pharmtech.

com
The Industrys Authoritative Source
March 2011
Volume 35
Number 3
Performance excipients targeted for
direct compression must provide
high flowability, good compressibility
under pressure, and excellent blend
uniformity when mixed with active
pharmaceutical ingredients (APIs)
or other ingredients. The authors
investigated the tableting properties
of PanExcea MHC300G, a high-
performance excipient with spherical
particle morphology containing filler,
binder, and disintegrant.
Liliana A. Minea is a senior research
chemist, Rajendra Mehta is a
principal chemist, Madhu Kallam is
an applications engineer, James A.
Farina is a group leader of research
and development (R&D), and Nandu
Deorkar* is a director of R&D, all at
Avantor Performance Materials (formerly
Mallinckrodt Baker), 1904 J. T. Baker
Way, Phillipsburg, NJ 08865, tel.
908.213.6720, fax 908.859.6932, nandu.
deorkar@avantormaterials.com.
*To whom all correspondence should be ad-
dressed.
Submitted: Aug. 18, 2010. Accepted: Nov. 19, 2010.
Excipients
D
irect compression (DC) is a preferred manufacturing process as the continu-
ally modernizing pharmaceutical industry strives to improve its manufactur-
ing output while reducing operating costs (1, 2). Compared with wet-granula-
tion technology, direct compression offers the advantage of product stability,
simplification of manufacturing process, and lower process cost (see Figure 1) (3). The
tableting blend for a DC process contains the active pharmaceutical ingredient (API),
a filler, a binder, a disintegrant, auxiliary excipients (e.g., glidants and solubilizers),
and a lubricant. DC technology and the use of modern tableting machines demand
that the excipients and API form a compressible mixture with excellent flowability
and a low tendency of particle segregation.
The choice of tableting process is highly influenced by the flowability and com-
pressibility of the API-excipient mixture (see Figure 2) (1). The particle size/shape,
density, moisture content, and composition of the excipients affect flowability and
compressibility, which ultimately drives the tableting process (see Figure 3) (49).
Traditional excipients have limited ability to provide flowability and compress-
ibility in mixtures with cohesive and poorly flowable APIs. Tableting parameters,
such as equipment geometry and energy input add to the complexity of the DC
system when dealing with multiparticulate powder systems (10).
To increase the use of direct compression in pharmaceutical tableting, novel
excipients with enhanced flow and compressibility, which can accommodate API
variability, are needed. Nonetheless, this is not an easy task to achieve as the more
compressible a material is, the less flowable it will be. The most cost-effective meth-
odology is to enhance certain functionality of an existing excipient by using novel
processing techniques, or synergistically combining it with other commonly used
excipients. For example, processing techniques, such as spray drying or granulation,
have been used over time to improve microcrystalline cellulose (MCC) properties.
By using combinations of excipients classified as generally recognized as safe (GRAS)
and innovative processing techniques, particles can be engineered to provide desired
properties for use in a DC process. The resulting engineered excipients are commonly
named coprocessed, high functionality, multifunctional, or performance ex-
cipients. This new class of excipients streamlines the process such that, in the end, the
Evaluation and Characteristics of a New
Direct Compression Performance Excipient
Liliana A. Minea, Rajendra Mehta, Madhu Kallam, James A. Farina, and Nandu Deorkar
2 Pharmaceutical Technology MARCH 2011 Phar mTech. com
Excipients
formulator will have the choice of preparing a DC blend consisting of
API, coprocessed excipient, auxiliary excipients, and lubricant. This
approach may be acceptable to the industry and regulatory agencies
because the novel excipients created are not considered new chemical
entities (11).
The current status of high-functionality excipients has been re-
viewed in various articles (1215). This class of excipients should
be very appealing to implementation in a pharmaceutical process
governed by a quality-by-design (QbD) approach (16). Based on
QbD principles, the quality of the drug product is a function of
drug substance, excipients and, manufacturing process; thus using
a performance excipient in a QbD formulation should simplify the
scheme.
Taking into consideration the requirements of QbD and a DC pro-
cess, a performance excipient, PanExcea MHC300G, based on MCC,
hydroxypropyl methylcellulose (HPMC), and crospovidone (CPVD),
has been developed. The performance excipient was designed to pro-
vide good flowability and compressibility by optimizing particle shape,
size, porosity, density, composition, and surface roughness (1718). The
objective of this paper is to evaluate the physical properties and func-
tionalities of PanExcea MHC300G and to correlate these properties
with its performance in a high-speed tableting machine.
Experiment
Materials. The authors obtained the following materials: PanExcea
MHC300G, Avantor Performance Materials (formerly Mallinckrodt
Baker); microcrystalline cellulose (102 RanQ, RanQ Pharmaceuticals
& Excipients); microcrystalline cellulose (Emcocel 90, JRS Pharma);
magnesium (Mg) stearate (Product No. 2256-05, Mallinckrodt Chemi-
cals); stearic acid (Hystrene, PMC Biogenics); colloidal silica (RxCipi-
ents GL100, J. M. Huber); hydroxypropyl methylcellulose, USP grade
(Pharmacoat, grade 603, SHIN-ETSU Chemical); crospovidone (Poly-
plasdone XL-10, International Specialty Products (ISP)); and ibuprofen
(respectively, Product grade: Albemarle 20, Albemarle 40 and Albe-
marle 70, Albemarle; and Ibuprofen 50, BASF).
Methods. High-shear wet granulation (HSWG) of MCC (89%)/HPMC(2%)/CPVD (9%).
In a 1-L stainless-steel bowl were placed 133.5 g MCC, 3.0 g HPMC
and 13.5 g CPVD. The bowl was attached to a vector micro high-shear
mixer/granulator (GMX.01, Vector). The dry mixture was mixed for 2
min at 870 rpm impeller speed and 1000 rpm chopper speed.
Drop by drop, 70 g of deionized water (i.e., the liquid binder) was
added to the dry blend using a peristaltic pump at a dose rate of 12 g/
min. During the liquid binder addition, the impeller speed was 700 rpm
and the chopper speed was 1500 rpm. The wet massing time was 60
s, maintaining the same impeller and chopper speed as during liquid
addition.
Following the granulation, the wet granular material was dried
in a tray at 60 C. The resulting granular material (moisture con-
tent 2.35%) was screened through a 30 mesh sieve. The yield of the
granular material that passed through 30 mesh was 116.73 g (79.3 %
API API
Excipients
Engineered Excipients
Process
(WG; RC)
High-speed
tableting
machine
Blend auxiliary
excipients
Blend auxiliary
excipients
(optional)
DC = Bypass WG or RC = COST SAVINGS and SPEED UP MANUFACTURING
Figure 1: Simplification of a manufacturing process using
engineered excipients with direct-compression technology (API is
active pharmaceutical ingredient, DC is direct compression, WG is
wet granulation, and RC is roller compaction).
Figure 3: Critical performance parameters for excipients to be
used in direct compression (DC). (LOD is loss on drying.)
Figure 2: Powder blend compressibility and flowability
requirements for various tableting technologies (DC is direct
compression, WG is wet granulation, and RC is roller compaction).
High
RC
WG
Powder Compressibility
Low High
WG
DC
P
o
w
d
e
r
f
l
o
w
Particle size/
particle-size
distribution/
particle shape
Aerated and
tapped
bulk density
Flowability
Compressibility
Uniformity of
composition
DC
Robust,
consistent
tableting
Tablet
performance/
hardness/
disintegration/
dissolution
LOD
Stability
Blend-content
uniformity/
chemical
composition
Excipient
properties
Dilution potential
Functionality
Tableting
properties
A
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L

F
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C
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T
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F

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A
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T
H
O
R
S
Pharmaceutical Technology MARCH 2011 3
referenced to dry starting materials and dry product).
Physical characterization. Particle-size analysis was performed using an air
jet sieving instrument (Micron Air Jet Sieve, Hosokawa Micron Powder
Systems). Angle of repose, aerated bulk density/tapped bulk density, and
total flowability index were measured using a powder tester (Model
PT-S, Hosokawa Micron Powder Systems). Particle morphology was
assessed using an environmental scanning electron microscope (ESEM,
XL30, FEI) using a voltage of 5 kV, spot size of 3, and SE detector. The
samples were sputtered with iridium before SEM analysis (sputtering
time 40 s).
Granule strength was determined using the following three meth-
ods. Method A: The particle-size distribution of 75100 g of MHC300G
was measured and the material was loaded in a 4-L V-blender (Maxi-
Blend, GlobePharma) and tumbled for two hours. After tumbling, the
granular material was collected and analyzed again for particle-size
distribution. Method B: 60 g of MHC300G were charged in a 1-L stain-
less-steel bowl that was attached to a vector micro high-shear mixer/
granulator (GMX.01,Vector). The powder was processed by applying an
impeller speed of 950 rpm and a chopper speed of 3600 rpm for 5 min.
The particle-size distribution was measured before and after the high
shear experiment. Method C: 100 g of MHC300G were passed through
a mill (Quadro Comil model U3, Quadro Engineering) at 3000 rpm
using US # 16 (1180 m) screen.
Dilution potential of MHC300G was assessed by preparing blends
of ibuprofen (IBU), MHC300G and silica. The blends were prepared in
a V-blender (MaxiBlend, GlobePharma). Before blending, the powder
mixture was passed through a 30 mesh sieve to break the IBU clumps.
A blend containing IBU/MCC/HPMC/CPVD/silica was prepared in a
similar manner. Powder characteristics as well as IBU content unifor-
mity were analyzed for all blends.
Tableting studies. Unless otherwise specified, tablets were produced
on an instrumented 10-station rotary tableting press (RIVA-Piccola,
SMI). The tablet press was configured with 10-mm (0.3937 in.) round
standard concave Tableting Specification Manual (TSM) B tooling.
A compaction profile (i.e., the variation of tablet properties with in-
creasing compression force at constant tablet weight and turret rotation
speed) and a strain-rate study (i.e., the variation in tablet properties with
turret rotation speed at constant tablet weight and compression force)
were performed for powder blends containing: a) 88.75% MCC (RanQ
102), 2% HPMC, 9% CPVD, Mg stearate 0.25%; b) 99.75% PanExcea
MHC300G, 0.25% Mg stearate; c) 30% ibuprofen, 61% MCC (Emcocel
90), 1.5% HPMC, 6.0% CPVD, 1% silica, 0.5% stearic acid; d) 30% ibu-
profen, 68.5% MHC300G, 1% silica, 0.5% stearic acid.
The blends for the tableting studies were prepared in the follow-
ing manner: all ingredients except the lubricant (Mg stearate or stea-
ric acid), were mixed, passed through a mill (Quadro Comil model
U3, Quadro Engineering) at 3000 rpm using US # 16 screen and then
blended in a V-blender (MaxiBlend, GlobePharma) for 15 min at 20
rpm. The lubricant was added to the resulting mix in the V-blender and
everything was blended for 3 min at 20 rpm. The final blend was dis-
charged from the V-blender and transferred to the tableting machine.
Director Software (SMI) was used to collect and analyze the tablet-
ing data.
Tablet characterization. A friability test was performed according to the
United States Pharmacopeia (USP) recommendations for friability
Figure 4: Evaluation and characteristics of a new direct-compression
performance excipient. Scanning electron microscope micrographs of A:
MHC300G (engineered particles); B: EMB001 (engineered particles); C:
EMB002 (traditional high-shear wet granulation); and D: microcrystalline
cellulose. The scale bar in the images in the left column represents 100
m, and the scale bar in the right column represents 20 m.
A A
B B
C C
D D
Table I: Composition of PanExcea MHC300G, EMB001,
EMB002, and EMB003 excipients.
Ingredient
PanExcea
MHC300G EMB001 EMB002 EMB003
Microcrystalline
cellulose (MCC)
89 86 89 89
Hydroxypropyl
methylcellulose
(HPMC)
2 5 2 2
Crospovidone (CPVD) 9 9 9 9
Process Spray
granulation
Spray
granulation
HSWG* Physical
blend
*HSWG is high-shear wet granulation. PanExcea MHC300G is a
product of Avantor Performance Materials. EMB001, EMB002, and
EMB003 are blends prepared according to reference 17 (see also the
Experiment section of this paper).
4 Pharmaceutical Technology MARCH 2011 Phar mTech. com
Excipients
determination of compressed, uncoated tablets (Chapter <1216>)
using a tablet-friability tester (Varian Friability Tester, with Varian
drum, Varian). The hardness of the tablets was measured using a tablet-
hardness tester (Benchsaver series, VK 200, Varian). Tablet thickness
was measured using a micrometer. Tablet-disintegration tests were per-
formed with a disintegration system (3100, Distek) using 900 mL deion-
ized water at 37 0.5 C.
Results and discussion
Physical characterization of PanExcea MHC300G performance excipient.
Composition and particle morphology. The SEM micrographs (see Figure
4) of particles obtained using several manufacturing processes and
compositions (see Table I) show the particle morphology of all ma-
terials as being different. The MHC300G containing 89% MCC,
2% HPMC, and 9% CPVD has homogeneous spherical to quasi-
spherical particles with a rough surface and some open pores (see
Figure 4A). The increase in concentration of HPMC to 5% (EMB001)
triggered a significant increase in the open pores (see Figure 4B). The
difference in porosity is also reflected in changes in aerated bulk
density and tapped density. The higher densities of MHC300G in-
dicate denser particles as compared with EMB001 (see Table II). The
composition of MHC300G was finalized to provide optimal particle
shape, size, and porosity needed for direct compressible materials
(see Figure 3). The SEM micrographs of the high-shear granulated
material (EMB002) having similar composition to that of MHC300G
show agglomerated particles (see Figure 4C), while the MCC shows
typical needle-shaped particles (see Figure 4D) (19).
Particle-size distribution and flowability parameters. The average particle size
and the particle-size distribution of a granular material is known to
impact flowability, blending ability, wetting, drying, mechanical prop-
erties, and stability (4). The flowability of pharmaceutical blends (i.e.,
API plus excipients) is critical for effective use of direct compression.
Poor flow can cause bridging, arching, surging, and enhanced move-
ment of particles in the die cavity. There are few simple acceptable tests
to evaluate the flowability of a powder, the Hausner ratio and measure-
ment of total flowability index being just few of them (20, 21). The
Hausner ratio is defined as the ratio of tapped to aerated bulk density,
where values 1.25 indicate good flow properties. The total flowability
index, as described by Carr, is calculated based on a series of measure-
ments of powder properties (e.g., angle of repose, aerated and tapped
bulk density, and particle-size uniformity) using a Hosokawa powder
tester (21, 22). The values of the flowability index range from 0 to 100,
with 100 being the material with the best flow properties. A material
with a total flowability index of 80 has very good flowability.
Table II: Bulk density, compressibility index, and Hausner ratio for various grades of microcrystalline cellulose (MCC) and
coprocessed excipients containing MCC.
Type of
excipient Brand Name
Aerated bulk
density (g/cc)
Tapped bulk
density (g/cc) Hausner ratio
Compressibility
Index (%)
MCC Emcocel 50 0.301 (0.004) 0.421 (0.003) 1.40 (0.02) 28.36 (1.21)
Emcocel 90 0.328 (0.008) 0.416 (0.002) 1.27 (0.03) 21.21 (2.18)
Avicel PH101 0.324 (0.002) 0.460 (0.004) 1.42 (0.02) 29.58 (0.87)
Avicel PH102 0.322 (0.004) 0.427 (0.005) 1.33 (0.00) 24.65 (0.21)
RanQ102 0.298 (0.001) 0.386 (0.000) 1.30 (0.00) 22.80 (0.26)
EMB003 - 0.326 (0.004) 0.416 (0.002) 1.27 (0.01) 21.50 (0.92)
EMB002 - 0.323 (0.002) 0.401 (0.002) 1.24 (0.00) 19.55 (0.15)
MHC300G PanExceaMHC300G 0.300 (0.010) 0.360 (0.006) 1.21 (0.03) 17.44 (1.75)
EMB001 - 0.205 (0.004) 0.249 (0.003) 1.23 (0.01) 18.72 (1.18)
*Values represented in this table are averages of five measurements with standard deviation given in parentheses.
Table III: Particle-size distribution and physical
characteristics of PanExcea MHC300G (three sample lots).
Physical characteristic PanExcea MHC300G
Lot A Lot B Lot C
Particle size
a) cum. retained on 60 mesh (%) 3.96 4.24 3.20
b) cum. retained on 200 mesh (%) 84.68 87.2 83.04
c) cum. retained on 270 mesh (%) 92.08 92.8 92.80
d) D50 (m) 132 130 128
Moisture content 2.26 2.76 3.33
Angle of repose (deg) 33.6 34.0 33.2
Aerated bulk density (g/cc) 0.31 0.30 0.29
Packed bulk density (g/cc) 0.37 0.36 0.36
Hausner ratio 1.19 1.20 1.24
Compressibility index (%) 16.2 16.6 19.4
Total flowability index 89.5 84.5 87.5
D50 (m) is the average particle diameter (i.e., 50% of the particles
have a diameter below this value).
Table IV: Granules friability test* for the MHC300G using a
V-blender. Comparison with a granular product of similar
composition obtained by high-shear wet granulation.
Sample % of particles with
diameter < 50 m
(before test)
% of particles with
diameter < 50 m
(after test)
MHC300G 5 4
EMB002 14 30
*Test was performed by tumbling ~ 100 g sample in a 4 L V-blender for
two hours and measuring the particle-size distribution before and after
the test.
Pharmaceutical Technology MARCH 2011 5
The particle-size distribution and the physical characteristics of
MHC300G are summarized in Table III. A total flowability index
greater than 80, an angle of repose below 35, and a Hausner ratio
less than 1.25 indicate that MHC300G has very good flowability.
When compared with various grades of MCC, EMB001, EMB002,
and EMB003, MHC300G provides superior performance in terms
of flowability (see Table II and Figure 5). For example, Avicel PH 102
has a Hausner ratio of ~ 1.33, a compressibility index of ~ 25% and
a total flowability index of 72, and MHC300G has a
Hausner ratio of 1.21, a compressibility index of ~ 17 %
and a total flowability index of 87. These data suggest
that the processing methodology used in MHC300G
particle engineering improved flowability attributes
significantly.
Particle strength. The particles used in a DC process
should be strong and not produce fines during blend-
ing or mixing operations. The MHC300G granules
and a granular material of similar composition pre-
pared by conventional HSWG (EMB002) were tested
in a particle friability experiment. Upon tumbling
samples of excipients in a V-blender for two hours,
the percentage of fines was unchanged for MHC300G,
but for EMB002 (see Table IV) they were doubled. The
strength of the MHC300G particles was tested also in
a high-shear process in which the impeller was run
at 950 rpm for 5 min, or by passing the MHC300G
excipient through a mill at 3000 rpm and a mesh size
corresponding to US # 16 (1180 m). All tests showed
(see Table V) that the particles did not break during
the process and the percentage of fines did not in-
crease. The granule-strength studies and the SEM mi-
crographs indicated that the MHC300G performance
excipient consists of strong particles with robust bond-
ing bridges between the granules components, result-
ing in a unique structural morphology.
Tableting study of MHC300G. PanExcea MHC300G
was designed to ensure its use in high-speed tablet-
ing machines. Its physical properties, functional
characteristics (i.e., flowability and compressibility)
and particle strength indicate its suitability for DC
processes in high-speed tableting machines. A tableting study was
undertaken to understand the compaction profile and the variation
in tablet properties with tableting parameters. The effect of turret-
rotation speed on tablet quality (i.e., the strain rate) was studied as
it is very important for tableting process scale-up. Placebo tablets of
MHC300G/Mg stearate (0.25%) and a powder blend of MCC/HPMC
(2%)/CPVD (9%)/Mg stearate (0.25%), respectively, were obtained
using a 10-station rotary tableting machine configured with 10-mm
round standard concave TSM B tooling.
A compaction profile was performed for various compression-
force levels at constant turret-rotation speed (32 rpm) and tablet
weight. Tablets were collected at each run to measure the average
weight, thickness, breaking force (i.e., hardness) and disintegration
times. The plots of tensile strength versus compression force (see
Figure 6) show similar profiles and an increase in tensile strength
with compression force for both MHC300G/Mg stearate and the
blend of MCC/HPMC/CPVD/Mg stearate. MHC300G produces
strong compacts (i.e., tablet radial-tensile strength of 1.24.5 MPa
or tablet breaking forces of 95260 N for 10-mm diameter compacts)
in the compression-force range used in current tablet manufactur-
ing (i.e., 515 kN) (see Figure 6). These values are lower than the
ones corresponding to tablets prepared from MCC/HPMC/CPVD/
Mg stearate blend. The results are not unexpected as it is well
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Emcocel 90
Avicel PH 102
EMB003
EMB002
MHC300G
90
80
70
60
50
40
30
20
10
0
Figure 5: Flowability index for EMB003 (powder blend), EMB002 (HSWG), MHC300G, and
commercial grades of microcrystalline cellulose (MCC) (Avicel PH 102, Emcocel 90). Higher
index indicates better flowability (see Reference 21).
Table V: Granules friability test for the MHC300G using high shear or mill.*
Method d
10
(m) d
50
(m) d
90
(m)
Before test After test Before test After test Before test After test
High Shear 66.4 62.3 130.6 128.1 228.1 219.4
Mill 66.4 63.5 130.6 134.0 228.1 215.5
*For test details see Experiment section of this paper
d
10
is 10% of the particles have a diameter below this value; d
50
is average particle diameter (or
50% of the particles have a diameter below this value); and d
90
is 90% of the particles have a
diameter below this value
Table VI: Ibuprofen formulations used in tableting studies.
Nr. Ingredient
Formulation 1
(Physical mixture)
Formulation 2
(PanExcea MHC300G)
1 Ibuprofen (50 m) 90.0 g (30.0%) 90.0 g (30.0%)
2 PanExcea MHC300G - 205.5 (68.5%)
3 MCC 183.0 g (61.0%) -
4 HPMC 4.5 g (1.5%) -
5 CPVD 18.0 g (6.0%) -
6 Silica 3.0 (1.0%) 3.0 g (1.0%)
7 Stearic acid 1.5 g (0.5%) 1.5 g (0.5%)
MCC = microcrystalline cellulose; HPMC = hydroxypropyl
methylcellulose; CPVD = crospovidone
6 Pharmaceutical Technology MARCH 2011 Phar mTech. com
Excipients
known that processing MCC via a wet-granulating
technique results in some reduction of the compress-
ibility of MCC, the mechanism of which is not well
understood (23, 24). It has been suggested that the
decrease in MCC compactibility after granulation is
associated with the decrease in MCC primary par-
ticle porosity (23). The formulation containing 30%
ibuprofen and PanExcea MHC300G, however, gives
stronger compacts at compression forces up to 15
kN than the corresponding formulation containing
MCC (see Table VI and Figure 7). Tablets prepared
when using MHC300G are shown to retain the tensile
strength (3.2 MPa for placebo and 3.0 MPa for 30%
ibuprofen formulation at ~ 9 kN compression force)
and the tensile strength of tablets prepared using the
blend of MCC/HPMC/CPVD is reduced after mix-
ing with ibuprofen (4.7 MPa for placebo and 2.5 MPa
for 30% ibuprofen formulation at ~ 9kN compres-
sion force; see Figures 6 and 7). No significant tablet
weight variation, capping or laminating tendencies
were observed.
A strain-rate study was performed on both
MHC300G/Mg stearate (0.25%) and a blend of MCC/
HPMC (2%)/CPVD (9%)/Mg stearate (0.25%). The tablet
properties and the tableting parameters were monitored
when the turret-rotation speed was increased at constant
compression force and tablet weight. Increasing the tur-
ret rotation speed from 13 rpm to 99 rpm led to very
small change in tablet weight (~ 2.0 %) for MHC300G/
Mg stearate, indicating that MHC300G shows a very
good weight control throughout the full range of the
tablet press (see Figure 8). The consistent weight control
resulted in little compression-force variation. The tablet
strength (i.e., breaking force) of the MHC300G compacts
decreases with ~ 20% from 13 to 50 rpm showing a mod-
erate strain-rate sensitivity at relatively low turret speeds,
and levels off showing no strain-rate sensitivity for turret
speeds ranging from 50 to 99 rpm (see Figure 9). Con-
versely, the blend of MCC/HPMC/CPVD/Mg stearate
(0.25%) shows overall higher strain-rate sensitivity as
evidenced by a 34% decrease in tablet weight (see Fig-
ure 8) and a 35% decrease in tablet strength (i.e., break-
ing force) when varying the turret speed from 13 to 99
rpm (see Figure 9). This is consistent with MCC being a
ductile material that undergoes plastic deformation (25).
Figure 6: Tensile strength versus compression force profile for tablets (10 mm diameter)
prepared from MHC300G/0.25%Mg stearate blend, and MCC/2%HPMC/9%CPVD/0.25%Mg
stearate blend (MCC is microcrystalline cellulose, HPMC is hydroxypropyl methylcellulose,
and CPVD is crospovidone).
Figure 7: Tensile strength vs. compression force profile for tablets (10 mm diameter)
prepared from 30%IBU/MHC300G/silica/stearic acid blend, and 30%IBU/Emcocel90/
HPMC/CPVD/silica/stearic acid blend (IBU is ibuprofen, HPMC is hydroxypropyl
methylcellulose, and CPVD is crospovidone).
Table VII: Bulk density, compressibility, and flowability index of IBU/MHC300G/SiO
2
and IBU/MCC/HPMC/CPVD/ SiO
2
.
Sample Aerated bulk density (g/cc) Tapped bulk density (g/cc) Compressibility index (%) Total flowability index
IBU (20 m)/MHC300G/ SiO
2
0.392 0.525 25.3 76.5
IBU (40 m)/MHC300G/ SiO
2
0.395 0.501 21.2 78.5
IBU (70 m)/MHC300G/ SiO
2
0.416 0.501 17.0 84.5
IBU (20 m)/MCC/HPMC/CPVD/silica 0.417 0.603 30.8 62.0
API recovery range 99102% with %RSD < 2.
IBU is ibuprofen, MCC is microcrystalline cellulose, HPMC is hydroxypropyl methylcellulose, and CPVD is crospovidone.
Pharmaceutical Technology MARCH 2011 7
The strain-rate studies for formulations containing 30% IBU (see
Table VI) indicated that both blends containing MHC300G and
MCC show strain-rate sensitivity, with blends based on MHC300G
having less strain-rate sensitivity. The decrease in average tablet
weight when increasing turret-rotation speed from 13 rpm to 99
rpm (see Figure 10) was 3% for the IBU/MHC300G
blend and 6% for IBU/MCC/HPMC/CPVD blend, re-
spectively. This trend is paralleled by the change in
tablet-breaking force (see Figure 11) as illustrated by
an overall 40% loss of tablet strength for IBU/MCC/
HPMC/CPVD/silica/stearic acid and ~ 25% loss of
tablet strength for IBU/MHC300G/silica/stearic acid
when increasing turret-rotation speed from 13 to 99
rpm. The tablets prepared in these tableting studies
have excellent disintegration times, the tablet weight
loss during the friability tests being negligible.
MHC300G dilution potential. The dilution potential can
be defined as the amount of an active ingredient (API)
that can satisfactorily be compressed into tablets with
the excipient mixture.
The dilution potential of MHC300G was studied
using ibuprofen, which is an API that is difficult to
tablet by DC. A 62.5% ibuprofen formulation, cor-
responding to the current commercial dosage, was
prepared by using different grades of ibuprofen (20,
40 and 70 m average particle size, respectively),
MHC300G and 0.5% silica. The flowability of these
blends was good as indicated by total flowability in-
dices ranging from 76 to 85 and percent-compress-
ibility indices ranging from 17 to 25. A similar blend
prepared by using a mixture of MCC, HPMC (2%),
CPVD (9%) and ibuprofen (20 m) had poor flow-
ability with a percent-compressibility index of 31, and
a total flowability index of 62 (see Table VII). The API
content uniformity for the blends containing PanEx-
cea MHC300G was excellent, and the IBU recovery
was in the range of 98102% with %RSD 2 (RSD is
relative standard deviation).
Conclusion
PanExcea MHC300G was engineered as a perfor-
mance excipient containing the three main compo-
nents of a solid-dosage formulation: filler, binder, and
a disintegrant. MHC300G is composed of homoge-
neous spherical particles in which the individual com-
ponents cannot be distinguished from one another.
Its physical properties and the consistency achieved
by maintaining good control over the manufacturing
process make this performance excipient ideal for use
in drug-product manufacturing under the QbD prin-
ciples. Placebo tableting studies by direct compression
on a 10-station tableting machine showed very good
weight control throughout the full range of the tablet
press. The consistent weight control resulted in steady
compression force when the turret speed was increased to 100 rpm.
The tableting of MHC300G requires very little lubricant. Under the
conditions used in this study, the resulted compacts were strong, with
no capping tendency and excellent disintegration times. MHC300G
has a very good dilution potential allowing the tableting of blends
Figure 9: Variation in tablet breaking force with turret rotation speed for tablets
(10 mm diameter) prepared from MHC300G/0.25%Mg stearate blend, and
MCC/2%HPMC/9%CPVD/0.25%Mg stearate blend (MCC is microcrystalline cellulose,
HPMC is hydroxypropyl methylcellulose, and CPVD is crospovidone).
50
60
70
80
90
100
110
0 20 40 60 80 100 120
%
T
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b
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Turret rotation speed (rpm)
MHC300G/0.25%Mg Stearate MCC/2%HPMC/9%CPVD/0.25% Mg Stearate
Figure 8: Variation in tablet weight with turret rotation speed for tablets (10 mm diameter)
prepared from MHC300G/0.25%Mg stearate blend, and MCC/2%HPMC/9%CPVD/0.25%Mg
stearate blend (MCC is microcrystalline cellulose, HPMC is hydroxypropyl methylcellulose,
and CPVD is crospovidone).
50
60
70
80
90
100
110
0 20 40 60 80 100 120
%
T
a
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Turret rotation speed (rpm)
MHC300G/0.25% Mg Stearate MCC/2%HPMC/9%CPVD/0.25%Mg Stearate
Excipients
of up to 62.5% ibuprofen. Extended tabletability stud-
ies by direct compression of API/MHC300G blends
with various percent content API will be reported in
a follow-up paper.
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Turret rotation speed (rpm)
30%IBU/MHC300G 30%IBU/Emcocel90/HPMC/CPVD
Figure 11: Variation in tablet breaking force with turret rotation speed for tablets (10
mm diameter) prepared from 30%IBU/MHC300G/silica/stearic acid blend, and 30%IBU/
Emcocel90/HPMC/CPVD/silica/stearic acid blend (IBU is ibuprofen, HPMC is hydroxypropyl
methylcellulose, and CPVD is crospovidone).
Figure 10: Variation in tablet weight with turret rotation speed for tablets (10 mm
diameter) prepared from 30%IBU/MHC300G/silica/stearic acid blend, and 30%IBU/
Emcocel90/HPMC/CPVD/silica/stearic acid blend (IBU is ibuprofen, HPMC is hydroxypropyl
methylcellulose, and CPVD is crospovidone).
90.00
92.00
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