PHARMACEUTICALS Crystalline sorbitol.

A pharmaceutical
excipient for direct
compression

INTRODUCTION hydrogenation of D-glucose. According to

JACQUES MICHAUD the crystallisation process, differences in
Cerestar
Production of tablets by direct crystal morphology are obtained, which
Application Centre Pharma & Chemical compression is a more and more popular have an influence on the tabletting
Vilvoorde, Belgium technique. It is a simpler procedure, behaviour of sorbitol. Depending upon
which involves only dry blending and the application Cerestar has developed
subsequent compaction, and can two types of sorbitol powder: the P-grade
therefore be considered as being a more and the S-grade. Both grades fulfil the
efficient and economical process. Of requirements of a direct compression
course the choice of the excipients is far excipient.
more critical, since they must fulfil The differences in crystal morphology
specific requirements. But with the makes the P-grade the excipient of
availability of more suitable excipients for choice for sugar-free lozenge-type tablets,
direct compression, this method while the S-grade is more suitable for
becomes more and more applied. chewable tablets.
Cerestar is participating in this trend
by developing excipients that combine
both good compressibility and MATERIALS AND EQUIPMENT
flowability.
As direct compression diluents Materials
several polyols are used, from which
sorbitol tends to be the most widely CSorbidex P 16616
used in several pharmaceutical CSorbidex P 16656
Figure 1 - SEM of CSorbidex P 16656 at
formulations. Its CSorbidex S 16603
30 magnifications specific properties Ascorbic acid (Merck)
make sorbitol an Magnesium stearate (Pharmachemic
attractive trading)
excipient for
sugar-free
formulations. It is Powder Properties
50% as sweet as
sucrose and due Morphological study - Figures 1
to the absence of and 2 show the SEM pictures of two
fermentation by different grades of Cerestar Sorbitol.
the oral bacteria, Moisture content was determined by
sorbitol does not the method of Karl Fischer, a
Figure 2 - SEM of CSorbidex P 16603 at
lead to tooth titrimetric method of water
30 magnifications
decay. Its determination, according to the USP
negative heat of 23/NF 18.
solution helps Density measurement, loose and
impart a pleasant, tapped, was carried out using a
sweet and Stamfvolumetre JEL. The loose
cooling sensation density was calculated from the
in the mouth. powder mass and the volume
Sorbitol is (250 ml). The cylinder was then
produced by the tapped for 5 minutes, until the
catalytic volume did not change anymore. The

62 JANUARY/FEBRUARY 2003 PHARMACEUTICALS

Table I - Physical characteristics of the different sorbitol grades pharmacopoeia, was considered as
acceptable.
CSorbidex CSorbidex CSorbidex
P 16616 P 16656 S 16603
Mass median diameter (m) 200 250 250 RESULTS
Angle of repose 32.6 30.6 29.3
Loose density (g/l) 585 655 710 Placebo Tablets
Tapped density (g/l) 765 820 825
Carr Index (%) 23.5 20.1 13.9 In the following pre-formulation
Hausner ratio 1.30 1.25 1.16 study of the different sorbitol grades
the products were compressed with
only the addition of 1% magnesium
volume was read again, giving the compression force were selected and stearate. The relationship between
tapped density. tested on weight, hardness, thickness the crushing strength, expressed as
Powder flow was determined by and diameter using an Erweka, model tensile strength, and the compression
means of the measurement of the TBH. The mean of 20 weights, hardness, force is shown in Figure 3. Due to
angle of repose and the relationship thickness and diameter values were differences in morphology the P- and
between the loose and tapped calculated and for all measurements the S-grade show different tabletting
density, being the Carr Index and relative standard deviations were behaviour. The P-grade provides
Hausner ratio (1). The angle of calculated. The crushing strength of 20 harder tablets and is therefore more
repose was measured with tablets of each compression force is suitable for the manufacturing of
Pharmatest equipment. expressed by means of the tensile lozenges. The S-grade, on the
Particle size analysis was strength (TS), using the following contrary, yields softer tablets and is
determined by laser light scattering equation: therefore more suitable for chewable
(Sympatec). TS = 2 H / T D tablets. For both grades the tablets
Some physical characteristics of did not cap during
different CSorbidex grades Figure 3 - Compression profile of the different sorbitol grades ejection from the tablet
are shown in Table I. Lubricated with 1% magnesium stearate press at high
compression forces.
The properties of
Tablet Making the obtained tablets are
shown in Table II. The
All formulations were made flow is excellent for the
with 1% magnesium stearate. S-grade, due to its
Size analysis was specific morphology.
performed by sieving each But also the flowability
product over a sieve of of the P-grade is good,
0.8 mm. Of each formulation, as demonstrated by the
batches of 1 kg were mixed very low weight
together in a low shear mixer variations. The Carr
for 3 minutes. Tablets were Index and the Hausner
compressed on a Korsch ratio, as shown in
rotative triple punch tabletting Table I, also support this
press. Flat-faced punches were point. Thus it can be
used throughout this work. concluded that neither
Compression forces (upper and for the S-grade, nor for
lower punches) were recorded using where H is the mean crushing strength, the P-grade the addition of a glidant
a Hottinger-Baldwin system of D is the mean diameter and T is the is necessary. The good flowability of
measuring and recording ejection mean thickness of the tablets. Additional both sorbitol grades is also
forces. The tabletting force varied 20 tablets of each compression force investigated on an experiment on
from 5 kN up to 30 kN. The speed of were used for the test on friability, which speed. Tabletting at different speed
tabletting was 40 rpm. An additional was determined on a Pharmatest. The limits, ranging from 40 rpm to
test on speed, 60 and 80 rpm at a pre-weight tablets were rotated for 100 80 rpm at a compression force of
compression force of 20 kN, was rotations and then re-weight. A weight 20 kN, still gives efficiently hard
carried out to investigate the loss of less than 1%, required by the tablets. This again is an indication of
flowability of the different sorbitol
grades. The obtained tablets had a Table II - Tablet properties of the different sorbitol grades.
target weight of 350 mg and a Lubricated with 1% magnesium stearate and compressed at 15 kN
surface of 1 cm2.
CSorbidex CSorbidex CSorbidex
P 16616 P 16656 S 16603
Tablet Testing
Average tablet weight (mg) 357 337 348
Variation of tablet weight (%) 0.18 0.27 0.33
After compression all tablets were Tablet diameter (mm) 11.3 11.28 11.29
allowed to stand in tightly closed Tablet thickness (mm) 2.51 2.30 2.51
containers for 24 hours before testing. Tablet crushing strength (N) 265 221 177
Analyses of the tablets were done Tablet tensile strength (N/mm2) 5.94 5.43 3.98
according to the methods prescribed by Tablet density (g/ml) 1.42 1.47 1.39
the European Pharmacopoeia. From Friability (%) 0.53 0.32 0.81
each batch 20 tablets of each

PHARMACEUTICALS JANUARY/FEBRUARY 2003 63

the good flow of both sorbitol
grades. That sorbitol is not a speed
sensitive material is shown in
Table III. The relationship between
how a solid consolidates and the
influence of speed on the tablet
quality has already been described
(2). Solids that compress by
deformation are more speed
sensitive than solids that
consolidate by fragmentation.
Fragmentation can be regarded as
Figure 4 - Effect of ascorbic acid on the tensile strength
(15 kN - 40 rpm)
an instantaneous process.
Deformation, on the other hand,
takes a finite time, which means
that as punch speed increases there
is not enough time for the full
Figure 5 - Calculation of the dilution potential
deformation and these materials
will only consolidate to a reduced
extent. For both sorbitol grades, at
higher punch speed, only a very low
reduction of tensile strength is
noticed, which is an indication of
compression by fragmentation.
Friability results were for both
sorbitol P- and S-grades largely under
the required pharmacopoeial limit of
1%, even at the lower compression
forces.
64 JANUARY/FEBRUARY 2003
Table III - Influence of speed on the tensile
strength at a compression force of 20 kN
Speed CSorbidex CSorbidex
P 16616 P 16656
40 rpm 5.3 4.2
60 rpm 4.9 4.5
80 rpm 4.9 3.8
% reduction 7.5 9.5
Ascorbic Acid Tablets
In pharmaceutical
formulations excipients are
always used in combination
with drugs and other
excipients, therefore it is
necessary to demonstrate
the compatibility in terms of
compressibility with other
products. In a formulation
study ascorbic acid, which is
used as a model drug, is
blended in different ratios,
ranging from 5% up to 50%,
with both S- and P-grade.
Formulations were blended
by the method of dilution
and lubricated with 1% magnesium
stearate. Figure 4 shows the
relationship between the amount of
ascorbic acid added to the formulation
and the tensile strength. For both
grades the
tensile
strength
decreases
only steadily
with
increasing
ascorbic acid
percentage,
which
indicates a
high capacity
(3). In general
the capacity is
expressed by
the dilution
potential as
being an
indication of the maximum amount of
other material that can be compressed
with the excipient, while still
obtaining tablets of Table IV - The dilution potential of different sorbitol
acceptable quality. By using grades. Lubricated with 1% magnesium stearate
an identical method to that
of assessing the effect of % Ascorbic acid
reworking (4) the dilution
potential can be calculated.
Tablets composed only out
of the S- or P-grade
(formulation A) and out of
a mixture of sorbitol and
ascorbic acid (formulation B)
were made at different
CSorbidex compression forces, ranging
S 16603 from 5 to 30 kN. On the
4.4 compression profile of both
4.2 formulations it is possible to
4.0 calculate the dilution
9.1
potential (Figure 5, Table IV),
which is the ratio under both
profiles.
Dilution potential = 100
Area under comp. curve of form. A
Area under comp. curve of form. B
CONCLUSION
This study describes the compression
characteristics of both the P- and
S-grade, Cerestar has especially
developed for direct compression. The
weight variation is very low and there is
no problem of workability during
tabletting, even at high speed. Hard
tablets are obtained for the P-grade,
which makes it suitable for the
manufacturing of lozenges. For the
S-grade, which is more recommended
for chewable tablets, the hardness of
the tablets is slightly lower. Both sorbitol
grades show high compatibility with
other excipients or drugs and the ability
to carry high quantities of active
ingredients is demonstrated by the high
dilution potential.
REFERENCES
1. WELLS, J.I. Pharmaceutical Preformulation, the
Physicochemical Properties of Drug
Substances, in Series in Pharmaceutical
Technology; Rubenstein, H.M. Ed.; Ellis
Horwood Limited: Chichester, UK, 1st Ed.,n,
1988, pp. 209-214
2. ARMSTRONG, N.A. Int. Journal of
Pharmaceutics 1989, 49, 1-13
3. MINCHON, C.M.; ARMSTRONG, N.A. J. Pharm.
Pharmacol. 1989, 39, 69P
4. MALKOWSKA, S.; KAHN, K.A. Drug Dev. Ind.
Pharm. 1983, 9, 331-347
CSorbidex CSorbidex
P 16616 S 16603
15 75 85
25 62 75
50 30 34
PHARMACEUTICALS