Evaluation of the physical & mechanical properties of high drug load formulations (Metformin, APAP, and Aspirin) - Wet Granulation vs. Foam technique

1. Powder Technology 195 (2009) 15–24
Contents lists available at ScienceDirect
Powder Technology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c
Evaluation of the physical and mechanical properties of high drug load formulations:
Wet granulation vs. novel foam granulation
Stuart L. Cantor a,1, Sanjeev Kothari b,1, Otilia M.Y. Koo c,⁎
a
ICON Development Solutions, 6031 University Blvd., Ellicott City, MD 21043, USA
b
AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850, USA
c
Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, NJ 08903, USA
a r t i c l e i n f o a b s t r a c t
Article history: The purpose of this study was to evaluate the influences of intrinsic drug mechanical properties and different
Received 9 July 2008 granulation binder delivery processes on the physical and mechanical properties of high drug load
Received in revised form 2 February 2009 granulations after wet granulation. Formulations (80% w/w) of acetaminophen (APAP), metformin and
Accepted 6 May 2009
aspirin, which are brittle, viscoelastic, and ductile, respectively; were granulated by high-shear wet
Available online 12 May 2009
granulation. Two modes of binder delivery for wet granulation, either conventional or binder foam, were
investigated. Particle size, surface area and pore size of the granulations were characterized. Compacts were
Keywords:
Hiestand tableting indices prepared at a solid fraction of 0.9 under tri-axial decompression and Hiestand indices (worst-case bonding
Conventional wet granulation index (BIw) and brittle fracture index (BFI)) of the compacts were determined. APAP formulations exhibited
Foam granulation the smallest geometric mean particle sizes (dg) and showed only slight differences in dg values between the
Viscoelastic two granulation processes. Binder delivery mode affected mechanical properties of the granulated model
Ductile drugs differently. Foam granulation appeared to enhance the granule plasticity for APAP while aspirin
Brittle showed a mixed deformation mechanism based on both its high BIw and high BFI values. The higher BIw
value for aspirin after foam granulation may be attributed to improved binder distribution among particles
during granulation. On the other hand, conventional wet granulation improved the plasticity of metformin as
measured by the higher BIw and lower BFI values. Therefore, conventional wet granulation process conferred
advantages in manufacturability and product quality for metformin; as compared to foam granulation which
did not enhance plasticity for metformin. Based on this study, a wet granulation process can be selected
based on knowledge of the intrinsic drug mechanical properties.
© 2009 Elsevier B.V. All rights reserved.
1. Introduction different binder delivery processes have on the properties of the final
granules.
The understanding of both physical and mechanical properties of The two granulation processes compared in this study are the
pharmaceutical granulations is critical for successful tablet formula- conventional wet granulation and a new foam granulation process.
tion. Costly problems such as low tablet crushing strengths, poor High drug loads, i.e. 80% w/w, were used in this study to minimize
friability, poor coating uniformity, and capping/lamination can formulation effects and enable an accurate comparison of the
potentially be avoided through an improved understanding of the differences between the mechanical properties of the three model
physico-mechanical properties of granulations. Such useful informa- drugs in affecting granulation properties. The foam-mediated wet
tion to quantify a granulation's degree of brittleness or plasticity can granulation process where the binder is delivered as foam has been
be gained by using dimensionless parameters known as the Hiestand gaining increasing attention in the pharmaceutical industry due to its
tableting indices. In this study, the physical and mechanical properties advantages over conventional wet granulation. Foam granulation
of high drug load granulations prepared via both conventional wet yields a more homogeneous dispersion of binder throughout the
and foam processes were evaluated. It was desired to determine both powder bed during granulation and can potentially reduce drying
the influences that the intrinsic drug mechanical properties and time due to the lower soak-to-spread ratio of binder foam compared
to a conventional spray of binder solution [1]. Moreover, delivery of
the binder foam through rigid plastic tubing eliminates the need to
⁎ Corresponding author. Biopharmaceutics Research and Development, Bristol-Myers optimize nozzle placement and geometry. Excipients suitable for foam
Squibb Company, 1 Squibb Drive, New Brunswick, NJ 08903, USA. Tel.: +1 732 227 5341; generation include commonly used binders such as hydroxypropyl
fax: +1 732 227 3986.
E-mail address: otilia.koo@bms.com (O.M.Y. Koo).
cellulose (HPC), hypromellose (HPMC) and other cellulose ethers [1].
1
All of the work described here was conducted by the authors at Bristol-Myers Surfactants (e.g., sodium laurel sulfate, Poloxamer® 188) may also be
Squibb Company, New Brunswick, NJ, USA. used as aids to generate foam. The typical binder solution viscosity
0032-5910/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.powtec.2009.05.003

2. 16 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24
range for foam generation is between 5 and 100 cP [2]. HPC solution plastic deformation occurs [4]. Plastic deformation is predominant in
has the viscosity and surface tension properties to generate high the decompression stage for viscoelastic materials that exhibit flow
quality foam of low density and was selected for this study. after release of the compression stress.
Recently, scale-up trials of sodium naproxen immediate- and Brittle fracture index (BFI) is the ratio of the tensile strength of the
controlled-release formulations using foam granulation technology tablets without a hole and with a hole at their center. This ratio may
showed that this process prevented localized over wetting during indicate the ability or inability of compact to relieve stress at a crack
granulation. Furthermore, drug dissolution rate profiles were similar tip within the compact by plastic deformation [12]. The BFI is based on
across the different batch sizes, from laboratory to pilot and the Griffith crack propagation theory, which states that a crack will be
manufacturing scale [3]. initiated and propagated when the incremental change of elastic
In addition to the granulation moisture level, physical properties of energy during crack growth provides the incremental gain of surface
granulations such as surface area, particle size, particle size distribu- energy for the new surfaces [13]. It is assumed that the origin of the
tion, and pore diameter can influence subsequent tablet strength on crack is from a defect site where the elastic stress is concentrated. It is
compaction. It is known that porous particles are mechanically higher than the nominal stress, and hence the first region to reach the
weaker and readily deform to create new bonding surfaces which stress level needed for crack growth. Since the crack tip may continue
can lead to increased inter-particulate bonding and thus, harder to be a stress concentrator; the crack often continues to propagate.
tablets [4,5]. Similarly, granulations with higher surface areas are Therefore the material fails at much lower applied stress than
expected to result in harder tablets through increased inter-particle expected from the theoretical bond strength and/or theoretical
bonding provided that true contact distances are reached between the shear strength. However, if a material relieves some of the stress in
deforming particles. Therefore, an adequate tensile strength, indica- the region of concentrated stress by plastic deformation, then the
tive of good bond formation, is one criterion to determine a successful stresses may not build to the level required for crack propagation. The
tablet formulation. However, physical measurements of granulations Griffith theory is modified to include the absorption of energy by
are typically studied because mechanical properties are not pre- plastic deformation when calculating the BFI.
dictable a priori [6]. Three representative model drugs with different deformation
Some processes such as conventional wet granulation can have a mechanisms were chosen: 1) metformin was selected as the model
significant effect on the mechanical properties of certain materials; for viscoelastic drug in this study. Viscoelastic materials are uniquely
example, the compactability of microcrystalline cellulose (MCC) is affected by their sensitivity to both moisture [9,12] and time under
significantly reduced after granulation [7]. It was found that a loss of load [12,14]; 2) acetylsalicylic acid (aspirin), a drug known to deform
compactability following conventional wet granulation is associated plastically [15], and 3) acetaminophen (APAP), known to undergo
with a decrease in the particle porosity of MCC [8]. This is due to the brittle fracture. APAP exhibits poor tableting characteristics because
strain hardening effect of the wetting and drying process that leads to the particles of this drug are very hard, and therefore, inter-particulate
strong hydrogen bonds between the hydroxyl groups of the cellulose bonding is very weak [16]. Furthermore, APAP has been shown to be
chains and results in an increased elastic modulus. Mechanical susceptible to capping following compression [16–19].
properties of pure excipients have been extensively studied since Interestingly, while the thermodynamically stable and commer-
they can impact a successful tablet formulation. For instance, cially available monoclinic polymorph of APAP (form I) requires
viscoelastic materials such as starch [9] or polyethylene oxides for binders for tablet formation, the metastable, orthorhombic form does
controlled-release applications [10] are known to be strain-rate not. The reason for the significant difference in mechanical properties
sensitive; thus, when scaling-up to faster tablet machines with lies in the fact that the crystal structure of form I consists of puckered
decreased dwell times, a reduction in tablet tensile strength can be hydrogen-bonded sheets which are relatively stiff and do not easily
observed because the material did not receive sufficient time under slip over each other during compression. However, the crystal
load for good bond formation. structure of form II has parallel hydrogen-bonded sheets which give
Hiestand tableting indices have traditionally been employed to rise to slip planes that allow for plastic deformation and improved
study the mechanical properties of pure excipients or drugs. These compression properties [20].
tableting indices, developed over 30 years ago, have been found to be Aspirin and APAP were chosen specifically because there is
sufficiently sensitive to detect lot-to-lot variations in raw materials representative data on the Hiestand indices already reported in the
[11]. Hiestand indices provide a fundamental understanding of the literature for comparison purposes [11]. On the other hand, to our
behavior of materials under compression and decompression. While knowledge, this is the first work that Hiestand tableting indices of
typically used to characterize pure materials, this research is an metformin are discussed. This work is also important because much
attempt to study the mechanical properties of pharmaceutical previous work has focused on the mechanical properties of pure
granulations prepared using two different binder delivery processes excipients [3,21–23] or pure drugs [11,23] as well as model formula-
for wet granulation and three drugs of different intrinsic mechanical tions without drug [24,25] but not on drug-based granulations.
properties. The indices of relevance here include the worst-case The objectives of this study are to 1) establish a fundamental
bonding index (BIw) and the brittle fracture index (BFI). understanding of the physico-mechanical properties of high drug load
BIw is a ratio of the compact's tensile strength to its dynamic granulations manufactured using conventional wet or foam granula-
indentation hardness and indicates the ability of intra-particulate tion techniques and determine the influence of the binder delivery
bonds formed during the compression phase to survive during the technique on the granulation mechanical properties; 2) provide
decompression process. Relatively speaking, a higher BIw value guidance for selection of the most appropriate granulation process
indicates a more plastic material, and such materials will likely have based on the mechanical properties of drug; and 3) determine if any
lower dynamic hardness values. Plastic deformation occurs during relationship exists between the physical properties (i.e., particle size,
tablet compression and decompression. As compression takes place, surface area) and mechanical properties of each granulation.
particles initially rearrange and repack to assume a smaller bed
volume. When no further reduction in volume is possible through 2. Experimental
rearrangement, particles begin to deform. When their elastic limit is
exceeded, permanent deformation occurs through brittle fracture Acetylsalicylic acid USP was purchased from Spectrum Chemicals
and/or plastic deformation, and the particle bed is sheared. When the (New Brunswick, NJ), metformin hydrochloride USP was obtained
shear strength is greater than the breaking strength, particle fracture from Bristol-Myers Squibb (Evansville, IN) and acetaminophen USP
occurs. When the shear strength is less than the breaking strength, and magnesium stearate NF were purchased from Mallincrodt Inc. (St.

3. S.L. Cantor et al. / Powder Technology 195 (2009) 15–24 17
Table 1 time of 12 h. The LOD of the granulations was determined using a
Formulations for conventional wet or foam granulations. Mettler DSC HFT-2000M Moisture balance (Columbus, OH). Samples
Material Wet process % Foam process % of approximately 2.0 g were dried to constant weight at 105 °C for
Drug 80.0 80.0 10 min.
Microcrystalline cellulose 17.0 17.0
Hydroxypropyl cellulose 3.0 Dry 2.0 2.2. Physical characterization of granulations
As foam 1.0
Water added during granulation 12–14 12–14
Particle size of the dried granulations was determined in duplicate
by sieve analysis using a sonic sifter (Allen Bradley ATM Model L3P
Sonic Sifter®, Milwaukee, WI). Sieving was run for 5 min at an
Louis, MO). Microcrystalline cellulose NF (Avicel® PH-102, FMC, amplitude setting of five and a pulse setting of 5. The percentage by
Philadelphia, PA) and hydroxypropylcellulose (HPC) NF (Klucel®, weight retained on each sieve was determined and the geometric
Aqualon, Wilmington, DE) were also used in this study. mean diameter, labeled as GMD or dg, and geometric standard
deviation, σg, of the particle size distributions were calculated using
2.1. Granulation batches using a high-shear mixer Eqs. (2) and (3), respectively [27]:
P
Table 1 lists the conventional wet and foam granulation formula- ðni T log di Þ
log dg = P ð2Þ
tions used in this study. The rationale for devising simple model ni
formulations consisting of only three ingredients is because a
comparison of results using the Hiestand Indices can become difficult where ni is the weight percent of particles in the ith interval, for all ni;
if a more complex system of materials is used [26]. The drug load was and di is equal to the midpoint of the diameter of the size interval in
kept constant at 80.0% w/w. Since a high drug load was used, it is the ith interval, for all di.
assumed that physical and mechanical properties of the drugs 2P 2 31 = 2
themselves exert a significant impact on the properties of the ni log dg − log di 7
6 P
resultant granulations. Granulations containing each of the three log σ g = 4 5 ð3Þ
ni
drugs (metformin, aspirin, and APAP) were manufactured by either
conventional wet or foam granulation processes. Mixing and
granulation was performed in a 6-L Diosna high-shear granulator The spread of the data was calculated as D90 − D10, where D90 and D10
(Osnabruck, Germany) at a batch size of 1 kg. All powders were pre- are the diameters of the 90th and 10th percentiles of the cumulative
blended in the mixer for 2 min before granulation, with the mixer particle size distribution, respectively. The particle size span, Sx, which
impeller set at 200 rpm and the chopper set at 500 rpm. gives a description of the width of the distribution and is independent
During conventional wet granulation, mixer impeller and chopper of the median size, was calculated according to Eq. (4) [28]:
were set at 300 rpm and 1300 rpm, respectively. Water was added at a
rate between 55 and 65 g/min using a peristaltic pump and the D90 − D10
Sx = ð4Þ
impeller power was recorded at several fixed time intervals during D50
granulation. The total amounts of water added were adjusted for each
drug, but kept constant for both conventional wet and foam According to Fan et al. [28] if the span of the distribution is b2, it is
granulation processes for a drug. considered narrow; ≥2 but b3, moderate; and ≥3, considered a broad
The foam granulation process utilized the same mixer impeller and distribution. All spans calculated from the granulation data were less
chopper settings as for the conventional wet granulation process. A than 2, indicating that the breadth of the distributions were relatively
10% w/w HPC stock solution was prepared by dissolving HPC in water narrow.
with gentle stirring overnight. The concentration of the HPC solution Optical microscopy was used to examine the particle morphology
was further adjusted before granulation so that 1% of HPC in the of the pure materials as well as the conventional wet granulation
formulation was added as foam and 2% HPC as dry powder in the pre- and foam granulation samples (Nikon SMZ 1500 digital camera using
blend. Therefore, final quantity of HPC (3%) was the same as in Act-1 v.1 2.63 software (Micron Optics, Cedar Knolls, NJ) at 50×
formulations used in conventional wet granulation. magnification.
HPC foam was generated utilizing the same concepts previously All granulations were hand sieved using a mesh cut of #30/#80
described by Keary and Shesky [1]. The compressed air and liquid flow (595–177 μm) to eliminate oversize and fines and only particles
rates were adjusted to achieve a ≥90% foam quality, according to Eq. retained on #80 were used for the following characterizations and to
(1): prepare compacts. Using a narrow particle size range minimized
particle size effects and improved comparability among the different
Rate of air flow − Rate of liquid flow drug granulations.
Foam quality = T100 ð1Þ
Rate of air flow The true densities of dried, sieved granulations were determined
by a helium pcynometer (AccuPyc 1330, Micromeritics, Norcross, GA).
Air flow rate and liquid flow rate were 2.0 L/min and 0.1 L/min, The true densities used in the solid fraction calculations were the
respectively. The rate of addition of the foamed binder was kept the average of five determinations.
same as for water during the conventional wet granulation process, Surface area and average pore diameter were determined by
approximately 55–65 g/min. A high foam quality enables the foam to nitrogen adsorption (Gemini 2380, Micromeritics, Norcross, GA) for
behave more solid-like and retain its properties better as it flows powdered formulations before conventional wet granulation (i.e.
through a rigid plastic pipe from the foam generator into the high- before water addition) and all dried granulations, which includes
shear mixer. The foam was homogeneously dispersed into the powder conventional wet granulation and foam granulation batches (i.e. after
during granulation. wet granulation). Accurately weighed samples (1.0–1.3 g) were
The wet granules were dried in a hot-air convection oven at 60 °C degassed by nitrogen flow and dried at 60 °C overnight (VacPrep
for 6 h to a loss on drying (LOD) value of less than 2.0%. For 061, Micromeritics). The amount of nitrogen adsorbed was deter-
comparison purposes using aspirin, an additional conventional wet mined at partial nitrogen vapor pressures (P / Po) ranging between
granulation batch was also prepared and dried for a longer drying 0.05 and 0.98. Surface area was determined by the Gemini software

4. 18 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24
using the Brunauer, Emmett, and Teller (BET) isotherm calculation for of 0.4 times the compact width; and a vertical fracture through the
the nitrogen adsorption data in the P / Po range from 0.05 to 0.30. Pore center of the compacts indicated that the failure occurred in tension.
size diameter was also calculated by the Gemini software using the The platens were padded with cardboard paper to decrease the
BET analysis (4 × pore volume / surface area) for the adsorption data in stress concentration at their edges and this minimized the shear
the P / Po range from 0.05 to 0.30 [29]. failure of the compact [32]. The time constant between loading to
fracture process was set at approximately 10 s, which is the amount
2.3. Mechanical characterization of granulations of time between 1 / e, or 0.368, of the fracture force and the time
of the fracture force (the mathematical constant, e, has a value of
The relative degree of brittleness or plasticity of a high drug load 2.718).
granulation can be calculated following the well established methods The tensile strengths of compacts without holes (σT) and of
of Hiestand [6,11,30,31]. Flawless square compacts were created using compacts with holes (σTo) were measured. A total of at least 6
tri-axial decompression. This method is selected due to its ability to compacts were tested for each granulation and the average was used
release elastic stresses in three dimensions following decompression. to calculate the Hiestand tableting indices.
Three discrete tests are then subsequently performed on the compact,
(tensile strength, dynamic indentation hardness, and chordal radius) 2.3.3. Dynamic indentation hardness
and this combined information was used to calculate the Hiestand The dynamic indentation hardness (H) test employed a custom-
tableting indices. Conventional wet granulation formulations, both built pendulum impact device using a steel sphere with a weight of
before and after water addition (e.g., dried), and foam granulation 0.0618 g as the indenter, which was suspended from a one-meter
batches were characterized for their mechanical properties. length of 15-pound fishing line. The face of the compact is covered
with a small strip of carbon paper before being clamped onto the
2.3.1. Preparation of square compacts by tri-axial decompression testing platform. The sphere is held in place by an electromagnet and
Square compacts of approximately 3.0 g measuring 2.0 cm × then released, once the sphere impacts the compact, the carbon is
2.0 cm × 0.6 cm were prepared using a custom-built tri-axial decom- transferred to the dent and enables easier viewing. The short dwell
pression press. A split-die block was used along with a computer- time of the indenter acting on the compact minimized any strain-rate
controlled hydraulic system (Loomis Engineering and Manufacturing dependent effects. The inbound and rebound velocities in m/s of the
Company, Caldwell, NJ). Compression forces ranged from 6000 to sphere were measured using an optical ballistic sensor and are
30,000 lb and a 10 s dwell time at maximum compression force was converted into the initial height, hi, and rebound height, hr, by using
used. The compression forces employed for aspirin, metformin, and Eq. (7):
APAP granulations were 6000, 20000, and 30000 lb, respectively. The
edges of the die surface were sparingly lubricated with magnesium ðvelocityÞ2 ðvelocityÞ2
h= = : ð7Þ
stearate suspended in acetone when needed. For evaluating the brittle 2×g 19:62
fracture index, a stress concentrator was also introduced in the center
of the compacts using an upper punch equipped with a 1.1-mm The degree of rebound of the sphere occurs as a result of the elastic
diameter, round, spring-loaded retractable pin. modulus or hardness of the material [32]. The chordal radius of the
This tri-axial press allows for release of elastic stresses in three indentation was determined using a Mahr Federal Perthometer
dimensions during decompression by allowing the split die to expand Concept #3754341 (Gottingen, Germany) equipped with a dia-
and hence to produce flawless compacts suitable for tensile strength mond-tip stylus to trace through the surface roughness of the indent
testing. While the compact dimensions were measured with a caliper on the compact. Two measurements were taken per compact by
immediately after ejection, compacts were allowed to undergo elastic rotating each sample by 90°. A total of 10 measurements were
recovery for a 24 h period prior to testing. The solid fraction is defined taken for the chordal radius of each granulation and the averages
as the proportion of solid material contained in the compact and was calculated. At least 5 compacts were tested for each granulation and
calculated according to Eqs. (5a) and (5b). The pressure of the tri-axial the dynamic indentation hardness (H) was calculated according to
press was adjusted for each granulation to achieve a constant solid Eq. (8):where:
fraction of 0.90 ± 0.01 or 10% porosity.
4mgrhr hi 3
compact weight H= − ð8Þ
Apparent density ρapp: = ð5aÞ πa4 hr 8
compact volume
ρapp:
Solid fraction = ð5bÞ where:
ρT
m mass of the indenter,
where ρT represents the average true density of the granulation g gravitational constant,
determined in Section 2.2. r radius of indenter,
hi initial height of indenter,
2.3.2. Determination of tensile strength hr rebound height of indenter, and
An Instron® Model 5567 stress–strain analyzer equipped with a a chordal radius of the dent.
30 kN load cell and using a Bluehill® software (version M-K2-EN
Revision B, Norwood, MA) was used for tensile strength (σT) testing of
compacts according to Eq. (6):
2.3.4. Hiestand tableting indices
Peak Force
The worst-case bonding index (BIw) is calculated according to Eq.
2
Tensile Strength N=m = ð6Þ (9):
ðlenght TwidthÞ
σT
The ramp rate was set at 1.0 mm/min and the failure was BIw = ð9Þ
H
determined both by when the true strain was ≤10% and when the
compressive load threshold fell below 5 N. Testing was performed where σT is tensile strength and H is the dynamic indentation
under transverse compression between two platens each with a width hardness.

5. S.L. Cantor et al. / Powder Technology 195 (2009) 15–24 19
Fig. 1. Granulation power plots for the different drugs (A) wet granulation and (B) foam granulation.
The brittle fracture index (BFI) is the ratio of the tensile strength of increases the surface area per gram of liquid several fold compared to
the compacts without a hole, (σT), and with a hole, (σTo), at their the sprayed system. Furthermore, foam has the capacity to spread
center and is given by Eq. (10): rather than to soak (i.e. a low soak-to-spread ratio), and particles that
are initially non-coated become surface-coated by the spreading foam.
σT 1
BFI = − ð10Þ
2σ To 2
The BFI scale ranges from zero, which represents highly ductile/
plastic materials, to one, which indicates highly brittle materials that
show a greater propensity to cap or laminate during decompression/
ejection [33].
3. Results and discussion
3.1. Granulation particle size
For a given drug, impeller power vs. time plots were higher for
conventional wet granulation (Fig. 1A) than foam granulation
(Fig. 1B). During conventional wet granulation, water droplet size
can influence the extent of development of large granules or oversize
and binder distribution at short mixing times [34]. However, Ax et al.
[34] also noted that the distinction between spraying binder liquid
with different droplet sizes becomes less pronounced on the
granulations as process time increases. This is likely due to the fact
that competing breakage and re-agglomeration phenomena will be
occurring simultaneously during high-shear mixing. Furthermore,
conventional wet granulation typically involves areas of localized over
wetting of particles which then become agglomerated. Therefore, in
order to optimize particle size distribution and improve flow proper-
ties, conventional wet granulations usually require a milling operation
after drying. Interestingly, the foam process showed a less steep slope
from the power profile and lower power consumption compared to
conventional wet granulation particularly for metformin and aspirin.
This suggests less viscous granulation and more controlled initial
granule growth for these two drugs due to improved binder
distribution and less localized over wetting during foam granulation
as compared to conventional wet granulation. Water added via the
conventional drip method have larger droplet sizes compared to a
binder solution added as aerated foam. On the other hand, APAP
power consumption profiles for both the conventional wet granula-
tion and foam granulations were more similar; therefore, the effect of
localized over wetting was not as pronounced for conventional wet
granulation of APAP.
Keary and Sheskey proposed the hypothesis of foam granulation
and how the foamed binder circumvents localized over wetting during
conventional wet granulation [1]. A foam is by definition, air dispersed
in a liquid continuous phase. In foams prepared using the same liquid, Fig. 2. Optical microscopy pictures of APAP particle morphology. Pure material (P), wet
this phase inverted relationship of liquid-to-air is significant and granulation (W), and foam granulation (F).

6. 20 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24
This is in contrast to the conventional wet granulation process where
the dry binder is dispersed in the powder bed and larger water
droplets are dripped or sprayed on top of the particles. In this case, the
spray droplets are typically of the same size range as the powders to
be granulated.
In general, there appeared to be some level of primary particle
agglomeration in all three drug samples for both granulation
processes. However, it is unclear whether there are differences in
the spatial distribution and thickness of the binder solution around
the granules in the conventional wet as compared to foam granulation
processes. It appears from the optical microscopy pictures that the
granulation processes had the most effect on the APAP particle
morphology and physical properties (Fig. 2). While pure APAP (P) is a
cohesive, poorly flowable powder comprised of acicular needles, this
drug became appreciably less cohesive following either conventional
wet (W) or foam granulation (F) processes. Furthermore, there also
appeared to be some particle agglomeration occurring in addition to
the distribution of uneven binder for both APAP granulation samples.
While there was some primary particle agglomeration occurring only
with the smaller size fractions of aspirin in conventional wet (W) and
foam granulation (F) samples (Fig. 3), granules from the two
granulation processes appeared similar. Pure metformin (P) (Fig. 4)
showed a heterogeneous mixture of particle size and shape. Both
Fig. 4. Optical microscopy pictures of metformin particle morphology. Pure material (P),
wet granulation (W), and foam granulation (F).
metformin granulations showed similar particle agglomeration,
however, there appeared to be an appreciable reduction in the
amount of fines for metformin granulations relative to APAP and
aspirin granulations.
Geometric mean diameter (dg) and geometric standard deviation
(σg) were similar for both conventional wet and foam granulation
processes for a given model drug (Table 2). Among the three drugs,
APAP granulations processed by both conventional wet and foam
granulation exhibited the smallest granule size as compared to
metformin and aspirin (Table 2). Granule particle size distributions
of the model drugs are illustrated in Fig. 5A–C. Generally, the higher
percentage of larger granules for aspirin and metformin compared to
APAP can be attributed to the relatively larger particle sizes of these
pure materials (P) (Figs. 3 and 4). Compared with the other two drugs,
the APAP granulations had the greatest percentage of fines, ca. 10%
b74 µm (Fig. 5A) and a wider span (Table 2). It is interesting to note
that the foam granulation process yielded a higher proportion of
larger particles (≥500 µm), for the APAP and metformin samples.
This, together with the generally lower impeller power current vs.
time plots observed for the foam granulation process (Fig. 1), suggest
Fig. 3. Optical microscopy pictures of aspirin particle morphology. Pure material (P), that other factors other than drug mechanical properties, such as drug
wet granulation (W), and foam granulation (F). surface hydrophlicity/hydrophobicity and wettability can influence

7. S.L. Cantor et al. / Powder Technology 195 (2009) 15–24 21
Table 2 mechanical properties of these conventional wet granulations. This is
Physical characterization of granulations for three model drugs. discussed further in Section 3.3.
Geometric mean Spread Span LOD Surface Average
diametera and of data of datac,d % area pore 3.3. Mechanical properties of granulations
geometric standard (μm)c,d (m2/g) diameter
deviationb (μm) (nm)
Mechanical properties of compacts from all granulations were
Dried granulations
characterized by their dynamic indentation hardness, tensile
Conventional Wet
Metformin 421.0 (1.7) 505.6 1.20 0.9 0.17 6.7 strengths, BIw, and BFI values (Table 3). The dynamic indentation
(2.5) (0.02) hardness (H) indicates the resistance of a material to permanent
Aspirin 541.6 (1.5) 483.9 0.86 1.7 0.19 4.5 plastic deformation under a compressive load and will vary depending
(0.5) (0.05) on the ductility or brittle nature of the material. The tensile strength
APAP 147.7 (1.9) 215.4 1.61 0.8 0.29 7.8
(0.7) (0.00)
represents the strength of a compact after permanent plastic
Foam deformation has occurred and gives an indication of the extent of
Metformin 507.9 (1.6) 503.9 0.99 1.3 0.13 7.4 intra-particulate bonding due to true contact areas formed between
(1.6) (0.01) the surfaces. In evaluating the different processes for metformin, foam
Aspirin 452.1 (2.2) 539.4 1.44 2.0 0.16 4.1
granulation showed a higher H, while the tensile strength was the
(4.1) (0.15)
APAP 157.8 (2.0) 232.3 1.47 1.1 0.28 10.1
(0.8) (0.01)
Powder before wet granulation
Metformin – – – – 0.213 10.20
Aspirin – – – – 0.180d 8.7d
APAP – – – – 0.304 8.99
a
Geometric mean diameter, (dg).
b
Values in parenthesis represent the geometric standard deviation, (σg).
c
Values in parenthesis represent the arithmetic standard deviation.
d
Values are the average of 2 measurements.
the granulation properties and granule growth during the 2 granula-
tion processes. It will be worthy to probe these factors and determine
if these are different during the 2 granulation process in future studies.
3.2. Surface area and pore diameter
The surface area of a granulation is an important physical property
that can affect granule flowability as well as final tablet hardness. The
surface area results for metformin and aspirin sieved granulations
were similar, while sieved APAP granulations had a smaller mean
particle size and a larger surface area than metformin and aspirin. In
order to investigate the effects of wet granulation and the method of
granulating liquid addition on the powder formulations, surface area
and pore diameters were also measured for the dry powder
formulations before granulation (Table 2). Generally, there were
minimal changes in the surface area and pore diameter results for all
samples, and when comparing between the two granulation
processes.
While all granulations were dried to b2.0% LOD for 6 h, to further
investigate the effect of over-drying aspirin formulation prepared by
conventional wet granulation, a batch was dried for an additional 6 h
to study the effect of additional drying time on the mechanical
properties of the granulation. The surface area and pore diameter
values for the aspirin granulation dried for 12 h (LOD 1.9%) were
0.05 m2/g and 3.2 nm, respectively. However, for the aspirin
granulation dried for 6 h (LOD 1.7%), the surface area and pore
diameter values were 0.19 m2/g and 4.5 nm, respectively. While the
pore diameter remained essentially unchanged, this additional drying
time for the aspirin conventional wet granulation sample caused a
significant reduction in the surface area. This can be attributed to the
drying process that removes the added water first from the surface
and then from the pores within the particles. As the internal water
was removed from the structure, the granules begin to densify due to
the collapsing of their pore structure. Even though there is a negligible
LOD difference between aspirin granulations dried for either 6 or 12 h, Fig. 5. Particle size distributions for (A) APAP, (B) aspirin, and (C) metformin,
such granule densification will likely have a major impact on the conventional wet granulation vs. foam granulation.

8. 22 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24
Table 3 than for either conventionally wet granulated sample, indicating
Mechanical characterization of granulations for three model drugs. enhanced plasticity. The chordal radius determined from the aspirin
Dynamic hardness Tensile strength BIw BFI before granulation compact was slightly less than the value from the
(H) N/m2 109 N/m2 × 106 10− 3 foam granulated compact. Thus, while the foam granulation process
Dried granulations appears to enhance the plasticity of aspirin, the conventional wet
Conventional Wet granulation process decreases its plasticity. However, the rebound
Metformin 0.4 (0.01)a 0.7 (0.0) 1.7 0.001
velocity data offers some contrasts. The highest rebound velocities
Aspirin wet (6 h drying) 0.1 (0.0) 0.7 (0.0) 7.0 0.002
Aspirin wet (12 h drying) 0.2 (0.0) 0.7 (0.0) 3.5 0.1 were obtained for the aspirin before wet granulation sample and the
APAP 0.5 (0.01) 0.7 (0.16) 1.6 0.02 lowest values observed were for the aspirin granulations dried for
Foam either 6 or 12 h. This data indicates that the conventionally wet
Metformin 0.7 (0.01) 0.7 (0.0) 1.0 0.1 granulated samples are more ductile than either the aspirin before
Aspirin 0.1 (0.0) 0.7 (0.0) 8.9 0.5
APAP 0.3 (0.0) 1.0 (0.03) 3.8 0.005
wet granulation or the foam granulated sample. The contrasts
between the chordal radius and rebound velocity results support
Powder before wet granulation the likelihood that aspirin undergoes a mixed deformation
Metformin – 0.03 (0.31) – 0.81 mechanism.
Aspirin 0.08 (0.00) 0.4 (0.15) 4.7 0.08
In their study comparing microcrystalline cellulose granulated
APAP 1.2 (0.01) 0.7 (0.0) 0.55 0.06
with 3% HPC, Badawy et al. [8] found that there was a significant
a
Values in parenthesis represent the arithmetic standard deviation. decrease in the surface area when comparing under-granulated with
over-granulated samples; 0.91 m2/g vs. 0.53 m2/g, respectively. The
authors reported that the difference in surface area can impact and
reduce the compactability of the microcrystalline cellulose to varying
degrees.
same for both processes. However, the higher H values resulted in a Similarly, lactose, an excipient with some brittle character, showed
lower bonding index, BIw for the foam granulation suggesting that this lowered compactability after being over-granulated with excess water
process may not be beneficial for metformin. Lower BIw indicates less and high-shear forces. The reason for this effect was found to be the
plastic deformation behavior and lower ability of intra-particulate inability of the larger, denser granules with reduced surface area to
bonds formed during the compression phase to survive during the significantly fracture or deform when subjected to a compressive load
decompression process. [35,36]. It is noteworthy to also mention that the extent of brittle
Compacts were prepared from the metformin formulations before characteristics and thereby the mechanical properties can vary quite
conventional wet granulation (dry powder) as well as after conven- significantly depending on the preparation method of the grade of
tional wet granulation (dried) in order to compare their tensile lactose selected [37,38]. In addition, such brittle excipients can cause a
strength values (Table 3). The average peak strengths of the before decrease in tablet crushing strength due to the fact that these
and after conventional wet granulation samples were 10.5 N/m2 and materials are characteristically harder and tend to be poor at forming
272 N/m2, respectively; which corresponds to tensile strength values strong inter-particulate bonds [39].
of approximately 0.026 × 106 N/m2 and 0.7 × 106 N/m2, respectively. It There were significant differences in dynamic hardness between
is interesting that after conventional wet granulation, the metformin the two granulation processes for APAP, the model drug known to
formulation displayed roughly a 27-fold increase in the tensile undergo brittle fracture. The results showed that the powder before
strength of the compacts. This significant increase in tensile strength conventional wet granulation had the highest H value of all the
with the addition of water from the conventional wet granulation samples tested, indicating the brittle character of APAP. However, the
process indicates that metformin has viscoelastic properties. Based on dynamic hardness was reduced by N50% after conventional wet
the data thus far, the conventional wet granulation process offers the granulation and further still after foam granulation (Table 3).
most benefit for metformin in terms of improvement in mechanical Furthermore, it was only for APAP that an improvement in tensile
properties. strength was observed when comparing after granulation samples
A brittle material will resist permanent deformation and hence, from the conventional wet and foam granulation processes to before
show a smaller indentation from the sphere, with a resultant smaller granulation samples. Tensile strength value of 1.0 N/m2 for APAP foam
chordal radius. Also, less of the impact energy will be absorbed by a granulation was the highest of all the granulations. These results
brittle material and that will result in a higher rebound velocity. This is indicate that for a brittle drug such as APAP, the foam process is more
in contrast to a compact composed of a ductile material. Such a plastic appropriate to improve the mechanical properties of the drug. This
compact is relatively softer and will deform around the sphere, may be attributed to the higher surface area of solution in the form of
absorbing its impact energy and leaving a much larger dent, therefore tiny bubbles of foam that enabled a more uniform distribution of the
displaying a larger chordal radius. plastic binder to cover the drug granules, thus modifying their
Different properties were observed for aspirin, a known ductile mechanical properties more effectively.
material. For the conventional wet granulation process three samples
were evaluated; before granulation (without any added water), after 3.4. Hiestand tableting indices
granulation dried for 6 h, as well as the granules over-dried for 12 h.
The conventional wet granulation sample that was over-dried for 12 h The BIw and BFI values can be used to further elucidate which
behaved very differently. The extra drying time caused the granule granulation process is best suited to improve the intrinsic mechanical
surface area to collapse. Therefore, as the water evaporated from properties of the drug. These two indices have an inverse relationship;
within the pores of the particles, the particles became denser, harder therefore, a higher BIw and/or a lower BFI are indicative of plastic
and more brittle. This is clearly seen in the doubling of the dynamic deformation behavior. BIw and BFI values of the formulations are listed
hardness value (H). in Table 3.
Furthermore, interesting relationships were observed when In comparing the conventional wet and foam granulations for
examining the chordal radius and rebound velocity data for the metformin, the conventional wet granulation (after) sample yielded
different aspirin granulations. While the chordal radii and rebound the highest BIw as well as the lowest overall BFI value of 0.001. On the
velocities were similar in both the 6 and 12 h granulations, the chordal other hand, the powder blend before conventional wet granulation
radius for the aspirin foam granulation was approximately 30% higher showed the highest overall BFI value of 0.81. The addition of water in

9. S.L. Cantor et al. / Powder Technology 195 (2009) 15–24 23
the conventional wet granulation process dramatically improved the was determined. While there do not appear to be major differences in
BFI value of metformin by 800-fold and showed markedly improved surface area and pore size for the different granulation batches, there
plasticity as compared with the powder blend before granulation. were discernible differences in their mechanical properties. The foam
These results were also an improvement over the foam granulation process appeared to significantly enhance the plasticity of a granula-
process. This supports the data discussed previously that conventional tion containing a brittle drug such as APAP. However, foam granula-
wet granulation is the best process for this drug (Table 3). BIw tion with a ductile drug like aspirin produced a material with mixed
measures the survival success of true contact areas formed at deformation behavior based on the high BIw and BFI values. This is in
maximum compressive stress; viscoelastic materials such as metfor- contrast to the conventional wet granulated aspirin that showed an
min will produce compacts with higher tensile strengths due to inverse relationship between high BIw and low BFI values.
enhanced intra-particulate bonding in the presence of higher Foam granulation did not enhance the plasticity for viscoelastic
moisture levels. BFI indicates the ability of a material to relieve stress materials like metformin and the conventional wet granulation
by plastic deformation in accordance with the Griffith crack propaga- process was observed to confer the greatest advantage for metformin.
tion theory. If the BFI is less than 0.2 there will typically be no capping The increase in plasticity for foam granulated formulations may be
or lamination. However, if the BFI is N0.2 in conjunction with poor BIw due to the improved surface coverage of HPC on the drug particles as
values, there is a greater probability of capping or lamination [4,11]. compared to the conventional wet granulation process. In conclusion,
Among the aspirin granulations, the lowest BIw value of 0.0035 the selection of the most appropriate granulation process (conven-
was observed for the over-dried, low surface area (0.05 m2/g) tional wet or foam) to improve a drug product's manufacturability can
conventional wet granulation sample, indicating relative brittle be guided by knowledge of the intrinsic mechanical properties of the
behavior. This effect has been previously reported for conventionally drug.
wet granulated microcrystalline cellulose where the authors found
that dense, less porous granules would be less prone to fragmentation Acknowledgements
or plastic deformation during compression [8]. A comparison of BIw
and BFI values before and after conventional wet granulation (6 h The authors would like to acknowledge BMS for providing the
drying) indicated that the aspirin formulation improved in plasticity opportunity and summer internship funding to S. Cantor to conduct
after conventional wet granulation. Foam granulated aspirin exhibited this work and also to the BMS foam granulation team members
the highest BIw value of 0.0089 of all the granulations. However, the especially F. Nikfar; C. Keary and P.J. Sheskey (Dow Chemical) for their
BFI value of 0.5 observed for foam granulated aspirin was high given technical input and assistance.
that aspirin is known to be ductile. Therefore, the deformation
behavior of the aspirin foam granulation can be considered as
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