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Powder Technology 266 (2014) 156166

Contents lists available at ScienceDirect

Powder Technology
journal homepage: www.elsevier.com/locate/powtec

Evaluation of lubrication methods: How to generate a comparable


lubrication for dry granules and powder material for tableting processes
Johanna Mosig, Peter Kleinebudde
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Universitaetsstrasse 1, 40225 Duesseldorf, Germany

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.

than other lubricants and reduces friction coefcients already in small


amounts [1,2]. Strickland et al. showed [3], that magnesium stearate adhered on the surface of the particles and formed a lubricant lm around
the particles during mixing. This resulted in lower friction as well as in
interference in particle bonding and in an increase of the hydrophobic
character. Due to the interferences in particle bonding, lubricants
weakened the tablets, resulting in an inferior tensile strength [3,4].
The coating of the particles with magnesium stearate increased the
water repellant character, resulting in slower disintegration [3,5]
and prolonged dissolution time [2,6]. Increasing amounts of lubricant or prolonged mixing [711] enhanced these adverse effects as
lm formation is promoted.
Materials differ in susceptibility for these adverse effects, in particular with respect to the sensitivity for the reduction in strength. De Boer
et al. [12] showed a dependence between the compression behavior and
the effect of magnesium stearate on the tablet strength. Materials

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

undergoing a complete plastic deformation were most inuenced by


the addition of lubricants. Brittle materials were less sensitive to magnesium stearate as strength did not decrease signicantly with an increasing amount of lubricant [13]. Moreover, factors other than the
fragmentation behavior can affect the lubricant sensitivity of excipients.
Vromans et al. showed [14], that materials with highly irregular surfaces
offered a lower susceptibility for magnesium stearate as lm formation
is unlikely to become complete. Almaya and Aburub [15] could relate
the lubricant sensitivity to the excipient particle size. According to
these publications, smaller particles, which have a higher specic surface area, will be less affected by magnesium stearate. Furthermore,
lubricant efcacy as well as the degree of the adverse effects depends
on the type of magnesium stearate. Johansson [16,17] investigated the
inuence of granular magnesium stearate on tableting. Compared to
powder material a higher amount of lubricant was required to prevent
sticking, whereas at the same time a less adverse effect on the tablet
properties was observed. The lm forming behavior of magnesium stearate could explain these observations. The granular type will be less
efcient in surface covering than the powder material. Frattini and
Simioni [18] conrmed these ndings by correlating the used quantity
of magnesium stearate with the specic surface area of different types
of magnesium stearate. The usage of equal amounts of magnesium stearate of the different types resulted in varying tablet characteristics,
whereas for the usage of amounts leading to equivalent lubricating
areas tablet properties were almost identical. Further studies afrmed
the approach of lubrication dependence on the specic surface area of
magnesium stearate [19,20]. Rao et al. [19] demonstrated, that particle
properties like size and specic surface area of the lubricant exerted
the most important impact on the lubrication efcacy. Due to this, magnesium stearate types with smaller particle sizes and higher specic
surface areas will be more efcient in lubrication [20] as distribution
on particle surface of the excipient is higher. Since the addition of magnesium stearate is a crucial aspect for tablet characteristics, it should be
well considered. Depending on the varying specic surface areas of
magnesium stearate and the tableting materials, surface coverage will
differ between different types of lubricants as well as for the lubrication
of different materials. Resulting from this, Duberg and Nystrm [21]
used amounts of magnesium stearate to generate a xed surface ratio
between the calculated surface area of the lubricant and the material.
As many materials are not suitable for direct compression often a
granulation step takes place prior to tableting. Roll compaction and
subsequently dry granulation of the compacted material is beside wet
granulation one common way to produce granules, which gained in importance for the pharmaceutical industry. It can be applied to moisture
and heat sensitive materials, the process is environmental friendly, as
no removing of solvents is necessary, and scale up is easily feasible
[22]. Nevertheless, roll compaction is also associated with drawbacks
like the accruing high amount of nes and a loss of strength after a recompression step. Malkowska and Khan [23] showed, that tablets
made from dry granules exhibited a lower strength as those from direct
compression and strength decreased with increasing force during the
rst compaction step. They explained it by a work-hardening of the material, which resulted in an increased resistance to the deformation. As
properties of granules will vary with changes in the production setup
during roll compaction/dry granulation, e.g. differences of the specic
compaction force, it is not useful to perform the addition of a constant
amount of lubricant when comparing different types of dry granules
or dry granules and the starting material. Moreover granule properties,
which are crucial for the lubrication efcacy, as the specic surface area,
should be considered.
The aim of this study was to investigate different lubrication
methods in order to nd a method for a uniform lubrication for different types of dry granules as well as for the raw powder material.
Specic external surface area as tool to generate a comparable internal lubrication was tested as well as the usage of an external lubrication method.

157

2. Materials and methods


2.1. Materials
Granules and tablets were prepared from ve different excipients.
Two qualities of microcrystalline cellulose (MCC), normal (Vivapur
102, Batchno. 5610206849,JRS Pharma GmbH & Co, Holzmhle,
Germany) and high density (Vivapur 302, Batchno. 5630290339,
JRS Pharma GmbH & Co, Holzmhle, Germany), powder cellulose
(Arbocel P290, Batchno. 74817101129, JRS Pharma GmbH & Co,
Holzmhle, Germany), -lactose monohydrate (Granulac 200, Batchno.
2019, Meggle Excipients and Technology, Wasserburg, Germany) and
magnesium carbonate (Magnesia 18, Batchno. 241118, Magnesia
GmbH, Lneburg, Germany) were used as received. Magnesium stearate
(Parteck LUB, Batchno. K42017563, Merck Millipore, Darmstadt,
Germany) served as lubricant. Calibration of the Friedrich-manometer
was performed with glass spheres (3 sizes: 170180 m; 100110 m;
160 m).
For equilibration all materials were stored at 21 C and 45% relative
humidity. First experiments were performed after a storage time at least
of one week.
2.2. Methods
2.2.1. Roll compaction/dry granulation
Roll compaction/dry granulation was performed with an instrumented roll compactor (Minipactor 250/25, Gerteis Maschinen +
Prozessengineering AG, Jona, Switzerland). Ribbons were compacted
at a gap width of 2 mm, a roll speed of 3 rpm and specic compaction
forces of 2, 8 and 12 kN/cm. Afterwards they were directly dry granulated through a 1 mm sieve with a star granulator, rotating 120 clockwise
and 180 counterclockwise and a rotor speed of 40 rpm clockwise and
60 rpm counterclockwise. Granules were sieved in portions of nearly
100 g for 5 min (Retsch Vibrio AS 200 control, Retsch GmbH, Haan,
Germany) to obtain a particle fraction between 315 and 630 m for
every batch. Further experiments were performed with granules of
this sieve fraction.
2.2.2. Particle density
Particle densities were measured with a helium pycnometer
(AccuPyc, Micromeritics, Norcross, USA). Measurements were performed at 25 0.1 C.

Fig. 1. Schematic gure of the Friedrich-manometer.

158

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

2.2.3. Scanning electron microscopy


SEM images were acquired by the microscope Phenom G2 pro
(Phenom-World, Eindhoven, Netherlands). If necessary samples
were sputtered with a 14 nm layer of gold (Automatic Sputter Coater
MSC 1T, Ingenieurbro Peter Liebscher, Wetzlar, Germany).
2.2.4. Specic external surface area
Specic external surface area for each granule fraction between 315
and 630 m as well as for the raw materials was determined by air
permeametry measurements in a Friedrich manometer [24] (selfconstruction of Evonik Industries, Darmstadt, Germany) equipped
with a sample holder according to Gupte [25] (Fig. 1). Water was used
as test uid. The uid level was raised by a vacuum pump (Pipetus,
Glaswerk, Wertheim, Germany) to mark A. Then air permeated through
the powder bed and lowered the water level. Measuring the time for a
constant decrease in the water level enabled measuring of the time a
constant volume of air needs to permeate the powder bed. Therefore,
the time interval was measured to decrease the water level from mark
B to mark C by a light barrier system (self-construction of Evonik
Industries).
The square of the volume specic external surface area can be calculated by Eq. (1) measuring the time a constant volume needs to permeate a dened powder bed. The mass specic external surface area can be
derived by Eq. (2).
2

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

volume specic surface area


particle shape factor
density of manometer uid
gravitational constant
cross-sectional area of the powder bed
length of the powder bed
volume of manometer uid in one arm from starting to
endposition
height difference of uid level in the manometer arms
porosity of the powder bed
permeation time
air viscosity
mass specic surface area
powder density.

The detected ow time has to be reduced by the running time


without any testing material to calculate the pure permeation time
t. The blank value of the instrument was determined to be 3.92
0.086 (n = 100). Furthermore, values for the viscosity of air ()
(0.018190.01829 mPa*s) and the density of water (m) (0.998203
0.997295 g/cm3) were used according to the measured room temperature. Due to the graded powder container, bed porosity () was calculated by measuring the weight of the testing material, the height (L) and

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

High density MCC

Powder cellulose

Magnesium carbonate

Lactose

1.594

1.596

1.559

2.305

1.544

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166


Table 2
BET surface of glass spheres (mean sd; n = 3) and the corresponding calculated
integral of Eq. (1) for test measurements with the Friedrich-manometer (mean sd;
n = 5).
Glass sphere size
[m]
160
100110
170180

BET surface area


[m2/g]

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

MCC (high density)


91
11
7
3

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

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

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

3.2. Tableting of powder and granules


3.2.1. Surface proportional lubrication
Adding an amount of MgSt proportional to the specic external surface area was used for surface proportional lubrication. To work with a
feasible lubrication, the correlation factor was scheduled to be
2.5 g/cm2. This resulted in amounts of 0.762% MgSt for the direct
compression of the powder material and in 0.10.25% MgSt for the
granule compression (Table 6). For the same material, differences of
the added amount of MgSt to dry granules produced with different
compaction forces were small, as the variations were between 0.12
and 0.03% of magnesium stearate.
The whole tableting process could be performed without sticking
and friction problems for all ve materials. Hence, lubrication proportional to the specic external surface area was considered to be suitable
for the direct compression as well as for the compression of dry
granules.
Fig. 5a to e shows the compaction curves for each of the ve excipients. Compactibility for the granules decreased with increasing specic
compaction force during roll compaction according to the work hardening phenomenon, described by Malkowska and Khan [23]. Thus, direct
compression should lead to the strongest tablets, but contradictory
results were found within the tableting experiments.
Both types of MCC and powder cellulose revealed similar behavior
comparing direct and granule compression (Fig. 5a, b and c). As described
before, tensile strength of granule tablets decreased with increasing specic compaction force during dry granulation. Compactibility of the direct
compression was much lower for these three materials compared to the
granule compression, especially for granules produced with 2 kN/cm.
This unexpected behavior was most pronounced for powder cellulose.
Compressing the powder with a nearly fourfold higher amount of MgSt
compared to the granules caused a dramatic decrease in compactibility
(Fig. 5c). Tensile strength of direct compressed tablets was even lower
than these of tablets made from granules compacted at the highest compaction force.
Although the added amount of MgSt was with 0.9% in a usual range,
the resulting tablets offered an unacceptable strength with a tensile
strength below 1 MPa. For MCC, the decrease in strength was also

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

obvious comparing direct and granule compression, but here a


higher strength (M: 4 MPa; Ms: 3 MPa) was achieved than in the
compression of powder cellulose. Tensile strength of direct compressed tablets of MCC with high density was for compression pressures above 200 MPa lower than the strength of all granule tablets,
also for those of granules produced with 8 and 12 kN/cm (Fig. 5b).
Although the compactibility of the DC tablets of the normal MCC
was much lower compared to those of the 2 kN/cm tablets, strength
was still in the region of those tablets consisting of granules produced with 8 and 12 kN/cm (Fig. 5a).
As the amount of MgSt was lower in the direct compression experiments for Ms and Pc (0.9%) compared to the MCC of normal density
(1%), differences in the reduction of strength could not be explained
by differences in the amount of MgSt. Moreover, different lubricant
sensitivities were responsible for the overall reduction in strength for
the direct compressed tablets and the differences of the loss in strength
between the three materials.
Compression of magnesium carbonate showed the expected behavior. An increase in the compaction force, from zero at direct compression
to 12 kN/cm, led to a decrease of the tensile strength (Fig. 5d). According to the work-hardening phenomenon, direct compression revealed
the strongest tablets, whereas those produced from granules compacted
with 12 kN/cm offered the lowest strength. For magnesium carbonate,
compactibility of the raw material was still higher compared to the
granules in spite of the tenfold lubricant quantity.
For lactose, no differences between the different granule tablets as
well as between DC and granule compression were found (Fig. 5e).
The decrease in tensile strength for the direct compression compared
to the granule compression at compression pressures above 350 MPa
resulted from the tableting process. As the ungranulated material
offered a poor owing behavior, lling of the dies was problematic
and caused the observed deviations.
Lubricating proportional to the specic external surface area resulted in different behaviors for elastically, plastically and brittle deforming
materials. Due to the plastically deforming behavior of MCC and powder
cellulose, they are highly sensitive to the addition of magnesium stearate. According to De Boer [12], no new clean surfaces were created
and thus, the former generated lms of MgSt around the particles
avoided bindings. Even if the amount of MgSt is calculated to the available surface of the particles (granules and powder) and therefore the
possibilities to form bonds should be equal for the direct compression
and the granule compression, DC revealed a lower binding tendency.
As the creation of new lubricant free surfaces will not differ between
the direct compression and the granule compression, it can be assumed,
that the here performed lubrication will in fact result in differences of
the surface occupation. This resulted in varying amounts of free surfaces
causing the observed lower binding tendency during direct compression for the plastically deforming materials. For brittle behaving
materials as lactose or magnesium carbonate, surface proportional
lubrication did not cause any problems. Although the amounts of lubricant were much higher, occurring fracture offered new binding
positions. Jarosz and Parrot [13] showed for the brittle behaving
dicalcium phosphate that tensile strength was not changed by the
addition of magnesium stearate, even the amount was up to 2%,
which is comparable to the added amount for the direct compression
of magnesium carbonate. For materials undergoing brittle fracture,
this way of lubrication seems to be promising.

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

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

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

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

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

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).

Duberg and Nystrm [21] used a similar approach to standardize the


addition of magnesium stearate aiming a constant surface ratio of nine
between lubricant and material surface. In this study the same type of
MgSt was used for all experiments. Therefore, specic surface area of
the magnesium stearate did not change during the experiments and
the addition of MgSt by the correlation constant of 2.5 g/cm2, will
also result in a constant ratio of the surface areas. In contrast to this
study, no lubrication problems occurred by Duberg and Nystrm [21].
They also compressed particles of different size fractions, but the size
differences were much smaller compared to this study. For ve materials, fractions of 90250 m and 355500 m were investigated,
whereas for the lubricant sensitive starch only the smaller fraction
was investigated. Due to the smaller differences in size, the amount of
MgSt varied just between 0.05 and 0.27%. Resulting from this, no lubrication problems occurred for most of the materials. The compression of
starch was problematic, as no coherent compacts could be formed with
an addition of 0.23% of MgSt. This also indicates an overlubrication in
the case of starch. Therefore both studies were not contradictory but

the actual study rather investigated the surface proportional lubrication


in more detail. Overall, standardizing the lubrication to the specic external surface area will not work as a universal method. Although it
could be expected that for ner materials a bigger surface has to be

Fig. 6. Magnesium carbonate tablets compressed from powder with 0.2% MgSt.

164

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

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).

J. Mosig, P. Kleinebudde / Powder Technology 266 (2014) 156166

strength. External lubrication led always to tablets with the highest


compactibility. Tablets containing MgSt proportional to the specic
surface area showed the lowest strength caused by the highest
amount of lubricant (Fig. 7a, b, c). Differences between the varying
amounts of MgSt during the internal lubrication as well as between
internal and external lubrication were more pronounced for these
materials compared to lactose and magnesium carbonate. Powder
cellulose presented the strongest increase switching from the internal lubrication with the highest amount to the external lubrication
(Fig. 7c). Considering differences in strength between lubrication
with 0.1 and 0.2% MgSt and external MgSt, increase is comparable
for both types of MCC and powder cellulose. Loss in strength was
above 30% for a usage of 0.1% MgSt and nearly 40% for 0.2% MgSt.
Even if the reductions were similar, high density MCC offered a
slightly higher decrease than both other materials of this group.
Compared to this remarkable reduction of strength for both types
of MCC and powder cellulose decline for magnesium carbonate is
just about 5%, changing from an external lubrication to a lubrication
with 0.2% MgSt. These differences occurred due to differing lubricant
sensitivity. As MCC and powder cellulose present a plastic and elastic
deforming behavior, no lubricant free surfaces will be generated
during the compressing step (see 3.1.1).
4. Conclusion
Tableting with amounts of MgSt proportional to the specic external
surface area was feasible as no sticking problems occurred for all of the
ve materials, for the raw materials as well as for the granules. The
amount of MgSt was sufcient, even the relative low amounts of 0.1
to 0.2% MgSt for the granule compression of lactose and magnesium
carbonate. With such amounts, tableting of these raw materials was
not possible. Hence, surface proportional lubrication seemed to provide
an indication for sufcient lubrication for brittle behaving materials.
However, for the direct compression of MCC and powder cellulose, a
loss in strength occurred due to the high amount of lubricant. Furthermore, for these three materials direct compression was also possible
with low amounts of MgSt, comparable to the concentrations added to
the granule compression. Although the specic surface area is much
higher for the powdered material, the amount of lubricant needed for
the compression will not differ between the raw material and the
granules in such dimensions as it was expected due to the differences
in the specic surface area. In this case, specic surface area is not the
crucial part for the lubrication decision and a lubrication proportionally
to the specic external area resulted in an overlubrication of the powder. Considering these results, the mechanism behind the lubrication
with magnesium stearate offered new questions. The effect of lubrication will not just occur due to lm forming around the particles. If this
was the case, surface proportional lubrication would not cause any
problems for plastically deforming materials as well as for brittle
deforming materials. Lubricant free surfaces for new bindings during
compression should be equal for the different granule compressions as
well as for the direct compression. Thus, even for the lubricantsensitive materials, strength of the direct compressed tablets should
be comparable to those of granule compression, if not actually be higher
in the case of dry granules.
Overall, the results showed that the addition of magnesium stearate
proportional to the specic surface area was not suitable as a universal
tool for a comparable lubrication. For a comparable internal lubrication
more factors in addition to the specic external surface area have to be
taken into account. Lubrication phenomena are more complex as just
the coverage of the external surface area of the material with MgSt,
that considerations of the particle morphology and the lubricant distribution might be useful for further investigations on the lubricant
addition.
The results for the external lubrication were promising. The tableting
process was practicable without sticking for all ve different materials

165

and the compactibility was higher or comparable to tablets with the


lowest concentration of MgSt.
Even if tableting with equal amounts for direct compression and
granule compression will be practicable, critical examination of the results should be performed. Otherwise lubrication within the tableting
processes is not comparable and the impact of the lubricating might
be underestimated, even neglected. Hence, especially literature about
the reduced compactibility of dry granules should be reconsidered
with respect to lubrication phenomena. In conclusion, external lubrication should be the rst choice to receive truly comparable results for
tableting processes. Using this method, there is no risk for an over- or
underlubrication as well as for complications within the tablet strength.
Acknowledgments
The authors would like to thank Evonik Industries for providing
the Friedrich manometer to the Institute of Pharmaceutics and
Biopharmaceutics in Duesseldorf. This applies in particular to
Mr. Weisbrod for the support in organization and startup.
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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.

Peter Kleinebudde is a full professor for Pharmaceutical


Technology at the University Duesseldorf since 2003. Peter
was the president of the International Association for
Pharmaceutical Technology (APV) from 2002 to 2010.
Since 2010 he is the head of the APV focus group Solid
Dosage Forms. He is a member of the editorial boards of
the Eur J Pharm Biopharm, J Pharm Sci, AAPS PharmSciTech,
and Pharm Dev Tech. In 2004 he was designated as AAPS
Fellow and 2013 he received the Doctor honoris causa from
the University of Szeged. His main research interests are
solid dosage forms and pharmaceutical processes like roll
compaction/ dry granulation, extrusion and coating.