RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Excipient–Process Interactions and their Impact on Tablet

Compaction and Film Coating
PREETANSHU PANDEY, DILBIR S. BINDRA, SHRUTI GOUR, JADE TRINH, DAVID BUCKLEY, SHERIF BADAWY

Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901

Received 17 June 2014; revised 21 August 2014; accepted 29 August 2014

Published online 15 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24169

ABSTRACT: The objective of this study was to establish the effects of the level of minor formulation components (sodium lauryl sulfate:
SLS, and magnesium stearate: MgSt) and manufacturing process on final blend compaction properties and the performance of the tablets
during film coating. A 2 × 2 × 3 factorial study was conducted at two levels of SLS (0% and 1%, w/w) and MgSt (0.5% and 1.75%,
w/w), along with three different manufacturing processes (direct compression, high-shear wet granulation, and dry granulation). The tablets
were compressed to the same solid fraction (0.9) and the resulting tablet hardness values were found to vary over a range of 13–42
SCU, highlighting large compactability differences among these batches. Increase in the level of SLS or MgSt in the formulation had a
significant negative effect on compactability and the performance of film-coated tablets. The detrimental effects on compaction and coating
performance were magnified for the dry granulation process, likely due to the overall increased shear experienced by excipients (SLS,
MgSt, microcrystalline cellulose) during the roller compaction and milling steps. The findings of this study highlight the importance of the
manufacturing process when considering the use-level of formulation components such as SLS and MgSt in the formulation.  C 2014 Wiley

Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3666–3674, 2014
Keywords: excipients; coating; compression; processing; powder technology

INTRODUCTION loss in compaction without affecting the dissolution behavior

significantly. Thus, for that particular formulation, an intimate
Three types of manufacturing techniques are commonly used
contact between the API and SLS was not found to be nec-
for formulating tablets—direct compression (DC), wet granula-
essary for dissolution performance. However, Aljaberi et al.6
tion (WG), and dry granulation (DG). Although DC is the sim-
found in their experiments that an intimate contact between
plest of the three, it may not always be feasible due to challenges
the API and SLS was critical in obtaining the desired disso-
with flow, compaction, and content uniformity.1,2 Granulation
lution profile. This demonstrates that this observation may be
can overcome most of these challenges and can be performed
formulation-specific and/or that the granulation process (and
either in a wet or dry manner. WG is usually performed in a
sometimes even the test methods) played a role in the observa-
high-shear or fluid-bed granulator. The use of water during WG
tion.
can sometimes lead to form change and/or chemical instability
Even though SLS has some lubricant properties, it is not
of the drug.3,4 DG, using roller compaction, is commonly used
as effective a lubricant as stearates. Therefore, an additional
given the ease of use, the fact that there is no drying step, and
lubricant may still be needed in formulations containing SLS.
the continuous nature of the process.
Commonly used lubricants such as magnesium stearate (MgSt)
When formulating APIs with low aqueous solubility, it is a
have a high surface area, low particle size, film or layer forming
common practice to add a surfactant such as sodium lauryl
tendency, amphiphilic activity, and low shear stress.7–9 MgSt
sulfate (SLS) to the formulation. SLS is an effective wetting
has a very low maximum shear stress (85 kg/cm2 ) and has
agent and has been shown to offer significant dissolution en-
little affinity for metal surfaces. MgSt has been shown to form
hancement of poorly water-soluble drugs.5 However, SLS also
a thin film on the surface of its carrier particle and is known to
exhibits lubricant properties, and, therefore, could potentially
cause dissolution challenges due to the hydrophobic nature of
pose processing challenges depending upon its use-level. In a
the groups it presents on the surface.10 Lubrication with MgSt
recent study by Aljaberi et al.6 it was shown that a 0.57% (w/w)
causes a decrease in the compactability of the blend, but helps
of SLS in a wet granulated formulation offered the desired
in mitigating punch sticking and reduces the ejection forces
dissolution profile without compromising the compaction prop-
experienced by the tablets during compaction.
erties of the granules. In another study by Moore et al.,5 it
Several lubrication studies have been conducted showing the
was shown that the mode of incorporation of SLS during a DG
risks of over-lubrication related to MgSt.7,11–13 These studies
process affected the compaction properties. It was concluded
establish that the concentration of MgSt and blending factors
in that study that adding SLS during the final blending step,
such as blending time, blending speed, and blender scale can
rather than before the granulation process, can prevent the
have an impact on granule compaction. It was also shown that
MgSt can have a negative impact on the coating performance of
Correspondence to: Preetanshu Pandey (Telephone: +7322275918; Fax:
+7322275150; E-mail: preetanshu@gmail.com)
tablets, with a higher number of logo bridging coating defects
Journal of Pharmaceutical Sciences, Vol. 103, 3666–3674 (2014)
observed at higher MgSt concentrations. This was explained by

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association the hydrophobic nature of MgSt that renders the tablet core

3666 Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014

 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 3667

Table 1. Experimental Design Details on the Split of SLS and MgSt Between the Intra- and Extragranular Portions for the Three
Manufacturing Processes

Batch # 1 2 3 4 5 6 7 8 9 10 11 12

Direct Compression Wet Granulation Dry Granulation

Intragranular portion
MgSt – – – – 0 0 0 0 0.25 0.25 0.75 0.75
SLS – – – – 0 1 0 1 0 1 0 1
Extragranular portion
SLS 0 1 0 1 0 0 0 0 0 0 0 0
MgSt 0.5 0.5 1.75 1.75 0.5 0.5 1.75 1.75 0.25 0.25 1 1
Total
SLS 0 1 0 1 0 1 0 1 0 1 0 1
MgSt 0.5 0.5 1.75 1.75 0.5 0.5 1.75 1.75 0.5 0.5 1.75 1.75

to be quite hydrophobic in nature, which in turn results in a of these excipients are shown in Table 1 and explained in the
loss of adhesion between the tablet substrate and the coating subsequent manufacturing process section. Statistical regres-
film.14–18 sion analysis was conducted using JMP statistical software
R

There are two important aspects in this field that have not
been explored, and form the motivation for the current work: (1)
interaction of the effects of SLS and MgSt with the manufactur-
ing process, and (2) the impact of manufacturing process and
SLS level on tablet coating performance. With this knowledge-
gap in mind, the objective of this work is to establish the main
effects and interactions of manufacturing process, SLS level,
and MgSt level on the final blend compaction properties and
performance of the core tablets during the film coating. A DOE
(design of experiments) study was conducted using two levels
of SLS (0% and 1%, w/w), two levels of MgSt (0.5% and 1.75%,
w/w), and three different manufacturing processes (DC, WG,
DG). The responses of the DOE study included granule com-
paction properties and performance of core tablets during film
coating as measured by logo bridging coating defects.
(SAS).
Manufacturing Process
The three manufacturing processes used in this study are de-
scribed below (Fig. 1). The blending conditions such as, blender
scale, blending time, and blender speed were maintained con-
stant across all batches to eliminate any blending-related dif-
ferences in blend lubrication. Final blends from each of the
manufacturing processes were compressed into oval-shaped
tablets at a press weight of 200-mg using embossed punches.
These oval-shaped tablets were used for the coating perfor-
mance evaluation. For film coating studies, the tablets were
compressed to a solid fraction of 0.9. Compaction profiles (over
a range of solid fractions) using flat-faced punches were gen-
erated using a Stylcam compaction simulator (Medel’Pharm,
R

Beynost, France) press to compare compaction properties

MATERIAL AND METHODS
The formulation used in this study consisted of approximately
1:1 ratio of anhydrous lactose and microcrystalline cellulose
and 4% w/w croscarmellose sodium (distributed equally be-
tween intragranular and extragranular additions). The con-
centrations of SLS and MgSt were varied according to the
study design using microcrystalline cellulose as the compen-
sating excipient. Microcrystalline cellulose (Avicel PH101)
R
and croscarmellose sodium were purchased from FMC Corpo-
ration (Philadelphia, Pennsylvania). Anhydrous lactose (60M)
was purchased from Kerry Bio-Sciences (Norwich, New Jer-
sey), SLS from BASF (Dusseldorf, Germany), and MgSt from
Mallinckrodt Chemicals (Saint Louis, Missouri). A HPMC-
across different batches.
Direct Compression
Direct compression batches were manufactured at a 4-kg batch
size. SLS was added along with anhydrous lactose, micro-
crystalline cellulose, and croscarmellose sodium to a 25-L bin
blender and blended at 25 rpm for 263 revolutions. MgSt (pre-
screened) was then added to the blender and blended for 100
revolutions at a speed of 25 rpm. A schematic diagram of the
DC process is shown in Figure 1a.
Wet Granulation
Wet granulation experiments were conducted in a 30-L GEA
Pharmaconnect (Columbia, Maryland) high-shear granulator
R

based Opadry coating system (Colorcon, North Wales, PA) con-

R
taining polyethylene glycol 400 (PEG 400) as a plasticizer was
utilized for the coating studies. All excipients used in this study
met the USP/NF requirements and the same lots of excipients
were used throughout the study.
Experimental Design
A 2 × 2 × 3 factorial DOE study was conducted at two lev-
els of SLS (0% and 1%, w/w), two levels of MgSt (0.5% and
at a 6-kg batch size. SLS was added as part of the intragran-
ular components. During preblending, liquid addition, and wet
massing steps, the impeller tip speed was kept at 4.8 m/s, and
the chopper speed was kept at 1500 rpm. Preblending was per-
formed for 3 min. Water was used as the granulating fluid and
was added to the granulator at a rate of 100 g per min per
kg through a tube attached to a precalibrated pump. After
water addition, the granules were wet-massed for 1 min. The
wet granules were then passed through a Quadro Comil Model
R

1.75%, w/w), and three different manufacturing processes (DC, 197S (Quadro Engineering, Waterloo, Ontario) running at 1300
WG, DG). The split of SLS and MgSt between the intragran- rpm using a 8 mm opening screen and dried in a 25-L Freund
ular and extragranular portions (for the DG and WG batches) Vector fluid bed at an inlet temperature of 50◦ C to a target LOD

DOI 10.1002/jps.24169 Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014

3668 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Figure 1. Schematic representation of the three manufacturing processes: (a) direct compression, (b) wet granulation, and (c) dry granulation.
(loss on drying @ 105◦ C) value of less than 3.0% (w/w). The dry
granules were then passed through a Quadro Comil running
R
at 2300 rpm using a 1.1 mm screen opening. Extragranular
croscarmellose sodium was mixed with the milled granules in a
bin blender at 25 rpm for 75 revolutions followed by lubrication
with MgSt (prescreened using 30-mesh) for 100 revolutions at
25 rpm. A schematic diagram of the WG process is shown in
Figure 1b.
Dry Granulation
Dry granulation batches were manufactured using a roller com-
paction process at a 4-kg scale. SLS was added along with
anhydrous lactose, microcrystalline cellulose, and croscarmel-
lose sodium to a 25-L bin blender and blended at 25 rpm
for 263 revolutions. The intragranular portion of MgSt was
screened using a 30-mesh screen, prior to blending for 125 revo-
lutions at 25 rpm. The resulting preblend was granulated using
the Alexanderwerk WP-120 (Montgomeryville, Pennsylvania)
R
roller compactor equipped with a smooth upper roll and knurled
bottom roll. A roll gap size of 2.2 mm was targeted to achieve a
ribbon density in the range of 1.00–1.20 g/cc. This was achieved
by adjusting the screw speed (8–12 rpm) and roll pressure
(45 ± 5 bar). The ribbons were crushed using the mill integrated
Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014
into the granulator. The granulator mill was fitted with a 3.15
mm upper screen and 1.00 mm lower screen, and operated at
80 rpm. The granulated material was placed into a 25-L bin
blender and extragranular excipients were added. Croscarmel-
lose sodium was added and blended at 25 rpm for 75 revolutions
followed by lubrication with MgSt (prescreened using 30-mesh)
for 100 revolutions at 25 rpm. A schematic diagram of the DG
process is shown in Figure 1c.
Coating Process
The tablets were coated in a 12 in. Vector pan coater, equipped
R
with 1 spray gun, to a target theoretical weight gain of 4.0%
(w/w) at a batch size of 800 g. A coating suspension at 15% (w/w)
solids was used. Coating process conditions were kept constant
across all batches and were monitored using PyroButton data R
loggers (Opulus, Philadelphia, PA). Information on PyroBut-
tons and their relevance to the coating process measurements
in terms of logo bridging tablet defects has been established
by the authors in other publications.18–20 Trial experiments
were conducted to estimate the coating conditions required to
achieve a wide range of logo bridging responses across the 12
batches. PyroButton data showed that a tablet-bed RH of 40%
showed no logo bridging for the DG batch with low SLS and
DOI 10.1002/jps.24169
 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 3669

MgSt level combination and 100% logo bridging for the high
SLS and MgSt level combination batch. Therefore, those pro-
cess parameters were selected for this study. The selected pro-
cess parameters selected were: a target spray rate of 7.5 g/min,
inlet airflow of 40 cfm, exhaust temperature of 43◦ C, pan speed
of 25 rpm, and a gun-to-bed distance of 3.75 in. The coater was
operated in “exhaust temperature-control” mode, meaning that
the unit self-adjusted the inlet air temperature to reach and
maintain the exhaust temperature at the set value.

Physical Characterization
True Density
True density of final blend was measured by AccuPyc II 1340
R

Gas Pycnometer (Micromeritics Instrument Company, Nor-

cross, Georgia). The true density data were used to estimate Figure 2. Compaction profiles for the direct compression batches.
the solid fraction of the tablets during compression. Error bars indicate one standard deviation values (n = 3 tablets).

Compaction
least one of the four letters of the logo on a tablet face was
Compaction data were generated using Stylcam compaction
R

significantly obscured such that the letter could not be easily

simulator. Stylcam compaction simulator is a full instrumented
single station tablet press used to duplicate and analyze pre-
compression, compression, and ejection phases of a selected
tablet press under identical conditions. It measures the forces
experienced by the punches and the punch displacements dur-
ing those phases. An 11.28 mm flat-faced round tooling was
used in the direct cam mode. Three tablets were compressed at
each of the five different solid fractions in the range of 0.75–0.95
and the weight, thickness, and hardness data on each tablet
was collected in order to generate the compaction profiles for
the 12 batches. Additionally, the simulator was used to com-
press tablets at a solid fraction of 0.9 for use in film coating.
For the analysis of compaction data in this work, compactability
data refer to the tensile strength as a function of solid fraction,
whereas tabletability data refer to the tensile strength as a
function of compression pressure.
Coating Performance
The incidence of logo bridging was used as an indicator of coat-
ing performance. A total of one hundred tablets were randomly
selected from each batch and visually inspected for logo bridg-
ing. The criterion used to define logo bridging was when at
read.20
RESULTS AND DISCUSSION
Compaction Properties
Direct Compression
The tabletability data (tensile strength vs. compression pres-
sure) for the four DC batches (# 1–4) are shown in Figure 2.
The tabletability of the batches were in the order of batch #
1>2>3>4. An increase in SLS level from 0% to 1% (w/w), or an
increase in MgSt level from 0.5% to 1.75% (w/w) both caused a
loss in compaction when compared individually to the DC ref-
erence batch # 1. A combination of high MgSt and SLS levels
resulted in a further decrease in the compaction characteris-
tics of the final blend with leveling of tensile strength beyond a
compression pressure of 250 MPa. Table 2 shows a comparison
of the tablet hardness values across these batches at a solid
fraction of 0.9. The data in Table 2 reveal that a combined use
of high levels MgSt and SLS in a DC process led to almost a
twofold decrease (46% reduction) in tablet hardness.

Table 2. Tablet Hardness Values for the 12 DOE Batches at the Same Tablet Solid Fraction of 0.9, as a Measure of the Compaction
Differences Between These Formulations

Formulation
Change in Hardness w.r.t.
Manufacturing Process SLS (%, w/w) MgSt (%, w/w) Hardness, SCU Reference Batch (%)

Direct compression 0 0.50 35 –

1 0.50 27 23
0 1.75 23 34
1 1.75 19 46
Wet granulation 0 0.50 42 -
1 0.50 28 33
0 1.75 35 17
1 1.75 26 38
Dry granulation 0 0.50 30 –
1 0.50 19 37
0 1.75 17 43
1 1.75 13 57

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3670 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Figure 3. Compaction profiles for the wet granulated batches. Error Figure 4. Compaction profiles for the roller compacted batches. Error
bars indicate one standard deviation values (n = 3 tablets). bars indicate one standard deviation values (n = 3 tablets).

MgSt is known to be an effective lubricant which means that were in the order of batch # 9>11>10>12. For DG, a more sig-
it coats the other particle during the blending process, result- nificant drop in tablet hardness (an indicator of compactabil-
ing in a reduced bonding between these particles.21,22 This can ity) was observed when using either 1% SLS (37% reduction,
explain the significant loss in compaction when MgSt is added Table 2), or 1.75% MgSt (43% reduction), or both in combina-
to a formulation. SLS also has some lubricant-like properties tion (56% reduction), as compared with the reduction in hard-
and works in a similar way resulting in a loss of compaction ness values observed for DC and WG for similar composition
when blends are compressed into tablets.5,23 It is worthwhile changes. It should be noted that a portion of MgSt and all of SLS
noting that the loss in compaction as a result of increase in was added intragranularly in case of the DG process. The higher
SLS amount alone (batch # 2 vs. # 1) was similar in magnitude observed reduction in compaction for the DG batches compared
to the loss of compaction due to the increase in MgSt amount with the other manufacturing processes is attributed to addi-
(batch # 3 vs. # 1). tional shear imparted on the blend by the roller compactor and
milling of the ribbons. These additional processesing steps can
Wet Granulation result in an enhanced negative effect of SLS and MgSt on com-
The tabletability data of the four wet granulated batches paction. A combined use of SLS and MgSt in this case led to
(# 5–8) are shown in Figure 3. The tabletability of the batches extremely poor compaction, and as a result, the lowest tablet
were in the order of batch # 5>7>6>8. Table 2 shows a com- hardness among all batches in the study.
parison of the tablet hardness values across these batches at a When comparing the three manufacturing processes with
solid fraction of 0.9. each other it must be kept in mind that the other formula-
An increase in SLS level from 0% to 1% (w/w) was observed tion excipients such as microcrystalline cellulose undergo dif-
to cause a greater loss in compaction than an increase in MgSt ferent amounts of processing and this will also contribute to
level from 0.50% to 1.75%. This trend was opposite to what the observed overall compaction properties of the final blend.25
was observed for the DC batches (Fig. 2). The reversal in trend However, when comparisons are made to the reference batches
is likely due to the differences in mode of addition of SLS be- within the same manufacturing process, those effects are nor-
tween the DC and WG batches. For the WG batches, the SLS malized.
was added in the intragranular portion causing it to undergo
additional high-shear mixing and compiling steps. It has been Statistical Analysis
shown in the literature that additional shear imparted to SLS Statistical analysis of the compaction data show that all the
can be detrimental to tablet hardness.5 SLS itself being a lu- three main factors (manufacturing process, SLS, and MgSt
bricant is observed to be exhibiting similar properties to that concentration) studied are significant (p < 0.05). The output
of MgSt. MgSt has a plate-like structure that tends to shear variable used in the statistical model was the hardness value
apart during processing (blending or any activities that tend to of the tablet at 0.9 solid fraction. RSD on tablet hardness val-
apply shear), thereby causing an increased effective concentra- ues was in the range of 3%–5%. Table 3 shows a summary of
tion of MgSt that tends to coat more particles and resulting in
further reduction in interparticle bonding.10,11,24 It is observed
that SLS shows a similar behavior with increased processing Table 3. Regression Analysis for the DOE with Tablet Hardness as
causing a more pronounced effect on the loss in compaction. the Response
Additionally, the addition of MgSt alone (batch # 7 vs. 5#) did Term Estimate Standard Error t Ratio Prob > t
not show the same extent of reduction in hardness (Table 2) as
was observed for the DC case (batch # 3 vs. 1). Intercept 37.53 1.89 19.88 0.0000
Process (DC) − 0.17 1.17 − 0.14 0.8904
Dry Granulation Process (RC) − 6.42 1.17 − 5.50 0.0009
MgSt − 6.40 1.32 − 4.85 0.0019
The tabletability data of the four dry granulated batches (# 9– SLS − 8.33 1.65 − 5.05 0.0015
12) are shown in Figure 4. The compactability of the batches

Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014 DOI 10.1002/jps.24169

 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 3671

the regression analysis. The regression analysis showed a p

value of 0.0009 for the process, 0.002 for MgSt concentration,
and 0.001 for SLS concentration. None of the interaction terms
were found to be significant.
Overall, both MgSt and SLS had a negative effect on the com-
pactability and tabletability. These effects seem to be magnified
for the DG batches, as is evident by the statistically significant
process term. The biggest drop in compaction properties were
observed when using high levels of SLS and MgSt for the dry
granulated process when compared with the reference batch
using low levels of both excipients in a DC or WG process.
In the DG process, SLS and a portion of MgSt, are added in
the intragranular portion and therefore get subjected to pro-
cessing steps such as blending, roller compaction, and milling.
This additional shear tends to increase the overall effective con-
centration of both these excipients. He et al.26 confirmed that
for a microcrystalline-based formulation an overlubrication ef-
fect caused by MgSt is observed during roller compaction and Figure 6. Tensile strength versus solid fraction across the three
especially by the subsequent milling step. Additionally, when manufacturing processes at 0%SLS + 0.5%MgSt (open symbols), and
ribbons are roller compacted to a relatively high ribbon solid 1%SLS + 1.75%MgSt (solid symbols).
fraction (>0.6), there is more intimate contact of the excipi-
ents such as microcrytalline cellulose and MgSt. Ribbons made
up. For instance, when scaling up to a commerical-scale press,
at higher solid fractions are harder to mill and tend to spend
a higher level of mixing may take place at the die table (due
longer time in the mill, causing a more intimate mixture of ex-
to increased residence time, higher paddle speed, larger con-
cipients with MgSt, and thus subject to overlubrication.26 These
tact surface with paddle, etc.) when using a force feeder,12 and
observations explain the large drop in compaction for the dry
a further risk of overlubrication may exist. For a formulation
granulated batches.
with such low tabletability and compactability, this additional
A comparison between the three manufacturing processes is
lubrication (mixing) may make it quite challenging to achieve
shown in Figures 5 and 6 for two formulations: one with no SLS
the desired target tensile strength.
and 0.5% MgSt, and other with 1% SLS and 1.75% MgSt. The
DC and wet granulated batches both show similar tabletability Coating Performance
(Fig. 5) and compactability (Fig. 6) for the same composition. It
should be pointed out that there is no binder used in the WG All the batches were film coated and evaluated for logo bridging.
formulation, therefore, an improvement in compaction proper- Logo bridging coating defects were observed for some of the
ties that may be conventionally expected from a wet granulated batches and quantified by visual inspection. The data are shown
product is not observed here. The dry granulated product shows in Figure 7.
a significant loss in compaction (tabletability and compactabil- Direct Compression and Wet Granulation
ity) for both cases for the reasons discussed earlier in this sec-
tion. The batch with 1% SLS and 1.75% MgSt manufactured It can be observed that DC and wet granulated batches gave
using DG shows extremely low tabletability and compactabil- similar coating performance for the matching tablet formula-
ity and can be expected to be sensitive to small changes in the tions. For both, DC and wet granulated batches, the addition
process (e.g., blending, compaction, and milling) during scale- of 1% SLS (at 0.5% w/w MgSt level) showed some signs of logo
bridging, with 3/100 tablets showing logo bridging for the DC
case (batch #2) and 1/100 tablet showing logo bridging for the
WG case (batch #6). Additionally, at the higher MgSt level, the
effect of adding 1% (w/w) SLS was magnified, with DC and
wet granulated cases showing 17% and 18% logo bridging in-
stances, respectively. In both cases, the combined use of SLS
and MgSt at the high levels led to significant logo bridging, in-
dicating an interaction between the two excipients. This com-
bined negative effect was similar in magnitude for both, DC
and WG batches. There appears to be some synergistic effect
of combined increase in SLS and MgSt levels on logo bridging
events (apparent for DC and WG processes, combined effect
was obscured in case of DG as MgSt alone produced 100% logo
bridging defect).
Dry Granulation
All of the observations from DC and WG batches were further
Figure 5. Comparison of compaction profiles across the three manu- magnified for the roller compacted batches. The addition of 1%
facturing processes at 0%SLS + 0.5%MgSt (open symbols), and 1%SLS SLS alone (batch #10) in the roller compacted batch, resulted in
+ 1.75%MgSt (solid symbols). a logo bridging incidence rate with 22% of the tablets showing

DOI 10.1002/jps.24169 Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014

3672 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Figure 7. Logo bridging coating defect response as a function of MgSt and SLS concentration when grouped by the manufacturing process.

logo bridging. A low level of MgSt with no SLS (batch # 1, 5, and
9), did not show any logo bridging for any of the manufactur-
ing processes. The worst logo bridging was observed in batches
containing high level of MgSt that were roller-compacted. At
the higher MgSt amount, the effect of adding 1% SLS was ob-
scured since both batches (batches #11, 12) resulted in 100%
logo bridging.
Statistical Analysis
Statistical analysis of the coating performance data reveal that
all the three main factors (manufacturing process, SLS, and
MgSt concentration) studied are significant (p < 0.05). Table 4
shows a summary of the regression analysis. The output vari-
able used in the statistical model was the% logo bridging of
the coated tablets. The analysis showed a p value of 0.0001 for
the manufacturing process, 0.0001 for MgSt concentration, and
0.03 for SLS concentration, with process and MgSt interaction
term being significant at p value of 0.0001.
A cross-sectional view of a tablet (sliced) showing logo bridg-
ing is shown in Figure 8, demonstrating the lack of adhesion
of film to the tablet substrate as the underlying reason for the
observed logo bridging. This is in agreement with reported lit-
erature on MgSt where it was shown that a higher amount of
MgSt results in an increase incidence of logo bridging or poor
adhesion between the film and tablet substrate.16 Lubricants
coat the granule particles and present a tablet surface that con-
sists mainly of non-polar hydrocarbon groups, thereby lowering
adhesion between the polymer (HPMC in this case) in the film
and the tablet substrate.16
In this study, the addition of 1.75% (w/w) MgSt alone did
not affect the number of logo bridging tablet defects for DC or
WG cases (Fig. 7). This indicates that the degree of lubrication
achieved for these cases was not high enough to cause a logo
bridging tablet defect, even though it may have affected the
adhesion between the film and the substrate to a certain extent.
There was an indication for the DC and wet granulated batches
that 1% (w/w) SLS in the tablet formulation had a negative
effect on the performance during coating (Fig. 7). This effect
was prominent for the roller compacted batch with 1% (w/w)
SLS, with 22% of the batch showing logo bridging. For all three
manufacturing processes, a combined use of 1% (w/w) SLS with
1.75% MgSt caused significant overlubrication to show-up as a
logo bridging tablet defect, with a more pronounced effect in

Table 4. Regression Analysis for the DOE with % Logo Bridging as the Response

Term Estimate Standard Error t Ratio Prob > t

Intercept − 6.25 4.27 − 1.46 0.1937

Process (WG and DC–RC) − 25.31 1.95 − 12.95 0.0000
Process (WG–DC) − 0.13 2.26 − 0.06 0.9576
MgSt 27.87 2.95 9.45 0.0001
SLS 10.17 3.69 2.76 0.0329
Process [(WG and DC–RC)–0.33333] × (MgSt − 1.125) − 32.50 3.13 − 10.39 0.0000

Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014 DOI 10.1002/jps.24169

 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Figure 8. A tablet showing logo bridging as seen from (a) top, (b) cross-section (sliced). The logo 468X is not easily readable due to the lifting
of the film (lack of adherence) from the substrate as obvious from the cross-sectional view.
the DG process, where the entire batch showed logo bridging.
To the author’s knowledge, this negative effect of SLS on the
performance of tablets during coating is not previously reported
in the literature. This is likely the result of coating of excipient
particles by SLS, thereby reducing adhesion between the film
and the substrate, and is clearly observed when SLS (added
intragranular) undergoes sufficient shear imparted during the
DG process. However, other possible causes playing a role in
adhesion of HPMC film such as an interaction of the coating
film with the anionic charge of SLS and/or hydrophobic portion
of SLS molecule can not be overruled and will require additional
mechanistic characterization studies.
CONCLUSIONS
It is clear from this study that MgSt and SLS play an important
role in both compaction and coating performance. The negative
influence of these excipients was shown to be a function of their
concentration and the manufacturing process used. It should be
pointed out that the purpose of the study was to assess differ-
ences between the manufacturing processes the way they are
typically utilized and not necessarily to compare them in abso-
lute terms. The magnitude of the observed effects will also be a
function of the mechanical properties of the other formulation
components (e.g., brittle versus ductile). The risks associated
with the use of these excipients must be carefully evaluated,
DOI 10.1002/jps.24169
3673
especially for a DG process. It is interesting to note how these
minor formulation components can play such a significant role
in the overall manufacturing scheme.
Additionally, as shown in this study, the formulation com-
ponents can also dramatically influence the performance of
tablets during a film coating process. Therefore, an understand-
ing and quantification of which formulation components may
play a role and the interplay of the tablet formulation with the
manufacturing process is important. Once such a link is es-
tablished, a formulator can make an informed decision when
selecting a certain manufacturing process and/or a coating
system.
In lieu of these findings, appropriate risk analysis must be
conducted when excipients such as MgSt and SLS are present
in the formulation at high concentrations (typically >1% w/w)
and shear is being applied during manufacturing. For exam-
ple, when considering addition of a milling step for preblend
preparation (to get rid of potential API lumps), a risk to down-
stream performance (compaction and coating) must be carefully
evaluated.
ACKNOWLEDGMENTS
The authors would like to thank Elena Zour, Jatin Patel, and
Brian Zacour from Bristol-Myers Squibb for their help with this
work.
Pandey et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3666–3674, 2014
3674 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology
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