Drug Development and Industrial Pharmacy, 2013; 39(9): 1464–1475

© 2013 Informa Healthcare USA, Inc.

ISSN 0363-9045 print/ISSN 1520-5762 online
DOI: 10.3109/03639045.2012.728227

RESEARCH ARTICLE

 ffects of powder flow properties on capsule filling

E
weight uniformity
Juan G. Osorio and Fernando J. Muzzio

Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA

Abstract
Filling capsules with the right amount of powder ingredients is an important quality parameter. The purpose of this
study was to develop effective laboratory methods for characterizing flow properties of pharmaceutical powder
blends and correlating such properties to weight variability in filled capsules. The methods used for powder flow
characterization were bulk and tapped density, gravitational displacement rheometer (GDR) flow index, Freeman
Technology V.4 (FT4) powder rheometer compressibility, FT4 basic flow energy (BFE), and cohesion parameters
[cohesion, (C) and flow factor (ffc)] measured in a shear cell also using the FT4. Capsules were filled using an
MG2-G140 continuous nozzle dosator capsule-filling machine. Powder flow properties were the most predominant
factors affecting the weight and weight variability in the filled capsules. Results showed that the weight variability
decreased with increasing bulk and tapped density, ffc and BFE, while the weight variability increased with increasing
compressibility, cohesion and GDR flow index. Powder flow properties of the final blends were significantly correlated
to the final capsule weight and weight variability of the filled capsules.
Keywords:  Particle processing, dosing systems, cohesion, flow factor, bulk density, flow energy, capsule filling

Introduction
Unlike tableting, where dosing mechanisms differ only
slightly among machines ranging from pilot to manufac-
turing scale, capsule filling machines use multiple filling
mechanisms, introducing a higher level of complexity
in the study of capsule filling processes. Dosing mecha-
nisms for capsule filling machines can be divided into
two groups: the capsule-dependent machines that use
the capsule body directly to measure the dose, filled as
a loose mass, and the capsule-independent machines
that measure the dose in a separate system, which is then
filled into capsules as a consolidated plug of material.
Powder flow properties are important; capsule filling
issues can arise from poor flowing powder blends as well
as good flowing powder blends.
There are two main types of dosing mechanisms in
capsule-independent machines, the dosator and the
tamping1. In either case, as reported by Stegemann2,
for optimum machine filling performance, the powder
must have the right flow properties and bulk density.
The dosator principle uses a dosing tube that dips into
the powder bed to a depth that is normally two times
larger that of the desired plug length. During the dipping
step, due to the dosator piston movement, the powder is
densified to form a cohesive plug. The dosing tube then
transfers the plug to the capsule body. The formation of
the powder plug might fail if the cohesion of the powder
is low, leading to inconsistent dosing weight. In a dosator
mechanism, if a plug formed is much larger than the
capsule body and cannot be compressed enough (for
non-cohesive powder blends) to fit into the capsule,
flooding might occur, resulting in larger filled weight
variability. Stegemann also described that poor powder
flow is characterized by the formation of a central cavity
in the feed hopper because the powder on the wall
remains static. “Good” powder flow (low cohesion) can
result in under-filled capsules due to flooding also when
using a tamping mechanism2,3.
In capsule filling, the most important property of the
powders and granules is often the tapped density, which

Address for Correspondence:  Fernando J. Muzzio, Department of Chemical and Biochemical Engineering, Rutgers University, 98 Brett Road,
Piscataway, NJ 08854 USA. Tel: 732-445-3357. E-mail: fjmuzzio@yahoo.com
(Received 06 April 2012; revised 29 August 2012; accepted 04 September 2012)

1464

is the maximum density obtained without applying a
major compressive force4. The active pharmaceutical
ingredient (API) dose used in the final blends to fill cap-
sules is often an important parameter. For low doses of
drug, the homogeneity of the powder blend can be dif-
ficult to achieve and is often the most critical parameter.
Minor segregation and agglomeration tendencies can
become critical for low-dose products. For such systems,
blend flow properties are typically governed by the con-
centrations and properties of filler and flow agents and
can usually be managed. However, this is not always the
case for cohesive APIs. As the API dose increases, the
properties of the API play a dominant role in capsule fill-
ing. For doses less or around 100 mg in total weight, the
smallest capsule size is typically used. Doses over 600 mg
in total powder weight are virtually impossible to put into
capsules of acceptable size2.
Tan and Newtown studied powder flowability, as a pre-
dictor of capsule filling performance, concluding that a
single powder flow property does not completely describe
the behavior of the powder blend in any complex manu-
facturing system5. In order to understand and choose
which powder flow property or properties determine the
performance of a system, (in the present case, capsule
filling), a wide range of powder flow properties should be
studied. Powder flow behavior varies depending on the
unit operation that is undergoing; this is also the case for
different powder flow measurements. Therefore, examin-
ing various powder flow properties and correlating them
to a specific manufacturing system is often critical to our
ability to understand and optimize it.
In early studies, Irwin et al.6 studied the flow rate of dif-
ferent powder blends through an orifice and correlated
it to the coefficient of variation (RSD) of hard capsules.
The results indicated that as the flow rate of the powder
decreased the coefficient of variation increased with an
R2 of 0.96. Similar studies correlating different powder
flow properties to the capsule filling performance in
dosator systems and simulators have been published.
Newton and Bader7 used the angle of internal flow as
indicator of filling performance for both tamping and
dosator systems. They showed that the bulk density was
directly correlated to the angle of internal flow and that
the capsule fill weight decreased as the angle of internal
flow increased. The angle of internal flow is high for cohe-
sive powder blends. Similar correlations were found in
the present study. The increase in cohesion of the blend
as measured by any of the powder flow properties pre-
sented here resulted in a decrease in capsule fill weight.
In a later study, Tan and Newton further studied the
capsule weight performance correlated to several pow-
der flow properties. The angle of repose, Hausner’s ratio,
Carr’s compressibility, Kawakita’s equation constant
(a), and the flow function and angle of effective friction
obtained from a shear cell were correlated to the coeffi-
cient of variation (RSD) of the fill weight5. The coefficient
of variation of fill weight increased with increasing Carr’s
compressibility index, Hausner’s ratio, angle of response
© 2013 Informa Healthcare USA, Inc.
Effects of powder flow on capsule weight uniformity  1465
and Kawakita’s constant (a) decreased with the flow
function. The same behavior was obtained in the present
study for which the variability of the fill weight increased
with Carr’s compressibility index and the Hausner’s ratio,
when calculated from the bulk and tapped densities, and
decreased with the flow factor (ffc) measured in the shear
cell. The variability increased with increasing cohesion in
the powder blend in both studies.
The capsule weight variability in dosing disc tamp-
ing filling machines has been considered as well. Gohil
et al.3 correlated the capsule weight and variability to the
powder flow properties in tamping mechanisms. They
showed that as the powder flow improved, the mean
weight as well as the variability decreased. Podczeck et
al.8 correlated the angle of internal friction to the capsule
weight variability. The angle of internal friction is high for
cohesive powders. The coefficient of variability increased
with the increasing angle of internal friction.
Recent studies by Freeman et al.9 used comparable
powder flow tests (FT4) correlating the capsule filling
performance in a dosing disc tamping machine. The
specific energy, the compressibility and cohesion were
correlated to blends with 0%, 10%, and 40% APAP con-
centrations. Formulations containing a higher APAP
concentration also showed an increased in weight vari-
ability. The tamping mechanism works differently than a
dosator where capsules are filled by a balance of gravity
filling (free flow) and forced filling9. Their results showed
a decreased in weight variability for blends with 40%
APAP when compared to those with 10% APAP. A blend
with higher concentration of APAP can be further com-
pressed in a tamping system, which was not the case of
the dosator system presented in this study. Here blends
with 50% APAP showed the highest weight variability for
both capsule sizes used. A dosator mechanism does not
have multiple stages in which the powder is compressed,
but rather the first plug formation obtained is what goes
into the capsule and determines the final weight3.
The purpose of the study is to develop effective labora-
tory methods for characterizing powder flow properties
and correlating such properties to weight variability in
filled capsules. Studies of powder flow properties and
capsule filling performance using continuous capsule
filling systems are found in the literature1,3–8,10–17. Material
and flow properties of pharmaceutical powders and
blends, such as mean particle size, shape, angle of repose,
angle of internal friction, bulk and tapped density, shear
cell flow function (ffc), flow rate and minimum orifice
diameter have been correlated to capsule filling per-
formance (capsule weight and weight variability, ejec-
tion force, and compressibility ratio). The relationship
between capsule weight variability and powder flow has
been the focus of several research articles. Correlations
for weight and weight variability depend on the capsule
filling mechanism used and the powder flow proper-
ties measured. In his review, Jones1 summarized all the
powder flow measurements correlated to capsule filling
performance published in the literature up to 2001.
1466  J. G. Osorio and F. J. Muzzio
Since then, older techniques have been improved
and new methods have been developed. Thus, in this
article, we re-examine the issue focusing on a wide array
of powder flow measurement techniques: bulk and
tapped density, gravitational displacement rheometer
(GDR) flow index, Freeman Technology rheometer V.4
(FT4) compressibility test, FT4 basic flow energy (BFE),
and cohesion parameters measured in the FT4’s shear
cell [cohesion, (C) and flow factor (ffc)]. These powder
flow measurements are correlated to the performance
of a high production continuous dosator capsule-filling
machine (MG2-G140). Five blends with varying powder
flow properties are used to fill gelatin capsules size 1
and 3. The concentrations of acetaminophen (APAP) and
additives are varied to generate blends with different
flow properties. Talc, magnesium stearate and Cab-O-
Sil are used as flow modifying agents, and Avicel PH102
(Microcrystalline Cellulose) and Fast-Flo Lactose are
used as fillers.
The remainder of this article is organized as follows:
Materials and methods section describes the materials
and experimental methods used in our study; Results
and discussion section presents experimental results
and main findings; and finally Conclusions section
is devoted to conclusions and recommendations for
future work.
Materials and methods
Materials
The materials used in all the experiments reported
here were: micronized acetaminophen (Mallinckrodt
acetaminophen USP/paracetamol Ph Eur micron-
ized, Raleigh, North Carolina, USA), microcrystalline
cellulose (Avicel PH102, FMC Biopolymer, Newark,
Delaware, USA), Fast-Flo® lactose (Monohydrate N.F.
modified-spray dried, Foremost Farms USA, Rothschild,
Wisconsin, USA), amorphous fumed silica (Cab-O-Sil
M-5P, Cabot Corporation, Tuscola, Illinois, USA), talc
(magnesium silicate, IMI FABI, LLC, Benwood, West
Virginia, USA) and magnesium stearate N.F. (non-Bovine,
Tyco Healthcare/Mallinckrodt, St. Louis, Missouri, USA).
Particle size information of the materials used is listed in
Table 1. Particle size was determined using a laser-dif-
fraction (LS-13320) analyzer with a Tornado Dry Powder
System (Beckmann-Coulter, Brea, California, USA).
Capsules used in the experiments were Coni-Snap® size
1 (76 ± 5 mg) and 3 (48 ± 3 mg)18 (Capsugel®, Greenwood,
South Carolina, USA).
Table 1.  Materials used with corresponding particle size.
Material Mean (µm) d10 (µm) d50 (µm) d90 (µm)
Micronized APAP 17.9 3.4 13.4 39.7
Avicel PH102 140.0 34.0 121.0 244.1
Fast-Flo Lactose 113.5 54.3 113.3 173.6
Talc 10.8 1.9 7.7 25.2
Mgst 8.9 1.9 7.8 16.6
 Drug Development and Industrial Pharmacy
Blending
Before blending, the micronized APAP was milled to
enhance blend homogeneity by breaking up agglomer-
ates in the API. Blends were prepared in a 5 ft3 (~141.6 L)
ribbon blender using a 5-spoke ribbon blade at an 86%
fill level19. Blends without MgSt were blended at rib-
bon speed of 20 RPM for 420 revolutions (21 min total).
Blends with MgSt were pre-blended at ribbon speed
of 20 RPM for 300 revolutions (15 min), then the MgSt
was added and blending continued for 120 revolutions
(6 min). The blends preparation was as follows: Materials
were loaded in layers from the top of the blender in the
following order: Fast-Flo Lactose, APAP, Avicel PH102,
Talc, and SiO2. Ample prior experience with these materi-
als indicates that the loading order is largely immaterial.
For blends containing MgSt, the blender was stopped
and a layer of MgSt was added to the pre-blend. The final
blends with corresponding compositions are presented
in Table 2.
Bulk and tapped densities
The bulk and tapped densities were measured using the
standard procedure20. The bulk density was measured
using a 150 mL graduated cylinder. The cylinder was filled
up to approximately 120 mL and the mass was weighed.
Once the numbers were recorded, an automatic tap-
ping machine (Model No. AT.4.110.60, Quantachrome
Instruments, Boynton Beach, Florida, USA) was used to
tap the material 1000 times, and the new volume was
recorded.
FT4: conditioned density, compressibility, cohesion,
flow function (ffc), and basic flow energy
The conditioned bulk density, compressibility, flow
function (ffc), cohesion (C), and basic flow energy (BFE)
were measured by the FT4 powder rheometer (Freeman
Technology Ltd., Worcestershire, UK). All tests in the FT4
were done using the 48 mm cylinder.
• The conditioned density was measured after the
standard conditioning cycle, which is performed
before every test in the FT4 powder rheometer to
ensure that the state of the each powder sample is
reproducible before every test21.
• Compressibility is a measure of how density changes
as a function of applied normal stress. The com-
pressibility is the percentage change in volume after
compaction at a specific normal stress. Cohesive
powders show a large change in volume, while non-
cohesive powders show little change in volume. The
compressibility values used were obtained at the
maximum applied normal stress of 15 kPa.
• Cohesion (C) is the shear strength when consolida-
tion stress is zero. ffc is the ratio of the major prin-
cipal stress and the unconfined yield strength. The
shear cell in the FT4 was also used to measure the
cohesion parameter and derive the flow function
(ffc) at consolidation pressure of 6 kPa.

Table 2.  Final powder blend compositions.
Blend Fast-Flo Lactose (%) Avicel PH102 (%)
1 43.0 43.0
2 41.5 41.5
3 41.5 41.5
4 40.0 40.0
5 19.5 19.5
• The flow energy in the FT4 measures the amount of
energy required to move the powder in the test cyl-
inder subsequent to the standard conditioning cycle.
The basic flow energy (BFE) is the specific energy
needed to displace the powder when the blade is
moving downwards in the cylinder while it applies a
minor compressive stress. The BFE for non-cohesive
powder is relative high when compared to cohesive
ones. The BFE should be able to quantify and differ-
entiate among slightly cohesive powders with similar
flow properties.
Quantification of unconsolidated powder
cohesion: powder flow index
A previously developed experimental method, the gravi-
tational displacement rheometer (GDR)22–25, was used
to characterize the flow properties of materials under
unconfined conditions. The GDR is composed of a rotat-
ing cylinder and its drive mechanism, both of which are
mounted on a pivoted table supported by a load cell. In
this device, the magnitude of avalanches is character-
ized by measuring the shift in the center of gravity of the
powder bed as it avalanches within the cylinder. As ava-
lanches take place, the shift in the center of gravity of the
powder bed alters the distribution of forces between the
pivot and the load cell. The weight variations recorded by
the load cell are the combined effects of the avalanche
size and its total displacement. The cohesive forces and
static friction between particles determine the size of
the avalanches and their displacement, while the speed
of the avalanche is controlled by dynamic friction at
the shear plane and the tensile cracking mechanism22.
Recent measurements by our group have demonstrated
that the flow index is directly proportional to the cohe-
sion parameter of the powder at minimum consolidation
stress26.
The GDR was used to measure the unconsolidated flow
characteristics of the blends described above. The drum
used was a cylinder measuring 20.3 cm in diameter and
40.0 cm in length. The entire cylinder was constructed of
transparent Plexiglas, which allowed for observation of
the flow dynamics within the drum, even though trans-
parency is not necessary for data acquisition22. As the
drum rotates, a load cell (5-lb subminiature compression
load cell, type 13/2443-06 by Sensotec, Ohio, USA) mea-
sures the change in the moment of inertia of the powder
bed as it avalanches. Data was acquired for speeds from
5 to 20 rpm to capture the relevant flow dynamics. In
all of the tests, the cylinder was loaded with powder to
© 2013 Informa Healthcare USA, Inc.
Effects of powder flow on capsule weight uniformity  1467
Acetaminophen (%) Talc (%) Cab-O-Sil (%) MgSt (%)
9.0 5.0 0.0 0.0
9.0 5.0 3.0 0.0
9.0 5.0 0.0 3.0
9.0 5.0 3.0 3.0
50.0 5.0 3.0 3.0
approximately 40% by volume and rotated at 5, 10, 15, and
20 RPM, and the load cell sampled at a frequency of 2000
Hz for 100 s. (Data collection begins approximately 5 min
after the cylinder is first started in order to get the steady-
state flow data and ignore the initial transient phase in
which avalanches are noticeably larger). The flow index
was measured at 5, 10, 15, and 20 RPM and averaged to
provide a single measurement for each blend. Speeds
higher than 20 RPM are not recommended because at
such speeds avalanches overlap for most powders and
the measurement becomes less defined.
Capsule filling
Capsules size 1 and 3 were filled in a nozzle dosator contin-
uous capsule-filling machine MG2-G140 (MG2, Bologna,
Italy) using three different production speeds (60,000,
80,000, and 100,000 capsules per hour). Various settings
were used for the bowl and piston height: For capsule size
1, the ratios of the bowl height and piston heights were
45 mm/15 mm and 35 mm/16 mm; and for capsule size 3,
the ratios 45 mm/11.7 mm and 35 mm/12.1 mm were used.
Two replications were performed for each experiment.
Filled capsule weight characterization
Approximately 500 capsules for each condition were col-
lected after capsule filling had reached steady state. A
total of 100 capsules for each experiment were selected
randomly from the larger samples and weighed, with the
shell, using an Ohaus Adventurer Pro scale model AV64
with precision of 0.1 mg (Ohaus Corporation, Parsippany,
New Jersey, USA). Previous studies in our lab, not
included in this article, showed that empty capsules did
not need to be weighed as they contributed negligibly to
the filled weight variability. The empty capsules contrib-
uted to 1.2% of the total variance of the filled capsules
with a covariance of the interaction of the empty capsules
and the powder filled contributing 0.9% of the total vari-
ance. Therefore, 97.9% of the total variance is generated
by the amount of powder filled into the capsules.
Statistical characterization
The mean (μ) and the variance (σ2) of the filled capsule
weight were calculated using sample statistics for each
experiment. From these values, the normalized variance
(σ2/μ2) was calculated. Since there were two replicas for
each experimental condition, the data was further reduced
for all identical experimental conditions by averaging
both the mean and the normalized variance and taking
the square root of it. The square root of the normalized
1468  J. G. Osorio and F. J. Muzzio
variance among experimental replications is the coef-
ficient of variability, also known as the relative standard
deviation (RSD). For further grouping of the results
obtained from different experimental conditions, the nor-
malized variance was used instead of the standard devia-
tion or the RSD, since neither the standard deviation (SD)
nor the RSD are averageable. Instead of using the RSD as
an indication of capsule weight variability for each blend
and capsule size, the square root of the normalized vari-
ance was used. Further grouping of the results combined
the results for the three speeds of production since analy-
sis of variance (ANOVA, Table 4) indicated that the only
statistically significant factors determining the differences
in weight and weight variability obtained from the filled
capsules was the blend and the ratios of bowl and piston
height where the speed was not statistically significant.
Results and discussion
As mentioned, several powder flow properties described
above were measured for 5 different pharmaceutical
powder blends (Table 3) and linearly correlated to the
capsule weight and capsule weight variability for capsules
size 1 and 3 filled in a MG2-G140 continuous-capsule fill-
ing machine. Various production speeds, bowl heights,
and piston heights were used. Analysis of Variance
(ANOVA) for each capsule size (Table 4) was conducted
in order to understand the effects of operational param-
eters and blend differences. The results indicated that
the capsule filling production speed did not yield sta-
tistically different results. The production speed did not
have a significant effect (p > 0.05) on capsule weight and
weight variability. For capsule size 1, the powder flow
properties, and the ratio of the bowl and piston heights
(p < 0.05) were the only significant factors determin-
ing the capsule weight and weight variability (Table 4).
For capsule size 3, the powder flow properties, and the
ratio of the bowl and piston heights were the only sig-
nificant factors (p < 0.05) determining the capsule weight
(Table 4). For the variability obtained in capsule size 3, the
only statistically significant factor was the powder flow
properties of the blends (p < 0.05) (Table 4).
Mean capsule weight and variability results were aver-
aged for all replications for each set of capsule filling
parameters used (Table 5). The coefficient of variability
(square root of the mean variance), also known as the RSD
in this case, was calculated by averaging the variances
between the replications of each set of capsule filling
parameters and calculating the square root. As previously
Table 3.  Powder flow properties.
Blend no Bulk density (g/mL) Tapped density (g/mL)
1 0.45 0.62
2 0.43 0.57
3 0.50 0.65
4 0.40 0.50
5 0.27 0.42
Compressibility (%) values at 15 kPa. Shear cell measurements were done at a consolidation pressure of 6 kPa.
 Drug Development and Industrial Pharmacy
shown, using ANOVA, it was determined that the speed
of production was not a statistically significant factor in
the difference in weight and variability. Therefore, the
average weight and variability results obtained from
the experimental replications were further grouped.
The final grouping of the results was done by averaging
the previously averaged capsule weights and normal-
ized variances between the three production speeds for
each set of bowl and piston height ratios. The square
root of the final average variance was taken to obtain the
final variability. The final mean weight and variability
(Table 6), between replications and then between pro-
duction speeds, was used to correlate the final weight and
variability with the measured powder flow properties.
To determine the significance of the linear correlation,
the R2 and the p value for each linear fit were calculated
(Table 7). The results will show that for R2 < 0.77, then
p > 0.05. Thus the linear correlation with an R2 < 0.77 is no
longer significant within a 95% confidence interval.
Bulk and tapped density
Weight and weight variability are shown in
Figures 1 and 2 as a function of the bulk and tapped densi-
ties, respectively. The mean weight increases as the blend
density increases, while the variability decreases as the den-
sity increases. Most pharmaceutical ingredients are organic
materials with true densities close to 1. Within this call of
materials, the bulk and tapped density of a powder provide
a short-hand indication of flow behavior, wherein the higher
the bulk and tapped density, the lower the cohesion (and
the better the “flowability”) of a powder blend. Therefore the
mean weight of the capsule increases for less cohesive pow-
ders (i.e. powders with “better flowability”). Both the bulk
and tapped density show good linear correlation for both the
mean capsule weight and weight variability. Summary of lin-
ear correlations for the mean weight and the variability are in
Table 7. These results indicate that bulk and tapped density
are good predictors of both weight and weight variability
in capsules. Correlations with the capsule weight yielded
linear fits (R2) ranging from 0.93 to 1.0 (p < 0.05) while cor-
relations with the weight variability yielded linear fits (R2) of
0.67–0.93 (Table 7). Bulk and tapped density measurements
are inexpensive and simple tests from which widely used
flow indexes, as the Hausner ratio and the Carr’s index, can
also be determined.
Compressibility
Compressibility results from blends 1–3 are similar to
each other. Most times, compressibility is a good test to
Compressibility (%) C (kPa) ffc GDR F.I. BFE (mJ)
14.5 0.50 6.0 43.8 877.0
14.4 0.63 5.0 44.6 822.5
14.3 0.48 6.2 44.3 735.0
19.8 0.66 4.6 47.1 575.0
22.9 1.06 3.1 88.4 289.5
 Effects of powder flow on capsule weight uniformity  1469

Table 4.  Analysis of variance for each capsule size.

Analysis of variance for mean weight (mg), using adjusted SS for tests
Source DF Seq SS Adj SS Adj MS F p
Mean weight – capsule size 1
  Blend no 4 70602.2 70602.2 17650.6 4592.83 0.0000
 Speed 2 21.1 21.1 10.6 2.75 0.0710
  Bowl/piston height 1 136.4 136.4 135.4 35.49 0.0000
  Blend no × speed (Kcap) 8 12.4 12.4 1.6 0.40 0.9140
  Blend no × bowl/piston height 4 663.4 663.4 165.8 43.15 0.0000
  Speed (Kcap) × bowl/piston height 2 13.7 13.7 6.9 1.78 0.1760
 Error 68 261.3 261.3 3.8
Total 89 71710.6
S = 1.96037 R2 = 99.64% R2 (adj) = 99.52%
Normalized variance – capsule size 1
  Blend no 4 0.0298253 0.0298253 0.0074563 25.30 0.0000
 Speed 2 0.0012122 0.0012122 0.0006061 2.06 0.1360
  Bowl/piston height 1 0.0025867 0.0025867 0.0025867 8.78 0.0040
  Blend no × speed (Kcap) 8 0.0039737 0.0039737 0.0004967 1.69 0.1180
  Blend no × bowl/piston height 4 0.0078193 0.0078193 0.0019548 6.63 0.0000
  Speed (Kcap) × bowl/piston height 2 0.0016109 0.0016109 0.0008054 2.73 0.0720
 Error 68 0.0200372 0.0200372 0.0002947
Total 89 0.0670653
S = 0.0171658 R2 = 70.12% R2 (adj) = 60.90%
Mean weight – capsule size 3
  Blend no 4 11479.41 11479.41 2869.85 803.11 0.0000
 Speed 2 15.1 15.1 7.55 2.11 0.1290
  Bowl/piston height 1 182.27 182.27 182.27 51.01 0.0000
  Blend no × speed (Kcap) 8 19.76 19.76 2.47 0.69 0.6980
  Blend no × bowl/piston height 4 118.6 118.6 29.65 8.30 0.0000
  Speed (Kcap) × bowl/piston height 2 5.11 5.11 2.56 0.72 0.4930
 Error 68 242.99 242.99 3.57
Total 89 12063.24
S = 1.89034 R2 = 97.99% R2 (adj) = 97.36%
Normalized variance – capsule size 3
  Blend no 4 0.021374 0.021374 0.0053435 6.60 0.0000
 Speed 2 0.0009248 0.0009248 0.0004624 0.57 0.5680
  Bowl/piston height 1 0.0022277 0.0022277 0.0022277 2.75 0.1020
  Blend no × speed (Kcap) 8 0.0052145 0.0052145 0.0006518 0.81 0.6000
  Blend no × bowl/piston height 4 0.0061614 0.0061614 0.0015404 1.90 0.1200
  Speed (Kcap) × bowl/piston height 2 0.0008271 0.0008271 0.0004135 0.51 0.6020
 Error 68 0.0550572 0.0550572 0.0008097
Total 89 0.0917866
S = 0.0284546 R2 = 40.02% R2 (adj) = 21.49

differentiate powder flow properties among blends, but
in this case it was not a very discriminating test for the
blends used here. In general, the mean capsule weight
decreases with increasing compressibility and the weight
variability increased with increasing compressibility
(Figure 3). The correlations obtained still showed the
predicted trends for the capsule weight (R2 ranging from
0.76 to 0.85). The capsule weight decreased as compress-
ibility increased. More cohesive powders are more com-
pressible indicating that compressibility can be used for
such correlations and it would be more discriminating
for blends with more distinctive powder flow properties.
Although no statistically significant linear correlation
was found between the compressibility and the weight
variability (p > 0.05), the variability increased as the com-
pressibility increased.
Cohesion and ffc
Cohesion (C) (Figure 4) and ffc (Figure 5), both mea-
surements obtained from the FT4 shear cell at con-
solidation pressure of 6 kPa, showed good linear
correlations (Table 7) for both the mean capsule weight
(R2 = 0.96–0.99 with p < 0.05) and variability
(R2 = 0.76–0.98, with p < 0.05 except for the R2 = 0.76) for
the blends used in this study. Lower cohesion (higher
ffc) means “better flowability” of a powder blend. The
mean capsule weight decreased with increasing C and
increased with increasing ffc. On the other hand, capsule

© 2013 Informa Healthcare USA, Inc.

1470  J. G. Osorio and F. J. Muzzio
Table 5.  Summary of mean weight, standard deviation, squared root of normalized variance.
Blend no Bowl height (mm) Piston height (mm) Speed (Kcap/h) Mean weight (mg) Std. dev. (mg) Sqrt. (normalized variance) (%)
Capsule size 1
 1 45 15 60 328.68 0.58 1.04
80 328.15 0.22 0.99
100 327.83 0.47 1.13
35 16 60 336.29 0.21 1.10
80 336.16 0.17 0.94
100 335.78 0.17 0.96
 2 45 15 60 309.69 2.61 1.43
80 306.38 3.10 1.83
100 307.83 0.83 1.30
35 16 60 309.64 3.30 1.73
80 311.27 1.18 1.38
100 309.84 0.66 1.53
 3 45 15 60 338.27 0.34 0.80
80 337.50 0.69 0.94
100 336.83 0.56 0.79
35 16 60 346.58 0.64 1.11
80 346.60 0.62 0.90
100 345.38 2.22 0.95
 4 45 15 60 307.70 0.65 1.22
80 306.47 0.65 1.30
100 305.73 1.25 1.20
35 16 60 307.69 1.75 1.44
80 305.35 4.52 1.43
100 305.32 3.38 1.27
 5 45 15 60 265.48 2.54 1.91
80 264.03 2.21 1.71
100 262.39 0.67 1.95
35 16 60 256.65 5.61 3.53
80 259.45 0.44 2.27
100 257.90 0.61 2.67
Capsule size 3
 1 45 11.7 60 181.10 0.50 0.59
80 181.04 0.20 0.74
100 180.77 0.47 0.59
35 12.1 60 181.00 0.21 0.87
80 180.95 0.09 0.81
100 180.90 0.06 0.91
 2 45 11.7 60 177.30 1.30 1.66
80 177.54 1.34 1.18
100 177.41 1.43 1.10
35 12.1 60 172.72 1.80 1.28
80 171.93 1.60 1.65
100 171.44 1.51 1.94
 3 45 11.7 60 187.73 0.02 0.76
80 187.43 0.55 1.00
100 187.49 0.24 0.69
35 12.1 60 184.34 0.30 1.22
80 184.48 0.16 0.64
100 184.39 0.62 0.79
 4 45 11.7 60 173.39 0.39 1.11
80 172.85 0.17 1.10
100 171.78 1.20 1.64
35 12.1 60 173.09 0.39 1.03
80 171.55 2.73 1.20
100 172.16 0.64 0.90
 5 45 11.7 60 156.83 1.11 1.45
80 155.44 1.20 1.82
100 154.38 0.17 1.67
35 12.1 60 152.38 1.81 2.24
80 147.79 8.57 3.38
100 150.66 3.39 2.05

 Drug Development and Industrial Pharmacy


Table 6.  Mean weight and square root of the normalized variance
for each blend and bowl and piston height ratios. This was done
since the statistical analysis showed that the capsule filling speed
used did not have a significant effect.
Mean weight Sqrt. (normalized
Blend no Bowl/piston height (mg) variance) (%)
Capsule size 1
 1 45/15 = 3 328.22 1.05
 2 307.96 1.54
 3 337.53 0.85
 4 306.63 1.24
 5 263.97 1.86
 1 35/16 = 2 336.08 1.00
 2 310.25 1.55
 3 346.19 0.99
 4 306.12 1.38
 5 258.00 2.87
Capsule size 3
 1 45/11.7 = 4 180.97 0.64
 2 177.41 1.34
 3 187.55 0.83
 4 172.67 1.31
 5 155.55 1.65
 1 35/12.1 = 3 180.95 0.87
 2 172.03 1.65
 3 184.40 0.92
 4 172.27 1.05
 5 150.27 2.63
weight variability increased with increasing cohesion
and decreased with increasing ffc. Typically, shear cell
measurements have been used in the design of hoppers.
Correlations of these parameters to capsule weight and
weight variability prove that powder flow measurements,
developed for different purposes, can be used to correlate
the performance of powder processes and unit opera-
tions, such is the case of continuous dosing capsule filling.
GDR powder flow index
A lower GDR flow index (F.I.) means lower cohesion, i.e.
“better flow”. Conversely, a higher GDR F.I. means that
the powder is more cohesive and would exhibit poorer
flow through a hopper (i.e. “bad flowability”). Thus, as
expected, as the GDR F.I. increased, the mean capsule
weight decreased and the capsule weight variability
increased (Figure 6). The GDR F.I. is a good indicator of
flowability for blends with somewhat distinctive flow
characteristics. The results for the blends used in this
study show that blends 1–4 exhibit very similar in flow
properties when measured with this technique. Thus,
the GDR F.I. was not able to differentiate among blends
with similar powder flow properties (blends 1–4) such
the ones studied here. The same trend as with other mea-
surements was obtained, i.e. the mean capsule weight
increased as the flowability of the powder increased
(lower GDR F.I.). Blend 5, having higher concentration of
acetaminophen (50%) and being more cohesive, showed
distinctive behavior when using this technique. In order
© 2013 Informa Healthcare USA, Inc.
Effects of powder flow on capsule weight uniformity  1471
to investigate further the correlation of this technique
with capsule filling performance, blends that differentiate
more in GDR F.I. are necessary, and can be obtained by
varying the drug concentration and/or the particle size of
the main excipients from blend to blend.
Basic flow energy
One of the objectives in this study was to evaluate newly
developed powder flow property measurements and to
determine whether they correlate to filled capsule weight
and weight variability. It was decided to measure the
basic flow energy (BFE) of the final powder blends since
the GDR flow index and the compressibility gave similar
results for several of the blends. The BFE results indeed
indicated a large difference in the flowability values of
the blends used, also leading to passable correlations
(Figure 7) with both the mean capsule weight and vari-
ability. Linear correlations between the capsule weight
and BFE presented R2 ranging from 0.74–0.77 having a
p ≈ 0.05. No significant linear correlations (p > 0.05) were
obtained between the variability and BFE. Higher BFE
value corresponds to better flow. Consequently, the cap-
sule mean weight increased, and the weight variability
decreased, as the BFE increased.
Conclusions
Powder flow properties for a variety of blends were
measured successfully using previously described and
new techniques, and correlated to capsule filling perfor-
mance in a continuous high-speed dosing capsule filling
machine. The comparison of different powder flow prop-
erties once again proved that one flow property is not
enough to describe any type of pharmaceutical process,
in this case capsule filling, but rather a combination of
flow property measurements are necessary to describe
the behavior of powder blends under different conditions.
Correlations between mean capsule weight and
weight variability and powder flow properties have been
obtained from these studies. All correlations showed the
same trends, indicating that blends with lower cohe-
sion (better flowability) resulted in capsules with higher
weight and less weight variability for the continuous cap-
sule filling dosator system used. The results also showed
that measuring one powder flow property is not enough
to describe the performance of a pharmaceutical unit
operation.
The best linear correlations for the mean weight and
weight variability with powder flow properties were
obtained from the measured bulk density, tapped den-
sity, cohesion parameter (C) and ffc. Bulk density and
tapped density are fast measurements obtained from
simple equipment available in most powder laborato-
ries. The correlations obtained can be used to predict
the mean capsule weight and variability for blends with
similar flow properties in continuous capsule filling
systems. Newly developed techniques, i.e. basic flow
energy (BFE), are also useful in describing and widely
1472  J. G. Osorio and F. J. Muzzio

Table 7.  Mean weight and variability linear correlations with powder flow properties measured (R2 and p value determine the significance
of the linear fit).
Capsule size Bowl/piston height Property R2 p Linear correlation
Linear correlation – mean weight (mg)
 1 3 Bulk density 0.97 0.0018 176.362 + 322.132 bulk density (g/mL)
2 0.97 0.0025 151.709 + 388.055 bulk density (g/mL)
 3 4 1.00 0.0001 117.806 + 138.639 bulk density (g/mL)
3 0.98 0.0016 109.876 + 150.999 bulk density (g/mL)
 1 3 Tapped density 0.93 0.0082 142.304 + 300.981 tapped density (g/mL)
2 0.95 0.0052 108.021 + 367.38 tapped density (g/mL)
 3 4 0.94 0.0063 103.527 + 128.851 tapped density (g/mL)
3 0.90 0.0137 95.1595 + 138.828 tapped density (g/mL)
 1 3 Compressibility 0.77 0.0499 417.501–6.33094 compressibility (%)
2 0.79 0.0439 444.128–7.73916 compressibility (%)
 3 4 0.85 0.0259 223.342–2.82693 compressibility (%)
3 0.76 0.0542 222.473–2.94219 compressibility (%)
 1 3 Cohesion 0.98 0.0017 388.543–119.64 C (kPa)
2 0.97 0.0024 407.283–144.082 C (kPa)
 3 4 0.96 0.0032 208.504–50.5597 C (kPa)
3 0.99 0.0005 209.563–56.4225 C (kPa)
 1 3 Ffc 0.98 0.0013 196.189 + 22.7578 ffc
2 0.99 0.0005 174.452 + 27.6455 ffc
 3 4 0.96 0.0037 127.415 + 9.57726 ffc
3 0.96 0.0031 119.652 + 10.5702 ffc
 1 3 GDR F.I. 0.82 0.0356 379.41–1.31486 GDR F.I.
2 0.79 0.0426 395.402–1.56703 GDR F.I.
 3 4 0.83 0.0303 205.179–0.565615 GDR F.I.
3 0.86 0.0226 205.955–0.633131 GDR F.I.
 1 3 BFE 0.74 0.0626 240.915 + 0.102983 BFE (mJ)
2 0.75 0.0589 228.673 + 0.125267 BFE (mJ)
 3 4 0.77 0.0496 145.226 + 0.0448707 BFE (mJ)
3 0.75 0.0565 139.812 + 0.048763 BFE (mJ)
Linear correlation – square root of normalized variance (%)
 1 3 Bulk density 0.81 0.0385 3.00991–4.13856 Bulk Density (g/mL)
2 0.93 0.0075 5.08887–8.57922 Bulk Density (g/mL)
 3 4 0.70 0.0776 2.77904–3.95157 Bulk Density (g/mL)
3 0.81 0.0368 4.58638–7.69478 Bulk Density (g/mL)
 1 3 Tapped density 0.74 0.0602 3.41157–3.80194 Tapped Density (g/mL)
2 0.81 0.0359 5.80545–7.67167 Tapped Density (g/mL)
 3 4 0.83 0.0303 3.43881–4.12937 Tapped Density (g/mL)
3 0.67 0.0911 5.11774–6.67958 Tapped Density (g/mL)
 1 3 Compressibility 0.47 0.2010 0.109601 + 0.0698149 Compressibility (%)
2 0.69 0.0796 −1.24508 + 0.163469 Compressibility (%)
 3 4 0.61 0.1201 −0.242447 + 0.0813587 Compressibility (%)
3 0.49 0.1877 −0.845543 + 0.132103 Compressibility (%)
 1 3 Cohesion 0.81 0.0365 0.280327 + 1.54249 C (kPa)
2 0.98 0.0010 −0.616158 + 3.26757 C (kPa)
 3 4 0.76 0.0529 0.133096 + 1.53239 C (kPa)
3 0.89 0.0168 −0.5666 + 2.9849 C (kPa)
 1 3 Ffc 0.84 0.0289 2.7805–0.297491 ffc
2 0.90 0.0130 4.5063–0.595084 ffc
 3 4 0.88 0.0189 2.69837–0.311999 ffc
3 0.80 0.0418 4.07938–0.536869 ffc
 1 3 GDR F.I. 0.61 0.1194 0.446956 + 0.0160411 GDR F.I.
2 0.92 0.0103 −0.475918 + 0.0379461 GDR F.I.
 3 4 0.51 0.1763 0.347128 + 0.0150323 GDR F.I.
3 0.82 0.0339 −0.430928 + 0.0345226 GDR F.I.
 1 3 BFE 0.44 0.2228 2.04856–0.00112297 BFE (mJ)
2 0.76 0.0550 3.43481–0.00284141 BFE (mJ)
 3 4 0.61 0.1170 2.05159–0.0013609 BFE (mJ)
3 0.58 0.1331 3.00258–0.00239654 BFE (mJ)

 Drug Development and Industrial Pharmacy

 Effects of powder flow on capsule weight uniformity  1473

Figure 1.  Capsule weight and weight variability for both capsule
sizes (CS) 1 and 3 as a function of the bulk density. The bowl and Figure 3.  Capsule weight and weight variability as a function of
piston ratio are denoted by B/P. (A) mean weight; (B) variability. compressibility (at 15 kPa). (A) mean weight; (B) variability.

Figure 4. Capsule and weight variability as a function of the

Figure 2.  Capsule weight and weight variability as a function of cohesion parameter (measured in the shear cell at 6 kPa of
tapped density. (A) mean weight; (B) variability. consolidation pressure). (A) mean weight; (B) variability.

© 2013 Informa Healthcare USA, Inc.

1474  J. G. Osorio and F. J. Muzzio
Figure 5. Capsule and weight variability as a function of ffc.
(A) mean weight; (B) variability.
Figure 6.  Capsule and weight variability as a function of the GDR
flow index (F.I.). (A) mean weight; (B) variability.
 Drug Development and Industrial Pharmacy
Figure 7.  Capsule and weight variability as a function of the basic
flow energy (BFE). (A) mean weight; (B) variability.
differentiating blends with similar flow properties which
otherwise would not be differentiated when using other
techniques, i.e. GDR F.I. also available.
The basic flow energy (BFE) also showed good correla-
tion demonstrating that as the BFE increased the mean cap-
sule weight increased and the variability decreased. For the
blends used in these studies, the compressibility and GDR
flow index are not very distinctive among the blends used
although the correlations still showed the same trends.
Such correlations can be used to predict which capsule
size and parameters to use in order to obtain a desired
dose and required variability. For example, if the powder
blend final tapped density has a value of 0.60 g/mL, a fill
weight of approximately 230 mg (300 mg total – 76 mg
of the empty capsule) would be obtained. In this case a
capsule size 1 would be used. The reproducible variability
in this case would be around 1.0% the square root of the
normalized variance which can be translated easily to
approximately 1.0% RSD for a production speed range of
60,000–100,000 capsules per hour.
It was concluded that the better the flow, the higher
the weight and the lower the variability for such as cap-
sule filling system. In parallel studies, capsules have
been filled with blends with a wide range of powder flow
properties using a capsule-dependent machine, which
uses the capsule body directly to measure the dose.
Correlations among capsule weight and weight vari-
ability with powder flow properties measurements will

be presented in the same manner. Future publications
will present results using a capsule-dependent machine
compared to the results obtained in this study that used a
capsule-independent machine. Next steps in this field of
work should include expanding the work to blends with
more distinctive powder flow properties produced using
a continuous powder mixer and filling capsules continu-
ously. Correlations between continuous blending and
capsule filling should be studied.
Declaration of interest
The authors report no conflicts of interest.
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