in this case included due to its disintegrating tested after production, after 12 months at room temperature and after
properties [18] and cross-linked polyvinylpyrrolidone (Kollidon CL, 6 months of storage under accelerated conditions [23].
BASF); magnesium stearate (Carlo Erba, Italy) and colloidal silicon
oxide (Syloid 244, Grace, Worms, Germany) as lubricant and glidant. 2.2. Tablet porosity
Other excipients were aspartam (Pancosma, Switzerland) and mint The percentage porosity of the compacts has been calculated using
flavor powder (Givaudan, France). In the second part of the work, the relationship p = (1-dapp/dtrue) × 100, where p is the porosity of the
a slightly soluble non-steroidal anti-inflammatory drug, Meloxicam compact, dapp is its apparent density (calculated from the ratio of tablet
(AMSA, Milan, Italy), has been included in the formulation by repla- mass to the tablet volume) and dtrue is the true density of the particles,
cing 15 mg of bulking agent with 15 mg of drug. determined using a helium pycnometer (AccuPyc 1330, Micromeritics).
The tablet dimensions (diameter and thickness) have been measured
2. Methods using a manual micrometer and the volume calculated.
2.1. Tablet preparation
In the first part of the work, nine placebo batches of tablets have 2.3. Tablet crushing strength
been prepared: they show the same size, same weight, same concen- A hardness tester has been used to measure tablets crushing
tration of disintegrants, but they differ according to the type of the strength: the tablet has been placed on a flat surface and the load has
direct-compression filler. From previous experience, the following been applied along its diameter by a movable platen; the tablets have
formulations percentage composition were selected (Table I). been broken along their diameter in a single fracture into two pieces
Formulations contain alternatively isomalt, maltitol, maltodextrin, of similar size and the fracture force has been recorded (MeCoDarec,
mannitol of two different particle sizes, corn starch, trehalose, xylitol Type 1675, Kistler, Italy). Ten tablets of each batch, at each compression
as fast-melting bulking agents with suitable organoleptic properties force level, have been analyzed; the mean hardness and its standard
and microcrystalline cellulose (Avicel PH101), as direct-compression deviation have been calculated and expressed in Newton.
excipient used as a reference material but characterized by worse
organoleptic mouth-feel. 2.4. Tablet friability
All the formulation components, except lubricant, have been mixed Tablet average weight and friability have been determined on 20
for 20 min using a tumbling mixer (Turbula, T2A, Bachofen, Basel, samples for each batch using respectively an electronic balance and
Switzerland) at 45 rpm, then magnesium stearate has been added a friabilator (Erweka, type TA3R) at 25 rpm for 4 min. The friability
and the blend mixed again for 3 min. The batch size was from 500 to has been expressed in terms of weight loss and has been calculated
700 g. The samples have been obtained by direct compression of the in percentage of the initial weight; according to Pharmacopeia speci-
powder mixtures using an alternative single punch tableting machine fications, friability under 1% has been considered acceptable.
(Kilian, Coln, Germany) instrumented with piezoelectric transducer
2.5. Tablet disintegration time
The disintegration test has been performed in two fluids at 37°C
Table I - Percentage composition of the nine placebo formulations.
using the disintegration test apparatus (Erweka, type ZT3). Nine
Formulation composition % hundred millilitres of distilled water have been used as disintegration
Bulking agent 72.5 medium, and to simulate the tablets’ condition in the oral cavity (pH,
Type-C polymethacrylate (Eudragit L 100-55) 8.0 salt concentration, etc), the test has also been carried out in simulated
Crospovidone (Kollidon CL) 10.0 saliva (pH 6.00). The composition of the artificial saliva used is: KCl
Mint flavour 6.5 1.20 g/L, MgCl2 6H2O 0.05 g/L, CaCl2 6H2O 0.15 g/L and KSCN
Aspartam 1.0 0.10 g/L [18]. The disintegration time has been expressed as the
Magnesium stearate 1.5 average of six determinations (± SD).
Syloid 244 0.5

200
Formulation design and development to produce J. DRUG DEL. SCI. TECH., 17 (3) 199-203 2007
orodispersible tablets by direct compression
L. Segale, L. Maggi, E. Ochoa Machiste, S. Conti, U. Conte, A. Grenier, C. Besse

2.6. Stability studies 200

The OTs have been tested after 12 months of storage in PE bottles, Isomalt - water Isomalt - simulated saliva

at room temperature (25°C and 60% relative humidity), besides an 180 Maltodextrin - water Maltodextrin - simulated saliva

accelerated stability test has been conducted according to the guidelines 160 Xylitol - water Xylitol - simulated saliva

suggested by ICH for solid dosage forms [23]: the samples, closed in
Trehalose - water Trehalose - simulated saliva
140
PE bottles, have been kept under artificial ageing conditions (40°C and

disintegration time (s)

120
75% relative humidity) for 6 months. After these periods, the samples
have been tested to verify whether, under the influence of different
100

conservation conditions, they are able to preserve their properties and 80

characteristics. 60

The standard deviations are not reported in the table to provide 40

clearer comprehension. 20

II. RESULTS AND DISCUSSION 0

An ideal excipient intended for direct compression in orodispersible

0 200 400 600 800 1000 1200 1400

tablets should show not only specific technological, but also good or-
compression force (kgf)

ganoleptic properties. It should be free flowing, chemically, physically Figure 1 - Disintegration time in water and in simulated saliva of isomalt,
and physiologically inert, relatively inexpensive and have excellent maltodextrin, xylitol and trehalose OTs as a function of compression
compressibility. Moreover, it should have a pleasant and sweet taste; force.
it should not be cariogenic and guarantee good mouth-feel to ensure
patient compliance. 80
Disintegration behavior, crushing strength and friability of orodis-
Maltitol - water

Maltitol - simulated saliva

persible tablets depend on the applied compression force during tablet 70

Avicel - water

production and on the excipients characteristics (compactability and 60

Avicel - simulated saliva

deformability) which influence the porosity of the solid final product.

Corn Starch - water

Corn Starch - simulated saliva

disintegration time (s)

Figures 1 and 2 show the disintegration time in water and in simulated 50 Mannitol 100 SD - water

saliva of the nine placebo formulations tested as a function of the com-

Mannitol 100 SD - simulated saliva

40 Mannitol 200 SD - water

pression forces applied. The reference excipient (Avicel, Figure 2) could Mannitol 200 SD - simulated saliva

be suitable for this type of formulation, since Avicel OT disintegration 30

time in water and in simulated saliva is always under the limit set (30 s). 20
However Avicel has an unpleasant mouth-feel and this formulation is not
accepted by volunteers. Similarly, corn starch OTs have an unpleasant 10

mouth-feel and, although they are characterized by a constant disinte- 0

gration performance in water, in a wide range of compression forces 0 400 800 1200 1600 2000 2400 2800 3200
(from 1,300 to 3,200 kg), this excipient must be compressed at very compression force (kgf)
high levels to reduce friability. All the other OT formulations have a
Figure 2 - Disintegration time in water and in simulated saliva of maltitol,
pleasant taste. In the case of isomalt, maltodextrin, xylitol (Figure 1),
Avicel, mannitol (100SD and 200SD) and corn starch OTs as a function
and maltitol (Figure 2) OTs, by increasing the compression force, the
of compression force.
tablet disintegration performance in water becomes worse. In particular,
the formulations containing maltodextrin and maltitol show disintegra-
tion times over the limit set, for all the compression forces considered, 110

while trehalose, xylitol and isomalt tablets have short disintegration

Isomalt
100

times only at the lowest compression forces applied. Moreover, for all
Maltodextrin
90

these formulations, except for trehalose, it is possible to evidence too

Xylitol
80

high increases in disintegration times as a function of slight increases

Maltitol
crushing strength (N)

70
in the compression force applied; this condition is incompatible with
Avicel

60
industrial tablet production.
Trehalose

50
Only mannitol 200 SD exhibits both a very nice taste and ap-
Corn Starch

40
preciable disintegration characteristics: short disintegration times
Mannitol 100 SD

over a wide compression force interval and moderate variation of

30 Mannitol 200 SD

tablet disintegration behavior correlated to valuable increases in the

20

compression forces; this makes mannitol 200 SD OTs an interesting 10

prototype for industrial scaling-up. 0

The same results have been obtained when the disintegration 0 400 800 1200 1600 2000 2400 2800 3200

test is carried out in simulated saliva (pH 6.00): in this medium, the compression force (kgf)

disintegration times of all formulations are slightly faster than in Figure 3 - Crushing strength versus compression force for all OT
water. Maltodextrin is completely out of the set limit; isomalt, xyli- formulations tested.
tol and maltitol are out of the limit only at the highest compression
force level, while trehalose OTs disintegrate in an acceptable time rapid disintegration time: therefore, ideal OT formulation requires a
at all compression forces applied. The mannitol 200 SD, Avicel and compromise among disintegration, hardness and friability.
corn starch satisfy the target, however mannitol 200 SD and starch Plotting tablet crushing strength versus compression forces
are better than Avicel because their disintegration time values remain (Figure 3), it is possible to show that Avicel OTs exhibit high tablet
almost constant over a wide range of compression forces. hardness. Maltodextrin, maltitol and starch tablets are too weak
In the case of OTs, the need to produce tablets with good me- (crushing strength lower than 20 N) at all compression forces; iso-
chanical properties contrasts with the need to produce tablets with malt, xylitol and trehalose samples show sufficient hardness only at

201
J. DRUG DEL. SCI. TECH., 17 (3) 199-203 2007 Formulation design and development to produce
orodispersible tablets by direct compression
L. Segale, L. Maggi, E. Ochoa Machiste, S. Conti, U. Conte, A. Grenier, C. Besse

the highest compression force. The two types of mannitol OTs have 8
good mechanical resistance. Isomalt Maltodextrin

Similar results are obtained considering tablet friability as a 7 Xylitol Maltitol

function of compression forces (Figure 4): only Avicel OTs show 6

Avicel Trehalose

friability under 1%, even if these tablets were produced at very low Corn Starch Mannitol 100 SD

compression force level. All the other OTs (except mannitol) always 5 Mannitol 200 SD

show friability exceeding 1%; furthermore a slight variation in the

friability %
4
compression force applied results in a considerable variation in the
friability. The two mannitol formulations show acceptable friability, 3

from moderate to high compression forces. 2

Tablet porosity, influencing tablet hardness and friability, depends
on compression force, but, while hardness and friability improve by 1

increasing the compression force applied, porosity is inversely pro-

portional to the pressure at which tablets have been compressed. For
0

this reason, to obtain a good product, it is necessary to find the poro-

0 400 800 1200 1600 2000 2400 2800 3200

sity which guarantees quick water absorption and, as a consequence,

compression force (kgf)

short disintegration time, but also high mechanical strength and low Figure 4 - Friability versus compression force for all placebo formula-
friability at the same time [24]. tions tested.
The relationship between disintegration time in water of the
nine placebo formulations and their porosity is reported in Figure 5. 180
Maltodextrin, maltitol, xylitol, isomalt and trehalose show a clear Isomalt - water Maltodextrin - water

trend: the sample disintegration performance improves according to 160 Xylitol - water Maltitol - water

an increase in porosity. Maltodextrin, maltitol, and trehalose samples 140

Avicel - water Trehalose - water

show disintegration times over the set limit. Xylitol and isomalt are
Corn Starch - water Mannitol 200 SD - water
120 Mannitol 100 SD - water
characterized by a satisfactory disintegration behavior only at the
disintegration time (s)

highest porosity levels at which friability is too high; only the two
100

mannitol types, avicel and corn starch tablets disintegrate in less than 30 80

seconds at almost all porosity values. In many cases, there is a marked 60

decrease of the disintegration time as a function of a slight increase
in porosity (maltodextrin, xylitol and isomalt). Outstandingly, only
40

the two mannitol formulations present disintegration times within the 20

set limit (less than 30 s) over a wide range of porosity. In view of all 0
the aforementioned test results, it is clear that the OT formulations 14 16 18 20 22 24 26 28 30 32 34 36 38
which satisfy all the study requirements are those containing micro- porosity %
crystalline cellulose and the two types of mannitol as bulking agents.
Figure 5 - Effect of tablets porosity on disintegration time in water for
However, mannitol possesses two important advantages compared
all placebo OTs tested.
to microcrystalline cellulose. First, mannitol OT formulation allows
not only the production of OTs with high disintegration ability and mannitol with the largest particle size (mannitol 200SD) show the best
good hardness and friability, but, unlike Avicel formulation, is able to agreement between technological, biopharmaceutical and organoleptic
maintain these properties under the set limits in a wide range of com- properties.
pression forces. This is a very important requirement for an industrial For all these reasons, mannitol 200 SD has been preferred for the
scale-up. Second, and equally important, mannitol OT formulation is second part of the work which investigates the influence of tablet size
superior to Avicel OT formulation from an organoleptic perspective: on the technological properties and disintegration ability.
mannitol OTs are sweet and have a very pleasant mouth-feel; on the The results of the tests carried out to characterize meloxicam-
contrary, Avicel OTs have a very unpleasant “sandy” mouth feel (taste, mannitol 200SD OTs with different diameter and shape are reported
sensation of grittiness). The two mannitol formulations studied show in Table II: the compression force to produce these batches has been
similar results, but it is possible to demonstrate that the OTs containing set so that disintegration times both in water and in simulated saliva

Table II - Technological characteristics of drug-loaded mannitol 200SD OTs of different shape and diameter. Immediately after production (t = 0), after
12 months at room temperature (t = 12 RT) and after 6 months of storage in accelerated stability conditions at 40°C and 75% RH (t = 6 AS).
Punches DT water (s) DT simulated saliva (s) Hardness (N) Friability (%)
diameter
t=0 t = 12 RT t = 6 AS t=0 t = 12 RT t = 6 AS t=0 t = 12 RT t = 6 AS t=0 t = 12 RT t = 6 AS
(mm)
6,5 flat 17 7 7 10 7 7 10 13 13 0.9 1.1 2.7
7 flat 18 8 7 8 8 6 14 22 22 0.1 0.6 0.9
7 concave 24 9 7 13 8 7 21 24 21 0.3 0.6 0.6
8 flat 19 11 9 13 10 9 39 36 38 0.3 0.2 0.6
8 concave 16 10 9 13 10 8 32 31 33 0.6 1.0 1.8
9 concave 16 9 8 12 8 7 31 24 28 0.3 0.1 0.9
10 flat 13 8 6 9 8 6 31 18 20 0.5 0.6 1.8
10 concave 15 7 6 9 7 6 22 16 17 0.4 0.2 1.0
11 flat 15 13 11 15 13 11 33 36 39 0.2 0.4 1.2
12 flat 19 13 10 17 13 10 56 53 60 0.6 0.8 1.2
12 concave 19 13 10 11 12 10 40 42 48 0.2 0.4 0.7
13 flat 18 12 10 15 11 9 48 49 54 0.3 0.5 0.3

202
Formulation design and development to produce J. DRUG DEL. SCI. TECH., 17 (3) 199-203 2007
orodispersible tablets by direct compression
L. Segale, L. Maggi, E. Ochoa Machiste, S. Conti, U. Conte, A. Grenier, C. Besse

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Deliv Technol, 3, 58-61, 2003.
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