Professional Documents
Culture Documents
Powder Technology
journal homepage: www.elsevier.com/locate/powtec
a r t i c l e
i n f o
Article history:
Received 17 December 2013
Received in revised form 10 June 2014
Accepted 14 June 2014
Available online 23 June 2014
Keywords:
Lubrication
External lubrication
External surface area
Roll compaction/dry granulation
Compression
Tablet
a b s t r a c t
Lubrication can strongly inuence tablet characteristics like strength, disintegration and dissolution and thus
should be performed appropriately taking properties of the materials into account. As magnesium stearate
coats the particles, determination of the specic external surface area could be an approach to nd the optimal
lubricant amount to prevent sticking, to obtain a minimal reduction in strength and to generate a comparable lubrication between different dry granules and the starting powdered material. Therefore, in this study a surface
proportional lubrication was investigated in comparison to a mass related internal and an external lubrication
for ve different materials (two types of microcrystalline cellulose, powder cellulose, magnesium carbonate
and lactose). The specic external surface areas of different dry granules as well as of the starting powdered materials were determined. Prior to tableting an amount of magnesium stearate proportional to the specic external
surface area (2.5 g/cm2) was added. For each material specic external surface area of the granules was smaller
than that of the raw material. Hence, the amount of magnesium stearate added to the granules was much lower
(0.10.25 (w/w) %) compared to the raw material (0.762 (w/w) %). Compaction curves for the granules showed
a decrease in tensile strength of the corresponding tablets with increasing specic compaction force during roll
compaction. Based on this work-hardening phenomenon, compression of the raw material should lead to the
strongest tablets. In contrast to this, compactibility of direct compressed microcrystalline cellulose and powder
cellulose was much lower compared to the granules. As both materials are lubricant sensitive, the added amount
of magnesium stearate was too high and prevented particle bonding. For magnesium carbonate, compactibility of
the raw material was still higher compared to the granules in spite of the tenfold lubricant quantity. Further experiments with equal amounts of magnesium stearate for powder and granules of magnesium carbonate were
problematic, indicating an insufcient lubrication of the powdered magnesium carbonate in this case.
External lubrication was practicable for all materials, brittle or plastically deforming, and resulted in the highest
tablet tensile strength. As lubrication was in the same magnitude for different materials and lubrication proportional to the specic external surface area was not practicable for plastically deforming materials, external lubrication should be the method of choice.
2014 Elsevier B.V. All rights reserved.
1. Introduction
Tablets are one of the most popular solid dosage forms, as production of large quantities is feasible and cost-effective and patients accept
this dosage form well. The starting material, e.g. powder or granules, is
lled into a die and pressure is applied by punches, compressing it into a
tablet. Tableting is usually not possible without small quantities of a lubricant in order to reduce wall friction during compression and ejection
out of the die and to prevent sticking of the material to the punches.
Different lubricants are available on the market like fatty alcohols,
fatty acids, metal salts of fatty acids and mono-, di- and triglycerides.
Magnesium stearate is most commonly used, as it is more effective
Corresponding author. Tel.: +49 211 81 14220; fax: +49 211 81 14251.
E-mail addresses: johanna.mosig@hhu.de (J. Mosig), kleinebudde@hhu.de
(P. Kleinebudde).
http://dx.doi.org/10.1016/j.powtec.2014.06.022
0032-5910/ 2014 Elsevier B.V. All rights reserved.
157
158
SV
Sm
SV
k
m
g
A
L
V
h
Sm
1 m g A
3
t h 2 i
Z
cm
2
dV 1
k
L
h
SV
"
#
2
cm
g
the use of the cross-sectional area (A) of the sample holder and the
determined material density (Table 1). For the particle shape factor
(k) an often in literature proposed value of ve was used [26]. As the
is not possible, a calibration step for the
solving of the integral dV
h
Friedrich manometer has to be performed, to determine an instrument
constant. For this, the specic BET surface area of three types of glass
spheres was determined (Tristar, Micromeritics Instrument Corporation, Norcross, USA), as well as the ow time in the Friedrich manometer (Table 2). Using the experimental derived values, Eq. (1) can be
dV
(Table 2). For further experiments the instrument consolved for
h
dV
stant ( ) was chosen to be 2.27, as the mean of the results for the
h
three different glass sphere types.
For determination of the specic external surface area approximately 100 g of material was lled in the graduated powder container, to
gain material heights of 30 2 cm. Pre-tests showed an experimental
sensitivity for different powder bed porosities. Due to this, the material
was tapped 1250 times within the powder container (volumetric
analyzer, J. Engelsmann AG Apparatebau, Ludwigshafen, Germany) to
keep the porosities comparable. Flow time was determined in triplicate
for each sample preparation and each material was measured three
times.
Specic external surface area was calculated according to Eqs. (1)
and (2) using the determined instrument constant.
2.2.5. Particle size distribution
The particle size of the starting materials was determined by laser
diffraction (Helos H1402+, Sympatec, Clasuthal-Zellerfeld, Germany).
Measurements were performed with the dry dispersing unit (Rodos,
Sympatec, Clausthal-Zellerfeld, Germany) and a dispersing pressure of
1 bar. Starting materials were measured three times and the distributions were evaluated by the instrument software. The particle size distributions of granules from each specic compaction force were
determined in triplicate by digital image analysis (Camsizer XT, Retsch
GmbH, Haan, Germany). The X-Jet module was used and a dispersing
pressure of 0.3 bar applied to avoid agglomeration of the particles as
well as a destruction. The quantiles of the particle size distributions
within the fraction 315 to 630 m were calculated using the instrument
software.
2.2.6. Lubrication
Granule fractions and raw powder materials were lubricated
with different amounts of magnesium stearate (MgSt). Two different
methods were used for the internal lubrication. In one case, materials were lubricated with an amount of magnesium stearate proportionally to the determined specic external surface area. For this,
2.5 g magnesium stearate per square centimeter external surface
area of the material was added to the granules as well as to the raw
materials. 2.5 g/cm2 was the lowest amount, which allowed tableting
for all components including lactose and magnesium carbonate. A higher
amount would result in even larger quantities for direct compression.
Furthermore, the raw materials were lubricated with concentrations of
0.10.5% (w/w) of MgSt. Powder and granule material were blended
for 2 min with magnesium stearate in a Turbula mixer (42 U/min, T2C,
Willy A. Bachofen AG, Basel, Switzerland) for the internal lubrication
and tableted. External lubrication was achieved by manually lubricating
punches and die by an eye shadow applicator.
Table 1
Helium density of the materials (n = 3, mean).
Density [g/cm3]
MCC
Powder cellulose
Magnesium carbonate
Lactose
1.594
1.596
1.559
2.305
1.544
0.073 0.001
0.043 0.004
0.034 0.006
dV
h
2.34 0.34
2.29 0.32
2.17 0.08
2.2.7. Tableting
Direct compression (DC) and granule compression were performed.
Flat-faced 8 mm tablets of 200 mg mass were produced on an instrumented rotary die press (PressIMA, IMA Kilian, Cologne, Germany)
with a rotation speed of 10 rpm. Seven compression pressures between
60 and 418 MPa were applied. Tablets were stored for 48 h after
production at 21 C and 45% relative humidity and characterized due
to their weight (CP 224S, Sartorius AG, Gttingen, Germany) height
and diameter (Digimatic Caliper, Mitutoyo, Hoshima, Japan) and
crushing force (TBH 210, Erweka GmbH Apparatebau, Heusenstamm,
Germany). The tensile strength was calculated according to Fell and
Newton [27]. Compactibility was dened as the ability to form compacts
of a specic tensile strength under pressure.
3. Results and discussion
3.1. Specic external surface area
Granulation decreased the specic external surface area. For all powdered materials, specic surface area was in the range between 3000
and 8400 cm2/g, whereas granules offered a specic surface area between 400 and 1000 cm2/g (Table 3). The raw material is declared
with 0 kN/cm, as the material was not subjected to a roll compaction
process and no pressure was applied prior to tableting. Measured
specic surface areas were smaller as BET surface areas reported in
literature. BET measurements detected the total surface area, internal and external. Measurements of the specic external surface
area acquired neither pores nor surface roughness and resulted
therefore in the smallest detectable surface area and could be performed by calculations out of the particle size distribution [26].
Permeatry measurements detected primarily the external surface
area, whereby surface structures (e.g. cavities) are included to a certain degree.
Comparing the ve different raw materials, magnesium carbonate
(Mg) offered the highest specic surface area whereas the other four excipients revealed comparable specic surface areas. Specic external
surface area for both types of MCC, normal density (M) and high density
(Ms), as well as for lactose (L) and powder cellulose (Pc) was approximately half of these of magnesium carbonate. This huge difference
could not be explained by the particle size. Although magnesium
carbonate offered a much smaller x50 value compared to MCC and powder cellulose, lactose presented a comparable small mean particle size
(Table 4). Even if the interquartile range is smaller as for lactose (64.1
159
to 88.1 m), the differences in the specic surface area of 5000 cm2/g
will not be a result of this, but may be caused by the particle structure
of the magnesium carbonate.
Freitag [28] pointed out that the particles were agglomerated and by
particle size measurements just the diameter of these agglomerates
were detected. SEM pictures of the magnesium carbonate showed the
agglomerate structure of the particles (Fig. 3d). Detected particles are
composed of much smaller particles. Due to the granular structure, specic surface area of the magnesium carbonate powder is higher compared to the other four materials, even if the measured particle size is
comparable.
Increasing the specic compaction force within the dry granulation
step resulted in a decrease in the specic external surface area of the
granules (Fig. 2). According to Jaminet and Hess [29], this is caused by
an increase in particle size. They demonstrated, that with increasing
compaction force stronger ribbons were produced which resulted in
coarser particles after the dry granulation step. Measurements of the
particle sizes within the fraction conrmed this suggestion. Table 5
showed the x50 values for the different batches and an increase in the
particle size with increasing roll compaction force is observable for
MCC, powder cellulose and magnesium carbonate. Lactose revealed
the lowest decrease and also the overall lowest specic surface area.
In contrast to the other investigated materials, granule size of lactose
did not increase over an increase in the specic compaction force
(Table 5). Parrot [30] also observed a lower increase in particle size
after roll compaction for the brittle behaving lactose compared to the
other investigated materials. This low tendency for particle growth
with increasing compaction force could implicate the observed low decrease of the specic surface area with increasing force.
The sharpest reduction of the specic surface area was found for
both types of MCC due to the plastically deforming behavior of microcrystalline cellulose under pressure. Specic surface area as well as the
decrease over an increasing force was higher for the normal MCC. Particle size measurements (Table 5) for the granules showed, that the increase in size is more pronounced for the normal density MCC. As the
increase in size was about 6% compared to 3% for the high density
MCC, the stronger decrease in the specic surface area with increasing
roll compaction force can be attributed to this. The overall higher surface area of the normal density MCC can be explained by differences
in the granule structure. SEM pictures (Fig. 4a,b) showed, that the brous structure of the primary particles persisted in the granules in contrast to the high density MCC. Granules from powder cellulose and
magnesium carbonate exhibited overall the highest specic surface
area and, comparable with lactose, a small decrease with increasing
compaction force during granulation. According to the starting materials, these differences could not be explained solely by the particle
size of the granules. SEM pictures (Fig. 4c,d) showed that the particle
shape properties of the starting materials survived the compaction
step and lead to the observed higher specic surface area compared to
the other investigated materials. Particularly the brous shape of powder cellulose granules, which is more pronounced compared to the normal density MCC will result in larger particle surfaces compared to
round particles. Just for the lowest specic compaction force of 2 kN/
cm the specic external surface area of MCC surmounted those of powder cellulose and magnesium carbonate.
Table 3
External surface area [cm2/g] of the different powder materials and granules (mean sd; n = 3).
Specic compaction
force [kN/cm]
0
2
8
12
MCC
4174
991
617
526
3489
838
529
436
259
12
6
11
Magnesium carbonate
8320
883
675
620
407
52
15
14
Powder cellulose
3715
972
758
752
233
8
3
33
Lactose
3022
578
479
398
346
37
15
43
160
Table 4
10%, 50% und 90% quantiles of the particle size distribution of the starting materials [m] (mean s; n = 3).
x10
x50
x90
MCC
MCC
(high density)
Magnesium
carbonate
29.36 0.18
103.37 0.27
219.57 0.06
24.67 0.32
102.37 0.98
207.95 0.58
5.76 0.25
31.18 0.36
69.83 0.30
Fig. 2. Specic external surface area [cm2/g] of the different granules of MCC, normal (M)
and high density (Ms), powder cellulose (Pc), magnesium carbonate (Mg) and lactose (L)
(mean sd; n = 3).
Powder cellulose
26.55 0.08
66.59 0.54
134.53 2.56
Lactose
3.77 0.03
26.93 0.15
91.82 0.28
161
Fig. 3. SEM pictures of the starting materials, MCC with normal density (a), with high density (b), powder cellulose (c), magnesium carbonate (d) and lactose (e).
Table 5
Mean particle size [m] of the granules between 315 and 630 m (mean s; n = 3).
Specic compaction force
2 kN/cm
4 kN/cm
8 kN/cm
10 kN/cm
12 kN/cm
MCC
453.4
470.9
478.4
479.2
481.1
High density
MCC
0.8
1.1
2.3
1.2
0.6
463.3
472.7
477.0
479.0
481.0
0.7
1.0
1.0
0.9
1.2
Powder
cellulose
486.0
488.6
490.7
490.9
489.8
4.0
1.1
0.3
1.1
0.5
Magnesium
carbonate
478.8
490.1
493.1
490.1
493.7
1.7
1.3
1.5
0.9
1.3
Lactose
488.2
483.4
484.9
485.0
485.4
4.0
2.0
1.7
0.5
0.5
162
Fig. 4. SEM pictures of granules from produced with a specic compaction force of 12 kN/cm, MCC with normal density (a), with high density (b), powder cellulose (c), magnesium
carbonate (d) and lactose (e).
Table 6
Added amount of MgSt in % for the surface proportional lubrication to the dry granules produced with different specic compaction forces.
Specic compaction force
MCC
MCC
(high density)
Magnesium
carbonate
Powder
cellulose
Lactose
0 kN/cm
2 kN/cm
8 kN/cm
12 kN/cm
1.04
0.25
0.16
0.13
0.87
0.21
0.13
0.11
2.08
0.20
0.17
0.16
0.93
0.24
0.19
0.19
0.76
0.15
0.12
0.10
163
Fig. 5. Compactibility curves of MCC with normal (a), and high density (b) powder cellulose (c), magnesium carbonate (d) and lactose (e) for the usage of surface proportional lubrication
(mean sd; n = 10).
Fig. 6. Magnesium carbonate tablets compressed from powder with 0.2% MgSt.
164
occupied for a sufcient lubrication, correlation with the specic external surface area of the material will not work for all materials.
3.2.2. Internal lubrication vs. external lubrication
External lubrication with manually lubricating die and punches was
possible for all ve excipients. No materials stuck to the machine parts,
which allowed a continuous process without any cleaning stops. Comparing the materials, different behaviors were observed during the internal lubrication with different amounts of magnesium stearate. As
before, the materials could be divided in two groups (see Section 3.2.1).
For the brittle behaving materials, magnesium carbonate and lactose, problems occurred during tableting with lower amounts of MgSt
within the internal lubrication. Powder compression with amounts of
0.1 and 0.2% of MgSt was not possible for lactose as material stuck to
the die and the punches. For magnesium carbonate, tableting process
could be performed with an amount of 0.2% of MgSt, however 0.1%
MgSt was insufcient to avoid sticking. In these cases, the surfaces of
the tablets were not smooth (Fig. 6) and the tableting process had to
be interrupted. Due to the sticking problems, just the surface proportional lubrication, with an amount of 0.76% MgSt, served as comparison
for lactose to the external lubrication. A slight increase in tensile
strength could be observed for the external lubrication (Fig. 7e). In the
case of magnesium carbonate the increase in strength for the external
lubrication was even smaller, for the tablets containing 2% MgSt
(surface proportional lubrication) as well as for those containing a tenfold lower amount (Fig. 7d). Due to the creation of lubricant free surfaces during the fragmentation described by de Boer [12], lubricant
sensitivity is small for magnesium carbonate and lactose. Especially for
magnesium carbonate, an increase in lubricant amount caused almost
no loss in strength. However, using too small amounts of lubricant
performing an internal lubrication will offer limits, as a tableting process
without problems was impossible.
MCCs and powder cellulose formed the second group. For these
three materials, tableting with internal lubrication was possible down
to 0.1% MgSt. All compaction curves showed the same behavior. Increasing the amount of lubricant resulted in a decrease in tensile
Fig. 7. Compactibility curves of the direct compression of MCC with normal (a), and high density (b), powder cellulose (c) magnesium carbonate (d) and lactose (e) with different amounts
of MgSt (mean sd; n = 10).
165
166
[25] A.R. Gupte, Messung der spezischen Oberche grober Granulate und der
mittleren Porengre von Tabletten, Acta Pharm. Technol. 22 (1976) 153168.
[26] B. Koglin, K. Leschonski, W. Alex, Teilchengrenanalyse. 7. Oberchenmessung,
Chem. Ing. Tech. 46 (1974) 984987.
[27] J.T. Fell, J.M. Newton, Determination of tablet strength by the diametral-compression
test, J. Pharm. Sci. 59 (1970) 688691.
[28] F. Freitag, Walzenkompaktieren und Trockengranulieren zur Verbesserung des
Tablettierverhaltens anorganischer Hilfsstoffe am Beispiel von Magnesiumcarbonat
und Calciumcarbonat, (Dissertation) Institute of Pharmaceutics and Biopharmaceutics,
2004.
[29] F. Jaminet, H. Hess, Untersuchung ber Kompaktierung und Trockengranulierung,
Pharm. Acta Helv. 41 (1966) 3958.
[30] E.L. Parrott, Densication of powders by concavo-convex roller compactor, J. Pharm.
Sci. 70 (1981) 288291.
Johanna Mosig studied Pharmacy at the Heinrich-HeineUniversity Duesseldorf, Germany from 2005 to 2009. Since
2011 she is a PhD student at the Institute of Pharmaceutics
and Biopharmaceutics at the Heinrich-Heine-University
Dsseldorf under supervision of Prof. Peter Kleinebudde.
Her research focuses on granulation methods, especially
dry granulation via roll compaction, and tableting.