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Quality by Design Methodology for Development and Scale-up of Batch

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Article  in  Journal of Pharmaceutical Innovation · December 2008

DOI: 10.1007/s12247-008-9048-9

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J Pharm Innov (2008) 3:258–270
DOI 10.1007/s12247-008-9048-9
RESEARCH ARTICLE
Quality by Design Methodology for Development
and Scale-up of Batch Mixing Processes
Patricia M. Portillo & Marianthi Ierapetritou &
Silvina Tomassone & Christine Mc Dade &
Donald Clancy & Petrus P. C. Avontuur &
Fernando J. Muzzio
Published online: 2 December 2008
# International Society for Pharmaceutical Engineering 2008
Abstract In this study, a quality by design approach was
applied to the design and scale-up of a batch mixing
process. Mixtures of acetaminophen and lactose were
sampled at different mixing times using a groove sampler.
Samples were subsequently analyzed using NIR reflection
spectroscopy. The effects of four processing parameters on
the empirical mixing rate in a bin blender were examined.
Blender rotation rate (two levels), powder fill level (two
levels), powder cohesion (two levels), and blender size
(three levels) represent the four parameters studied. Blender
geometry and blender loading method were treated as
constant parameters. Statistical analysis was used to assess
the impact each parameter had on the mixing rate. Blender
size (p=0.02), powder cohesion (p=0.05), and rotation rate
(p=0.07) all significantly affected the mixing rate. The least
significant parameter was the vessel fill level (p=0.18),
indicating mixing performance is not strongly affected by
fill level, given the range studied.
Keywords Quality by design . Batch powder mixing .
Bin blender . Statistical analysis . Mixing rate
P. M. Portillo : M. Ierapetritou : S. Tomassone : F. J. Muzzio (*)
Department of Chemical and Biochemical Engineering,
Rutgers University,
Piscataway, NJ 08854, USA
e-mail: fjmuzzio@yahoo.com
C. Mc Dade : D. Clancy
Process Technologies, Glaxo Smith Kline Company,
709 Swedeland Road,
King of Prussia, PA 19406, USA
P. P. C. Avontuur
GlaxoSmithKline R&D, New Frontiers Science Park,
Third Avenue, Harlow,
Essex CM19 5AW, UK
Introduction
Powder mixing has been the subject of substantial research.
This is motivated by applications in a variety of industrial
sectors, which include pharmaceuticals, food, ceramics,
catalysts, metals, and polymer manufacturing. Understand-
ing mixing mechanisms and identifying critical process and
material parameters is often a crucial step during process
development. Content uniformity problems have four main
root causes: (a) powder stream flow properties [1], (b) poor
equipment design or inadequate operation [2], (c) particle
segregation due to differences in particle properties, and (d)
particle agglomeration, driven by electrostatics, moisture,
softening of low melting point components, as well as other
factors.
Scale-up of mixing operations continues to present a
concern to the pharmaceutical development process. The
reliable scaling of a process requires an understanding of
the effects that processing parameters may illicit on
intermediate- and finished-product properties. Generally,
processing conditions are thoroughly examined at small
scales during process development of powder formulations.
The design and scale-up of blending operations is a
multivariate issue; the relative magnitudes of shear,
dispersion, and convective forces may be altered as the
process is transferred to larger scales [3].
A problem with the current scale-up philosophy is a
failure in addressing several critical variables. Shear rate
and total strain have been shown to affect blend micro-
structure [4], which may consequently affect the degree of
ingredient agglomeration, blend flow properties, tablet
hardness and final product dissolution, which may ulti-
mately result in failures during the scale-up process. An
example of this includes blend over-lubrication resulting
from the increase in shear (per revolution of the blender)
J Pharm Innov (2008) 3:258–270
intensity as a function of increasing scale [5]. In a separate
study, blender rotation rates were found to affect the relative
standard deviation (RSD) plateau of a given system [6].
Powder cohesion properties also affect the velocity gradient,
where interpaticulate forces dilate the powder bed density. This
may have further implications on downstream processing.
Optimization of the blending process requires an under-
standing of blending mechanisms and critical variables.
Although modifications to powder cohesion, blender size,
and geometry may not be feasible due to other constraints,
operating conditions such as rotation rate and fill level are
easier to alter. An understanding of the interactions among
these variables is essential.
V-blenders, tote blenders, and double-cone blenders are
examples of batch blenders that vary in geometric design.
For these systems, variables such as blender size and fill
level may affect mixing behavior [7–9]. Mixing in tumbling
blenders is limited in the ability to improve upon
component segregation, typically attributable to variations
in particle characteristics (e.g., size and shape), once it
occurs [10]. Further, initial load configuration (top/bottom
and left/right) of the active pharmaceutical ingredient (API)
and excipients has been shown to affect the mixing rate [11].
Brone and coworkers [12] examined the effect of
changing the rotation rate from 8 to 24 rpm for glass beads
in a V-blender. This study illustrated that the mixing
mechanism of free flowing materials was not affected by
rotation rate; however, the total mixing time was ultimately
reduced. Sudah and coworkers [13] varied the rotation rate
from 5 to 15 rpm for art sand in a rectangular tote blender.
This study showed rotation rate did not affect mixing rate
(per revolution) in earlier stages of the mixing process (up
to 64 revolutions of the blender) but did affect the
asymptotic variance plateau (total achievable homogeniza-
tion). The studies also showed that for a cohesive blend,
rotating the vessel at 10 rpm resulted in the smallest
asymptotic variance, which suggested the presence of
competing mechanisms. Later on, Arratia and coworkers
[6] examined the effects of blender fill level (40–85%) on
mixing rate. The study showed a decrease in mixing rate
with increasing fill level for Bohle-Bin blenders.
Alexander and Muzzio [3] generalized some simple
guidelines to help the scale-up process. Some of these may
be applicable for the formulations used in the present case
study.
1. When altering blender size, the dominant mixing
mechanism ratio (i.e., gravitational, shear, convective),
order of material addition, and powder arrangement
should be kept constant.
2. The number of blender revolutions is a key parameter
for free flowing powders. Rotation rates, however, are
largely unimportant.
259
3. Mixing is a function of shear rate for cohesive powders.
In summary, the main variables known to affect
mixing performance are: (1) the design of the mixing
system (e.g., geometry and blend mechanism), (2)
blender size, (3) the fill level, (4) the blender loading
mode, (5) the speed of rotation of the blender, and (6)
the material properties of the ingredients being mixed
(particle size, shape, and density, etc.).
Historical practices in pharmaceutical process develop-
ment have largely involved univariate (OVAT, “one variable
at a time”) approaches, where the effects of a single
variable are examined for a few conditions selected based
on prior experience from a “safe” subset of the permissible
design space. A value of the first variable is then selected
and kept constant as a second variable is examined, and so
forth. However, as suggested in the Process Analytical
Technology (PAT) Guidance [14], the OVAT approach does
not effectively address the effect of interactions between
multiple process variables. As a result, unless the effects of
all variables are nearly independent of one another, the
optimal conditions for operating the process will not be
determined.
The pharmaceutical industry has recently focused sub-
stantial effort on improving its understanding of key unit
operations and developing statistical, instrumental, and
fundamental methods for characterizing and controlling
sources of variability in product performance. Beginning
with the introduction of the PAT Guidance in 2003, and
continuing with the quality by design (QbD) initiative (for
which draft guidance exists in ICH Q8 [15], Q9 [16], and
Q10 [17]), the industry is transitioning from OVAT
approaches to a more multivariate statistical method for
assessing the effects of process variables on product quality.
The “process understanding” that is considered a keystone
of the PAT and QbD initiatives enables the process control
that facilitates the manufacture of quality products meeting
desired performance specifications..
Clearly, application of QbD methods is not a temporally
discrete activity to be completed at an early stage of
product/process development. Rather, QbD is a longitudinal
component of the product life cycle, which, early in the
development process serves as a risk assessment and
formulation screening methodology, later, as a product/
process optimization approach, and finally as a continuous
improvement method during commercial manufacturing.
While the philosophy of QbD methodologies is straightfor-
ward, with the necessary toolbox having been well
developed and long used in other industries, the actual
implementation, however, represents a significant task due
to the fact that (1) the mechanical and physicochemical
properties of many pharmaceutical APIs and excipients are
only partially understood, thus limiting identification of
260
Fig. 1 The three tote blenders used in this study. From left to right:
10, 0.5, and 2 ft3 blender
critical material variables, and (2) there is an incomplete
knowledge of critical process variables for many pharma-
ceutical operations.
As a result, prioritization (early screening) of factors
is difficult, and studies need to address the large
comprehensive parametric space of all conceivably
relevant variables. Because of this incomplete knowledge
of what is truly critical, naive attempts at application of
QbD methodologies are likely to be suboptimal due to a
poorly constructed design space. In this paper, we
attempt to introduce some prioritization guidelines for
batch blending in tumbling blenders, where a knowledge
base exists. The scale-up of blending and assurance of
homogeneity may benefit substantially from the devel-
opment and incorporation of a realistic QbD strategy.
QbD has already begun to be capitalized where new
methods for quantitatively assessing product quality are
being developed. A risk-based strategy for quality
assessment which uses model-based simulation to link
variation in drug product parameters and clinical perfor-
mance has been recently presented [18].
As mentioned, this paper outlines a QbD strategy for the
design of batch blending operations. In the next section, we
discuss the experimental method. This provides the scope of
experimental conditions investigated and the details behind
the fixed parameters, such as blender specifications, loading
pattern, and materials. This section covers all necessary
details concerning the experimental and analytical methods
used in obtaining the data. This includes the sampling
method, analysis technique, and the quantification methods
used to measure mixing performance. The “Effects and
Characterization of Cohesion” section describes cohesion, its
effect on mixing, and the methods used to quantify different
levels of cohesion. The “Results” section is devoted to a
statistical analysis of the factorial batch-blending experi-
ments. Finally, the “Outlook and Conclusions” section
provides closing comments and conclusions.
J Pharm Innov (2008) 3:258–270
Experimental Method
Blender Specifications
The blenders used in this study are shown in Fig. 1. They
have a fixed geometry comprised of a rectangular bin
blender and a pyramidal hopper that forms the tote. This
design was selected for several reasons, including: (1) it is
common, (2) it is available in our lab in three sizes, (3) it
has been thoroughly examined in previous studies, and (4)
a good working knowledge of the critical-to-performance
variables is available. The two larger blenders were
manufactured by the GEA group (Birmingham, UK) and
the smallest blender is a custom-made vessel run under a
step motor control. The rectangular bin blenders used in
this study have been previously employed in the assessment
of blender performance [9, 13, 19]. A schematic of the
blender geometry is illustrated in Fig. 2. The corresponding
dimensions for the three different blenders are shown in
Table 2. Baffles were used since they have been shown to
improve mixing performance [20] by increasing axial flow.
Powder Materials
A binary blend system was investigated. The two blends
examined contained acetaminophen (Mallinkcrodt, milled
to 30 μm) and one of two grades of lactose (De
Melkindustrie Veghel): lactose 125 (55 μm) or lactose
100 (130 μm). The bulk densities of the three powders used
were measured by taking the weight of a finite portion of
powder and dividing it by the volume the powder sample
occupied. The procedure was repeated ten times for each
powder. Experimental densities for lactose 100M, Lactose
125M and acetaminophen are reported as 0.785±9.02E−03,
0.765±1.33E−02, and 0.297±1.57E−02 g/ml.
Powder Loading
The method by which materials are initially loaded into the
blender vessel is a parameter that has been shown to affect the
mixing performance of tumbling blenders. Two particular
loading patterns previously examined are the top-to-bottom
and left-to-right starting configurations. In the top-to-bottom
Fig. 2 Bin blender schematic D
L
Axis of
rotation H1
θ
H2
V
J Pharm Innov (2008) 3:258–270 261

Table 1 Experimental conditions examined nondimensional parameter comparing inertial and gravita-
Tote size Fill Speed (rpm) Cohesion Fr no. tional forces. In theory, if you keep this number the same
(ft3) level for the varying blender sizes, the powder blends within the
mixers are maintaining a constant ratio of inertial and
0.5 50 Low (10) Lactose 100 4.11E−04 gravitational forces [3]. No first principle approaches
0.5 70 Low (10) Lactose 100 4.11E−04
currently exist for the design of a dry blend process scale-
0.5 50 Low (10) Lactose 125 4.11E−04
up, except for the application of the Froude number. The
0.5 70 Low (10) Lactose 125 4.11E−04
2 50 Low (10) Lactose 100 4.29E−04 Froude number can be justified from a generalized
2 70 Low (10) Lactose 100 4.29E−04 momentum balance under fairly drastic assumptions. The
2 50 Low (10) Lactose 125 4.29E−04 Froude number for tumbler mixers is given by:
2 70 Low (10) Lactose 125 4.29E−04
10 50 Low (8) Lactose 100 4.22E−04
Ω2 R
10 70 Low (8) Lactose 100 4.22E−04 Fr ¼ ð1Þ
10 50 Low (8) Lactose 125 4.22E−04 g
10 70 Low (8) Lactose 125 4.22E−04
0.5 50 High (14) Lactose 100 8.06E−04
0.5 70 High (14) Lactose 100 8.06E−04 where Ω is the rotation rate (revolutions per minute), R is
0.5 50 High (14) Lactose 125 8.06E−04 the radius (mm), and g is the acceleration from gravity
0.5 70 High (14) Lactose 125 8.06E−04 (millimeter per square minute). Conversely, semi-empiri-
2 50 High (14) Lactose 100 8.42E−04 cal approaches are based on the Rayleigh method to
2 70 High (14) Lactose 100 8.42E−04 develop similarity criteria. This yields a resulting equation
2 50 High (14) Lactose 125 8.42E−04 that is a function of particle velocity, vessel rotation rate,
2 70 High (14) Lactose 125 8.42E−04
radius, particle diameter, and gravitational acceleration
10 50 High (11) Lactose 100 7.97E−04
10 70 High (11) Lactose 100 7.97E−04
[3].
10 50 High (11) Lactose 125 7.97E−04
10 70 High (11) Lactose 125 7.97E−04 Sampling Method

For each treatment condition, powder samples were taken

configuration, one powder is initially loaded into the vessel,
above this powder bed another powder is layered. In the left-
to-right configuration, a separator is initially inserted into the
vessel where one side of the mixer is loaded with one powder
and the other side with another. In previous experimental
studies [11], the axial variance, defined as the variability
within the axial length of the vessel (axial length is
perpendicular to the axis of rotation) of a powder blend,
was examined in a 56-L tote blender for both loading
patterns. The top-to-bottom loading resulted in significantly
faster mixing rates than left-to-right loading. Thus, the top-
to-bottom loading was used for this study.
Experimental Design
A randomized full factorial design was used to determine
the effect of each parameter and their interactions on the
rate of the mixing process. The full list of experimental
conditions from the combined variable levels is shown in
Table 1. Experiments are conducted for three tote sizes (0.5,
2, 10 ft3) and two volumetric fill levels (50% and 70%).
Each tumbler gyrates at two speeds (low and high) as
shown in Table 1. The speeds are dependent on tumbler
size and are adjusted to keep the Froude number constant,
as illustrated in Table 1. The Froude number is a
after 5, 25, 50, and 100 revolutions using a groove sampler.
The groove sampler consists of a hollow sleeve (1 in. in
diameter) surrounding a solid inner steel rod possessing a
groove along most of the length of the rod. The inner pipe
has a sampling cavity that is 1/2 in. deep and 1/2 in. wide
along the middle 80% of the rod. Rotating the inner pipe
relative to the outer pipe opens and closes the groove
sampler. The sampler (in its open position) was inserted
into the powder bed and subsequently rotated to trap
material within the sampling cavity. After being removed
from the powder bin, the sampler was then placed
horizontally on a stand while open, and the entire device
was rotated to discharge the collected material into a series
of small trays. Sample size can vary with size or width of
the sampler [10, 18].
Sample size and sampling location were constant for all
experiments. The axial sampling locations lie on the axis of
rotation, and the vertical sampling locations lie perpendic-
ular to the axis of rotation. Samples were retrieved from
five radial positions for all three mixing vessels. Ten axial
positions were examined for the two larger mixers (10 and
2 ft3) and five axial positions were examined for the smaller
(0.5 ft3) mixer due to the smaller axial bed. The analysis
and limitations of accuracy and precision for the sampling
device used here have been discussed in detail by Muzzio
and coworkers [19, 21].
262 J Pharm Innov (2008) 3:258–270

NIR Analysis on Homogeneity Effects samples. The results indicated no real advantage from
agitating and scanning the sample multiple times, for the
Near-infrared spectroscopy (NIR) was used in this study system under study. Further, some potential segregation was
due to its rapid real-time analysis, high-throughput capa- detected. Therefore, samples were assayed a single time.
bility, and nondestructive nature. NIR technique details may
be found elsewhere [6, 20, 22]. Following extraction, Quantification of Mixing Performance
samples were collected into glass vials (Fisher, Pittsburgh,
PA, USA) and analyzed using single-point near-infrared Homogeneity Measurements
spectroscopy (FOSS NIR Systems, Silver Spring, MD,
USA). The composition of each sample was examined In order to determine powder homogeneity, the sample-to-
using a Rapid Content Analyzer (NIR 5082) manufactured sample variability was quantified in terms of the RSD. The
by FOSS NIR Systems, Inc. Empirical modeling of the full standard definition of RSD (also known as coefficient of
NIR (1,100–2,500 nm) portion of the spectra (second variance (CoV)) is given by:
derivative pretreatment) was performed using partial least
squares regression. The amounts of acetaminophen and s
RSD ¼ CoV ¼ ð2Þ
lactose varied in the calibration and validation samples. x
Samples ranged from 0% to 5% w/w acetaminophen (0.1%
increments) and 5–10% acetaminophen (1% increments). where s represents the sampling estimate of the standard
Each sample was scanned 32 times without repositioning deviation and x the average of all the samples. As
the vial to obtain an NIR spectrum. The performance of the mentioned, samples were retrieved from the vessel using a
calibration model was validated using 2-g samples with sampler and subsequently measured via NIR. For each
known acetaminophen concentrations. The NIR perfor- radial core position (denoted as j), xij is a sample
mance method was assessed by the root mean square error concentration, xj is the mean concentration, and Nj is the
of calibration (RMSEC) and the root mean square error of number of samples in that core [23, 24]. The standard
prediction (RMSEP). RMSEC and RMSEP values obtained definition of variance (s2) is given by Eq. 3:
in this study were 0.997 and 0.976, respectively. The
resulting model was use to predict the concentration of

X X xij
x 2
acetaminophen in each sample obtained from the groove s ¼
2
ð3Þ
sampler. Powder samples were collected in the same glass j i
Ni
vials (28 mm diameter, 61 mm long, 20 mL volume capacity)
used to analyze the calibration and validation samples. P
Sampling volume and size may substantially affect the i xij
xj ¼ ð4Þ
estimate of variability between sample concentrations. Due Ni
to the increase in scale of scrutiny, larger samples exhibit
smaller variability between acetaminophen concentrations. where N is the number of samples and x is the mean
When the analytical method interrogates the same surface composition found using Eq. 4. The total variance is
area of the powder, however, the measurement sample size decomposed into two components for axial and radial
is constant. The depth of powder in the vial should exceed variability (Eq. 5):
4 mm for reflectance measurements to ensure the effective
beam penetration depth does not exceed the powder depth 1 X
2 1 X X
2
bed. Reflectance spectroscopy may assay a small fraction of s2 ¼ Nj xj
x þ xij
xj ð5Þ
N j N j i
the entire sample, making it relatively more vulnerable to
inhomogeneities within the sample. To mitigate such
problems, multiple cycles of sample agitation followed by The first term is an estimate of axial variance (s2A ) and
sample analysis may be employed; however, this technique the second term, radial variance (s2R ) [11]. Axial variance
may result in sample segregation. When the particle size measures the differences in concentrations between the top
distribution is broad, larger particles will segregate by and bottom of the powder bed.
levitating to the top of the powder bed. To check for such Statistically, if random samples are taken from a
effects, we evaluated the effect of agitation and repeated mixture of average composition q, given the fraction of
assaying. Figure 2 illustrates the RSD profile of all 50 the first component is P and second component is (1−P),
samples (ten samples along the axial bed at 5 radial and the mixture has a random structure, the composition
positions) scanned a single time. The second RSD profile of the samples will be normally distributed. The theoret-
resulted from agitating and subsequently rescanning all the ical variance can be calculated for completely random
J Pharm Innov (2008) 3:258–270
mixtures using Eq. 6 and for nonrandom mixtures using
Eq. 7:
 
P
s ¼P 1

2
ð6Þ
N
 
ð P ð 1
P Þ
LÞ 2
s2 ¼ L þ L ð7Þ
N
where L represents a constant for a given mixture or state of
mixedness and may be determined experimentally when the
value of σ is known for a given value of N. For a system
where the two components are completely unmixed, the
initial variance (s 20 ) of the sample composition may be
calculated using Eq. 8 [21, 25]:
s 20 ¼ Pð1
PÞ ð8Þ
However if Eq. 8 was followed for a mass ratio of 97%
lactose and 3% acetaminophen, the initial RSD would
be ∼3%. This value should represent the largest obtainable
variance for this system. The initial RSD (RSD0) for these
experiments was calculated from a statistical approach
published elsewhere [22, 26]. The RSD0 is 2.45% for the
larger and medium tote (50 samples per time point) and
2.10% for the smaller tote (25 samples per time point). The
discrepancies in RSD values may be due to the differences
in the number of samples retrieved relative to the total
powder mass in each vessel.
Mixing Rate
Process performance monitoring for each parameter com-
bination was evaluated by the mixing rate of acetamino-
phen in lactose. The mixing rate was computed by
retrieving powder samples from the blender as a function
of revolutions. Sample variance and relative standard
deviation as a function of vessel revolutions were deter-
mined from NIR-predicted concentrations. In the absence
of segregation, the variance in a blender typically decays to
its asymptotic value as an exponential of time. Therefore,
mixing rate is measured as the slope of the logarithm of the
variance. The slope, m, is determined from Eq. 9:
P

  Interparticle surface forces such as friction and cohesion are
revolutionsi
revolutions log s2i
logðs2 Þ
m¼ P
2
revolutionsi
revolutions
ð9Þ
where revolutions is the revolution average and logðs2 Þ is
the logarithmic variance average.
263
Effects and Characterization of Cohesion
Cohesion
Powder cohesion is one of the most important properties
affecting flow, and by extension, powder mixing. Cohesion
is caused by Van der Waals, capillary, and electrostatic
attraction forces. Cohesion of a bulk solid is defined as its
resistance to shear (shear strength) under null normal stress
on the plane of failure [24, 27]. Cohesion of powders,
although poorly understood is known to depend on powder
moisture content, presence/absence of glidants, and particle
size. As the size of a particle decreases, the ratio of its
surface area to mass increases. A cohesive powder can be
defined as a material where the interparticle adhesive forces
exceed the particle weight by at least an order of
magnitude. In such systems, particles no longer flow
independently; rather, they move in “chunks” where the
size is dependent upon the intensity of the cohesive stresses
[25, 28]. The effective magnitude of cohesive effects
depends primarily on two factors: (1) the intensity and
nature of the cohesive forces and (2) the number of
interparticle contacts per unit area (packing density). The
effect of cohesion on mixing behavior is not always
obvious. Slightly cohesive powders have been observed to
mix faster than free flowing materials. Strongly cohesive
powders, however, blend much more slowly and often
require externally applied shear, which may be supplied by
an impeller [3]. Chaudhuri and coworkers [26, 29] showed
that material possessing a low intensity of cohesion
(defined as a bond number of 0.1) enhanced mixing relative
to no cohesion (bond number equal to 0) in a rotating drum.
Conversely, high values of cohesion (bond numbers greater
than 60) reduced the mixing rate. Slight cohesion was
shown to improve mixing rate in a rotating drum blending
process [27, 30]. In a separate report, slight cohesion may
also result in agglomerates [28, 29, 31, 32] that ultimately
result in segregation due to the variability in particle
diffusion in the vessel [26, 29]. Depending on the blending
process, size, and design conditions of the equipment, the
effect of cohesion varies as shown by several references in
the “Introduction” section. The following sections discuss
two methods for quantifying cohesion.
Hausner Ratio
dependent on the total surface area. Since mass is
proportional to the volume, the surface area to volume
ratio is a good general indication of the “flowability” of a
powder system [30, 33]. The Hall flowmeter and Hausner
ratio are two common techniques for analyzing the effect of
interparticle forces on the flow behavior of powder systems
264
Table 2 Bin blender and baffle dimensions
Mixer (ft3) D (mm) H1 (mm) H2 (mm) L (mm)
0.5 279.4 153 150 228.6
2 457.2 318.8 240 381
10 762 516 500 609.6
under the influence of gravity. The Hausner ratio is the ratio of
the tapped density to the apparent (poured) density of the
powder. The apparent density tends to decrease as the
interparticle friction in a powder system increases. The tapped
density tends to decrease as well, albeit a lesser extent due to
the additional energy imparted from tapping. The cohesive
behavior of a powder is a qualitative description of how
powder moves. Yield strength increases with powder cohesion
because a larger stress is required to deform the powder
[25, 28]. A cohesive powder will have a higher Hausner ratio
relative to one that is free flowing. The US Pharmacopeia
[34] defines ranges of the Hausner ratio which describe
powder flowability. Hausner ratio values between 1 and 1.11
are considered to reflect excellent flow properties. Values
greater than 1.6 typically suggest very poor flow, a character-
istic of cohesive powders. The larger the surface area to
volume ratio, the greater the probability a particle will cling to
another. DMV International reports Hausner ratios of 1.21 and
1.28 for lactose 100M and lactose 125M, respectively.
Gravitational Displacement Rheometer
Many studies measure the magnitude of cohesive forces
indirectly using “flow testers.” A common approach is to
use a “shear cell” to measure cohesion in the incipient
failure regime [24, 27]. A different approach to character-
izing cohesion of powder in the dilated state was adopted
here. A method using a gravitational displacement rheom-
eter (GDR) to characterize powder flowability, originally
developed by Faqih and coworkers [32, 35], is employed in
this study. This device produces a “flow index” that is
proportional to the yield strength of the dilated powder.
Higher flow index values indicate a more cohesive powder
and consequently decreased flowability.
In the GDR, a cylinder containing the powder sample is
mounted on a pivoted table supported by a load cell. As the
cylinder rotates, the powder avalanches down the cascading
surface, thereby resulting in a change to the center of mass.
This shift is measured by the force registered by the load
cell. The size and frequency of avalanches are analyzed. As
the cohesive nature of the material increases, the resulting
avalanches become larger and the frequency of avalanche
tumbling decreases. The RSD of the force signal is
calculated at several rotation rates and averaged to give an
accurate characterization of avalanche size.
J Pharm Innov (2008) 3:258–270
V (mm) θ Baffle width (mm) Baffle height (mm)
88.9 35 31.75 50.8
152.4 35 50.8 82.55
203.2 35 152.4 266.7
Results from this method were used to select grades of
lactose with different cohesiveness. The measured flow
indices of lactose 100M and lactose 125M were 17.3 and
20.26, respectively.
Results
In this section, we discuss the effects of four parameters
(tote size, cohesion, rotation rate, and fill level) on the
mixing rate of typical pharmaceutical materials in a tote
blender. The experiments were performed using acetamin-
ophen, which is typically regarded as a difficult-to-mix
API. Two lactose grades were used to simulate formulations
of varying cohesion (based on the Hausner ratio). The main
effects and interactions were examined. Statistical analysis
was used to: (1) identify the critical parameters and (2)
develop proper analytical methodology. The variance at
each experimental condition is listed in Table 2 for the 0.5-,
2-, and 10-ft3 blenders. The remainder of this section
presents the effects of the four experimental parameters on
mixing rate.
Statistical Analysis Methodology
Analysis of variance (ANOVA) is a mathematical proce-
dure for partitioning the variability of a data set into
components associated with different main and interaction
effects. The information provided by ANOVA is used to
construct statistical tests to determine the statistical signif-
icance of main effects and their interactions. An F-statistic
is computed for each effect (including main and inter-
actions), which is used to test hypotheses about the
existence of the effects of variables [33, 36].
In this work, a fully randomized factorial design of the four
processing parameters (n=1) was examined. All four
variables were treated as fixed-level variables (tote size 0.5,
2, and 10 ft3; speed: H, L; cohesion: lactose 100, lactose 125;
fill level 50% and 70%) resulting in a total of 24 treatment
conditions (Table 3). Data were analyzed under the usual
assumptions of normality and independence. Given the large
number of variables, which prevented replications, it was
necessary to assume that higher order interactions did not
exist in order to release degrees of freedom to estimate an
error term. Two models were examined: (1) a model where
J Pharm Innov (2008) 3:258–270 265

Table 3 Variance results for the three tote blenders 0.5, 2, and 10 ft3

Tote 0.5 ft3 Tote 2 ft3 Tote 10 ft3

Rev Var Log(var) Rev Var Log(var) Rev Var Log(var)

Details: low rpm, 50% fill, lactose 100

5 1.353 0.131 5 0.468 −0.330 5 0.187 −0.727
25 0.015 −1.825 25 0.159 −0.800 25 0.048 −1.322
50 0.014 −1.866 50 0.032 −1.490 50 0.020 −1.692
100 0.011 −1.948 100 0.011 −1.976 100 0.012 −1.932
Slope= Mixing rate= −0.017 Slope= Mixing rate= −0.017 Slope= Mixing rate= −0.012
Details: low rpm, 70% fill, lactose 100
5 1.210 0.083 5 0.652 −0.186 5 0.124 −0.906
25 0.343 −0.464 25 0.286 −0.544 25 0.064 −1.192
50 0.172 −0.765 50 0.038 −1.425 50 0.024 −1.621
100 0.076 −1.120 100 0.015 −1.816 100 0.016 −1.789
Slope= Mixing rate= −0.012 Slope= Mixing rate= −0.018 Slope= Mixing rate= −0.009
Details: low rpm, 50% fill, lactose 125
5 1.011 0.005 5 0.065 −1.190 5 0.067 −1.175
25 0.112 −0.952 25 0.016 −1.792 25 0.050 −1.303
50 0.042 −1.377 50 0.009 −2.067 50 0.023 −1.646
100 0.013 −1.881 100 0.005 −2.302 100 0.021 −1.670
Slope= Mixing rate= −0.018 Slope= Mixing rate= −0.011 Slope= Mixing rate= −0.005
Details: low rpm, 70% fill, lactose 125
5 1.472 0.168 5 0.520 −0.284 5 0.138 −0.859
25 0.123 −0.910 25 0.053 −1.275 25 0.049 −1.310
50 0.072 −1.144 50 0.059 −1.232 50 0.025 −1.610
100 0.014 −1.867 100 0.025 −1.609 100 0.023 −1.644
Slope= Mixing rate= −0.019 Slope= Mixing rate= −0.011 Slope= Mixing rate= −0.008
Details: high rpm, 50% fill, lactose 100
5 0.912 −0.040 5 0.173 −0.762 5 0.114 −0.942
25 0.194 −0.712 25 0.035 −1.454 25 0.029 −1.545
50 0.037 −1.434 50 0.002 −2.786 50 0.024 −1.626
100 0.005 −2.314 100 0.002 −2.754 100 0.004 −2.433
Slope= Mixing rate= −0.023 Slope= Mixing rate= −0.021 Slope= Mixing rate= −0.015
Details: high rpm, 70% fill, lactose 100
5 1.668 0.222 5 0.439 −0.357 5 0.177 −0.752
25 0.103 −0.988 25 0.091 −1.039 25 0.018 −1.748
50 0.020 −1.705 50 0.019 −1.728 50 0.015 −1.825
100 0.009 −2.024 100 0.009 −2.047 100 0.015 −1.832
Slope= Mixing rate= −0.022 Slope= Mixing rate= −0.017 Slope= Mixing rate= −0.009
Details: high rpm, 50% fill, lactose 125
5 0.275 −0.561 5 0.226 −0.645 5 0.156 −0.807
25 0.045 −1.349 25 0.016 −1.783 25 0.048 −1.320
50 0.035 −1.456 50 0.007 −2.156 50 0.035 −1.453
100 0.002 −2.737 100 0.006 −2.245 100 0.023 −1.629
Slope= Mixing rate= −0.021 Slope= Mixing rate= −0.014 Slope= Mixing rate= −0.008
Details: high rpm, 70% fill, lactose 125
5 1.117 0.048 5 0.260 −0.584 5 0.184 −0.734
25 0.105 −0.977 25 0.083 −1.081 25 0.029 −1.534
50 0.023 −1.634 50 0.039 −1.406 50 0.015 −1.832
100 0.013 −1.890 100 0.032 −1.498 100 0.012 −1.914
Slope= Mixing rate= −0.019 Slope= Mixing rate= −0.009 Slope= Mixing rate= −0.011

all two-way and three-way interactions are considered where where 9 degrees of freedom remain for the error term. The
2 degrees of freedom remain for the error term (from results are summarized in Tables 4 and 5.
assuming a four-way interaction did not exist), and (2) a The sums of squares, SS, were calculated using SAS
model where only the two-way interactions are considered version 9.1 (SAS Institute Inc., Cary NC, USA). The p
266 J Pharm Innov (2008) 3:258–270

Table 4 Four-way ANOVA

Source DF SS MS F p

Rotation rate 1 4.27E−05 4.27E−05 12.97 0.07

Fill level 1 1.35E−05 1.35E−05 4.10 0.18
Cohesion 1 6.02E−05 6.02E−05 18.29 0.05
Tote 2 3.44E−04 1.72E−04 52.22 0.02
Fill × tote size 2 1.75E−06 8.75E−07 0.27 0.79
Fill × cohesion 1 1.35E−05 1.35E−05 4.10 0.18
Fill × rotation rate 1 6.00E−06 6.00E−06 1.82 0.31
Rotation rate × tote 2 1.46E−05 7.29E−06 2.22 0.31
Rotation rate × cohesion 1 6.00E−06 6.00E−06 1.82 0.31
Tote size × cohesion 2 6.01E−05 3.00E−05 9.13 0.10
Fill × tote × rotation 2 7.75E−06 3.88E−06 1.18 0.46
Fill × cohesion × rotation 1 6.70E−07 6.70E−07 0.20 0.70
Fill × cohesion × tote 2 1.83E−05 9.13E−06 2.77 0.27
Tote × cohesion × rotation 2 1.68E−05 8.38E−06 2.55 0.28
Error 2 6.58E−06 3.29E−06

value was calculated using Microsoft® Excel’s pdist
function. A value of p≤0.05 was selected as the threshold
for considering an effect to be significant.
The first model (Table 4) indicates only tote size to be
significant. The calculated p values for the first model are as
follows: tote size (p=0.02), cohesion (p=0.05), rotation rate
(p=0.07), and fill level (p=0.18). The error estimate, once
again, was obtained from neglecting a four-way interaction.
The results obtained from the second model are given in
Table 5. This model assumed all three-way interactions to
be negligible, a reasonable assumption considering the
range of p values (0.27–0.70). The second model, therefore,
focuses on the contribution of the main and two-way
effects. This model resulted in p values lower than 0.05 for
three main effects (tote size, speed, and cohesion), while fill
level was not significant. Only one of the two-way
interactions (tote size × cohesion) resulted in a low p
value. This is consistent with the fact that both tote size and
cohesion were the most significant main effects. The error
term, again, was estimated through degrees of freedom
obtained by neglecting three-way interactions.
Further consolidation of the model does not change the
significance of factors mentioned above. A model (not shown)
where only the tote size × cohesion and the fill level × cohesion
interactions were retained gave nearly identical results. The
same three main effects, again, were significant (tote size (p<
0.0001), speed (p=0.016), cohesion (p=0.006)), while fill
level was not significant (p=0.15). The tote size × cohesion
interaction was significant (p=0.02) and fill level × cohesion
interaction was not significant (p=0.15). It must be stressed
that failure to prove significance for a given set of experi-
ments is not proof of statistical nonsignificance, especially
when a borderline p value is obtained.
Effect of Tote Size
The effects of tote size have been examined previously
[13], where it has been shown that the magnitude of the

Table 5 Four-way ANOVA with no three-way interactions

Source DF SS MS F p

Rotation rate 1 4.27E−05 4.27E−05 7.68 0.02

Fill level 1 1.35E−05 1.35E−05 2.43 0.15
Cohesion 1 6.02E−05 6.02E−05 10.83 0.01
Tote 2 3.44E−04 1.72E−04 30.92 0.00
Fill × tote size 2 1.75E−06 8.75E−07 0.16 0.86
Fill × cohesion 1 1.35E−05 1.35E−05 2.43 0.15
Fill × rotation rate 1 6.00E−06 6.00E−06 1.08 0.33
Rotation rate × tote 2 1.46E−05 7.29E−06 1.31 0.32
Rotation rate × cohesion 1 6.00E−06 6.00E−06 1.08 0.33
Tote size × cohesion 2 6.01E−05 3.00E−05 5.41 0.03
Error 9 5.00E−05 5.56E−06
J Pharm Innov (2008) 3:258–270 267

1.4
compressibility, dissolution, chemical and physical compat-
1st RSD 2nd RSD
1.2 ibility). Further, the “materials properties” subdomain is
1.0 limited to selecting different grades (e.g., particle size),
0.8 brands, and concentrations of a given excipient. Consistent
RSD

with this “real world” situation, the effect of powder

0.6
0.4
0.2
0.0
0 20 40 60
Revolutions
Fig. 3 The results of a blending experiment with acetaminophen and
lactose (highly cohesive) in the 2-ft3 mixer filled to 60% capacity. The
blending speed was set to 12 rpm
scale-up effect on mixing performance is dependent upon
blend flow properties. A number of process problems are
caused by powder cohesion. This is illustrated by interpar-
ticle forces resulting in API agglomeration.
Figure 3 illustrates the effect of tote size on mixing rates.
As expected, the smaller tote had the fastest mixing rate,
followed by the medium tote and large tote, respectively.
On average, the smallest tote had a mixing rate that was ∼2
times greater than the largest tote and 1.32 times greater
than the medium-sized tote. The ANOVA indicated that this
parameter had the lowest p value (p<0.0001). In the current
study, therefore, tote size had the most statistically
significant effect on mixing performance.
Effect of Cohesion
As mentioned above, material properties may also affect
mixing performance. This is a very wide subdomain of the
parametric space, potentially encompassing multivariate
ranges of particle size, morphology, and cohesion. In real
applications, however, ingredients are typically selected in
response to multiple performance requirements (e.g.,
0.025
.5 cu. ft 2 cu. ft 10 cu. ft
0.020
-Mixing Rate
properties was examined by selecting two lactose grades,
differing both in cohesion and particle size. Only one type
of acetaminophen was used in the study.
The increase in cohesion reduced the mixing rate for the
80 100 120 medium tote size blender (Fig. 4) and large tote size blender
(not shown). The less cohesive lactose gave a lower final
blend variance and higher mixing rates. The low p value
(p=0.01) indicates a significant effect. Additionally, the
most significant interaction was tote size × cohesion (p=
0.03) indicating tote size dependence of the cohesion effect
in mixing performance evaluation.
Effect of Rotation Rate
Previous work by Sudah et al. [13] has shown that for free
flowing materials, the mixing rate in bin blenders was
largely independent of the blender rotational speed.
However, different behaviors were observed for cohesive
materials. The effect of tumbler rotational speed on the
homogeneity of cohesive mixture was investigated compu-
tationally by Chaudhuri and coworkers [26, 29]. Simula-
tions were employed where a drum was rotated at three
different speeds. These simulations showed that the
homogeneity of cohesive mixtures could be affected by
blender rotational speed. Mixing performance was im-
proved at higher rotational speeds and optimal performance
was observed for an intermediate cohesion level.
In this study, the majority of the experiments showed an
improvement in mixing rate when the rotation rate was
increased. The effect of rotation rate on mixing rate in the
0.5-ft3 tote size is shown in Fig. 5. By increasing the
rotation rate from 10 to 14 rpm, a well-mixed state was
reached in fewer total revolutions. Changing the rotation
rate from 8 to 11 rpm for the 10-ft3 mixer improved the
0.025

Mid Cohesion
0.015
0.02 High Cohesion
-Mixing Rate

0.010
0.015

0.005
0.01

0.000 0.005
Lactose Lactose Lactose Lactose Lactose Lactose Lactose Lactose
100 100 125 125 100 100 125 125
0
Fill 50 % Fill 70 % Fill 50 % Fill 70 % Fill 50 % Fill 70 % Fill 50 % Fill 70 %
Fill 50 % Fill 50 % Fill 70 % Fill 70 %
Low Low Low Low High High High High
Speed Speed Speed Speed Speed Speed Speed Speed Low Speed High Speed Low Speed High Speed

Fig. 4 Mixing rate [(APAP%)2/rev] as a function of three varying tote Fig. 5 Mixing rate [(APAP%)2/rev] as a function of cohesion for the
sizes for all eight experiments 2-ft3 mixer
268
0.025
Low Speed
0.02
-Mixing Rate
0.015
0.01
0.005
0 fill level on mixing performance generally remained small
Lactose 100 Lactose 100 Lactose 125
Fill 50 % Fill 70 % Fill 50 %
Fig. 6 Mixing rate [(APAP%)2/rev] as a function of rotation rate on
mixing rate for the 0.5-ft3 tote mixer. For the 0.5-ft3 mixer, 10 rpm is
considered the low speed and high speed is 14 rpm
mixing performance for all conditions, with the exception of
the experiment conducted at a 70% fill level using lactose
100, where the mixing performance remained similar.
Changing the revolutions per minute from 10 to 14 rpm for
the 2-ft3 mixer improved the mixing performance at the
50% fill level for both lactose grades. Moreover, the
statistical analysis showed that the rotation rate affected
the mixing performance with a significant p value of 0.02.
Fill Level
From a production standpoint, finding an optimum fill level
is important given the desire to both maximize batch size
and avoid problematic processing conditions. Early studies
using free flowing materials showed extreme variations in
fill level (20% to 85%) and substantially affect mixing rates
in tumbling blenders, where higher fill levels correlate to
slower mixing [6]. Sudah and coworkers [9] found that
optimum mixing rates were obtained at 60% fill, where the
slowest mixing rate was observed at 80% fill over a 20–
80% range. In addition to a diminishing mixing rate, Arratia
and coworkers [6] measured concentration profiles for high
fill levels (greater than 85%) at low rotational speeds and
showed segregated regions present in the center of the
blender. Alexander and coworkers [10, 18], however, found
no significant difference in mixing rates for a sand mixture
employing a more practical range (40–60% fill), thereby
suggesting process flexibility within robust operation.
Moreover, using fill levels in this range was shown to
reduce the probability of dead zones formation [3].
However, the bulk of this work was performed on free
flowing powders. For the slightly cohesive systems studied
in this paper, the effect of fill level is largely unknown.
Building on the previous referenced tote blender work, the
effects of fill level on mixing performance at 50% and 70%
of total blender volume were examined.
Fill levels of 50% in the small tote size lead to higher
mixing rates relative to the 70% fill level (Fig. 6). The 50%
J Pharm Innov (2008) 3:258–270
High Speed fill level for the 2-ft3 tote size exhibited faster mixing rates
when conducted at a high rotation rate. The largest tote size
mixer showed a faster mixing rate at 50% fill levels when
using lactose 100 (Fig. 7). These observations indicate the
lactose/acetaminophen formulations used here are not
necessarily affected adversely at high fill levels. Given the
various findings for different size tote blenders, the effect of
Lactose 125 for the range examined. Supporting this conclusion,
Fill 70 % statistical analysis indicated that fill level was the least
significant parameter affecting mixing performance (p=
0.15).
Outlook and Conclusions
This study presented an example of the application of
statistical methods to examine the effects of multiple
variables on mixing performance. Further, this study
enabled the prioritization of the impact of variables using
the following order of significance: tote size (p<0.0001),
cohesion (p=0.01), rotation rate (p=0.02), and fill level
(p=0.15). Additionally, the results indicated main variables,
such as tote size, inherently interact. While this may explain
the obscure nature of blending process scale-up, it also
suggests that ANOVA methods may be used to unravel
some of its complexities. Unfortunately, some of the
interactions are difficult to examine in practice. Given the
typical small number of experiments that can be conducted
in a blending study, the risk of making erroneous
assumptions concerning large-scale batch behavior based
on small-scale observations is high. For example, small-
scale experiments may indicate fill level to have a
significant effect on the mixing performance; however, this
may not be the case when the same experiments are
analyzed at a larger scale. This, in fact, is caused by the
interaction between scale and cohesion.
If the study described above were conducted as part of a
pharmaceutical product development campaign, the next
0.025
50% Fill
0.02 70% Fill
-Mixing Rate
0.015
0.01
0.005
0
Lactose 100 Lactose 125 Lactose 100 Lactose 125
Low Speed Low Speed High Speed High Speed
Fig. 7 Mixing rate [(APAP%)2/rev] as a function of fill level for
experiments conducted in the 0.5-ft3 tote mixer
J Pharm Innov (2008) 3:258–270
logical step would be to design a follow-up study for
concentrating on significant variables to explore, in more
detail, their effects and interactions. Further, this would
enable determination of the range of variable values over
which the process could be operated with satisfactory
results. An iterative approach, where the findings from each
study are carried into the next study design, is clearly
needed.
Several additional comments deserve attention:
– Given that blender size likely interacts with other
variables, the results obtained at smaller scales (a
common practice in many industries) should be
evaluated very carefully. Scale-up studies going beyond
mere “performance equivalence” and aimed at devel-
opment of effective scale-up correlations are critical.
Material properties of powders clearly play an impor-
tant, scale-dependent role in blending performance.
This study merely touched the surface of assessing
these phenomena. Going forward, the pharmaceutical
industry should continue to enhance characterization of
relevant material properties.
– As previously addressed, materials and processes both
exhibit constant variability, making the optimum
process a moving target. Additionally, the amount of
work needed to identify, characterize, and control all
variables affecting product performance is significant.
With this in mind, only a first-pass design may be
achieved within the short time frames associated with
current pharmaceutical product development cycles.
However, valuable information is generated by the
manufacturing operation, for further refinement of
models for the improvement of product performance.
In an enlightened QbD-enabled regulatory framework,
continuous improvement is enabled through the process
understanding that is gained during process development
and manufacturing. An idea advanced by this work is that
of dynamic quality specifications. These ultimately allow
for more flexibility at the beginning of the manufacturing
life cycle, when knowledge is sparse, and lead to an
improved, but more narrowly defined process, as the
process approaches maturity.
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