As appeared in
Tablets & Capsules January 2015
www.tabletscapsules.com
Copyright CSC Publishing
granulation analysis
Density mapping of
roller-compacted ribbons
using terahertz spectroscopy
Mark Sullivan, David Heaps,
Richard McKay, Eiji Kato, and
Xiao Hua Zhou
Advantest America
Chuan-Yu Wu, Chun-lei Pei,
Jian-yi Zhang, and Serena Schiano
University of Surrey
Terahertz (THz) spectroscopy and imaging are non-destructive
tools for measuring the chemical and physical attributes of
pharmaceutical raw materials, intermediates, and finished
products [1]. Examples include determining the crystallinity and
polymorphism of drug substances, the 3D spatial uniformity of
tablet coating thickness, and tablet hardness. Terahertz
spectroscopy is also well suited to measure and control the density
(solid fraction, porosity) of roller-compacted ribbons. In this
article, we describe the principals of terahertz analysis and give
examples of how it can help with formulation development and
scale-up and commercialization of the roller compaction process.
T
amount of energy for drying, roller compaction can
operate as a continuous process and entails no drying.
Figure 1 illustrates the major parts of the equipment: a
feeder to introduce the powder blend, rollers to compact
the powder into a ribbon, and a mill to reduce the ribbon
to granules. The figure also shows the optical path of a
terahertz beam.
Figure 1
Roller compactor
he terahertz range (0.1 to 10 THz) lies between the
microwave and infrared regions of the electromagnetic
spectrum and offers a unique combination of high
material transparency and spectroscopic information.
Terahertz spectroscopy uses extremely short pulses that
yield a broadband response and provides a direct means
to measure the bulk physical properties of materials,
including refractive index, permittivity, and absorption
coefficient. As a result, we can measure the density of
roller-compacted ribbons—the most critical property of
the process—quickly, non-destructively, and without
contact in the lab and production settings.
The design of the pulsed terahertz spectrometer was
described previously [1], and its operation resembles that
of other types of Fourier transform instruments that collect
a background and analyze the intact solid sample using
acquisition times of less than a second. Sampling can be
done for at-line and in-line analyses, as detailed below.
Roller compaction
Roller compaction is a dry process that agglomerates
powders into ribbons and mills them into granules for the
manufacture of tablets and other solid dosage forms.
Unlike traditional wet granulation, which operates in
batch mode and requires a liquid binder and a large
1. Feeder introduces powder
2. Counter-rotating rollers compact powder into ribbon
3. Mill reduces ribbon to granules
4. Optical path of terahertz beam to ribbon
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The ribbon’s density is the most important quality
attribute to control because it determines how well the
granules flow and compact during tabletting. The
parameters that can be adjusted to control the ribbon’s
physical properties are feeding speed, roller speed, roller
gap, and roller pressure. In addition, one or both of the
smooth-surface rollers can be replaced with knurledsurface rollers in order to decrease slippage of the powder
as it enters the nip zone.
A deep understanding of the roller compaction process
is required to ensure consistent product quality and
performance across a range of environments. In fact, one
of the most important challenges of process scale-up and
technology transfer is identifying the process parameters
that will produce granules with consistent properties.
Accurate measurement of ribbon density is critical to
achieving that. Furthermore, because terahertz spectroscopy correlates the properties of raw and in-process
materials and process parameters to measurable product
performance attributes, it jibes with the goals of Quality
by Design. It can also serve as a Process Analytical
Technology tool by offering fast, non-destructive, and
real-time analysis of roller-compacted ribbons to provide
process understanding and help ensure product quality.
Roller-compacted ribbons are inherently porous and
can be characterized by apparent density, solid fraction,
and percentage porosity (Table 1).
There are several ways to measure the envelope volume
of roller-compacted ribbons (Table 2). Direct volume
measurement is the easiest to implement but can be tedious
when used routinely; it also lacks accuracy when applied to
textured ribbons. Volume displacement is a better
approach for measuring complex shapes and is not subject
to operator variability and bias. Yet it requires cutting the
ribbon into pieces small enough to fit inside a sample
chamber. Another option is laser scanning, in which a laser
micrometer pair is coupled with motion control to traverse
the sample and create a two-dimensional (2D) pattern of it.
Laser scanning can also be used to profile ribbon thickness
and thus calculate its volume.
The most direct way to determine apparent density is
to cut the ribbon into rectangular pieces, measure their
dimensions, and weigh them to calculate envelope volume. Despite its relatively poor precision, this technique
is often the primary method for calibrating the roller
compactor. But using volume displacement or laser
scanning provides substantially more accurate and precise
measurements of apparent density.
While this article focuses on applying terahertz technology to roller-compacted ribbons, other techniques can
also measure density profiles (Table 3). Each has its
advantages, but the terahertz method stands out as a fast,
non-destructive, non-contact technique suitable for spatial
mapping and in-line process applications. In addition, most
pharmaceutical materials are highly transparent to terahertz
radiation, which can penetrate approximately 10 millimeters into the material. Therefore, terahertz samples the
entire ribbon thickness, not just the surface. It is also highly
precise and sensitive to changes in apparent density.
Theory of terahertz density measurement
Table 1
Material properties of roller-compacted ribbons
Material property
Apparent density
or bulk density
Solid fraction
Percentage porosity
Definition
Weight envelope volume
(where envelope volume is obtained
by direct measurement of
the dimensions of the compact)
Apparent density true density
(where true density is the material
density in the absence of voids)
(1 solid fraction) • 100%
The unique characteristics of pulsed terahertz spectroscopy make it well suited for measuring the densities
of solid compacts. The terahertz source (emitter)
generates a very narrow, phase-coherent pulse of light
that reaches a phase-sensitive detector whose fast digitization rate makes it possible to measure in the picosecond range. When a terahertz pulse passes through a
homogeneous solid, its speed decreases relative to a
terahertz pulse that traverses the same distance through
air. The ratio of the speed of light in air to the speed of
light in a denser material is, in fact, the definition of the
refractive index (RI) of that material. The time difference
Table 2
Techniques for measuring envelope volume
Technique
Direct measurement
Device
Micrometer caliper
Advantages
Volume displacement
Pycnometer
Laser scanning
Laser micrometer
Accurate for irregular shapes
(e.g., textured ribbons), not subject
to operator variability
Fast, non-destructive, suitable
for in-line applications
Low cost
Disadvantages
Destructive, manual, subject to operator
variability, poor spatial resolution
Destructive (sample cut to fit in chamber),
poor spatial resolution
Sensor array or traversing sensor
required for ribbon profiling
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Table 3
Techniques for measuring apparent density of roller-compacted ribbons
Technique
Advantages
Terahertz
Fast, non-destructive, non-contact, deep penetration
(transmission), low-energy beam, no effect on sample integrity,
suitable for in-line process applications
Spatial resolution limited by material absorption
Fast, non-contact, suitable for in-line process applications
Indirect, surface only, sensitive to beam
orientation on patterned ribbons
Section and weigh
Micro-indentation [2]
X-ray micro-computed tomography [2]
Acoustic wave [5]
High spatial resolution, deep penetration
[dc]
Equation 1
where c is the speed of light and d is ribbon thickness.
Figure 2
Terahertz time-domain signals for measuring time-of-flight for
a solid compact vs. an air reference
0.4
Air reference
peak
Intensity (arbitrary units)
0.3
0.2
t
Sample peak
0.1
0
-0.1
-0.2
12.882 13.7 14.39 15 15.5 16 16.5 17 17.5 18 18.5 19 19.5 20 20.5 21 21.5 22 22.5 23 23.5 24
Destructive, indirect, surface only, requires
observation by skilled operator
Complex, radiation safety issues, may affect sample integrity
Fast, sensitive to elastic properties and mass density
(t) between the arrival of the air reference and sample
pulses can be obtained from the time-domain terahertz
spectrum (Figure 2). The RI, , is obtained using
(group frequency) 1 t
Destructive, poor precision, manual operation,
low spatial resolution
Sensitive to material’s elastic properties and hardness
Near infrared [3, 4]
0.5
Disadvantages
Low cost
Direct contact with acoustic couplant required
between sample surface and transducers, susceptible
to interference from roller compactor’s vibration
Alternatively, the RI can be obtained from the frequency domain spectrum (Equation 2) following Fourier
transformation of the time-domain spectrum.
[()] [dc]
() 1 Equation 2
where () is the RI and () is the phase shift at the
angular frequency .
Measuring the RI in the frequency domain gives you
the flexibility to select the frequency-dependent beam
diameter to obtain optimal spatial resolution in 2D
mapping of the density, which will be discussed and
shown in more detail later.
Figure 3
Time-of-flight concept: Air vs. high-porosity and
low-porosity solids
Air
High-porosity solid
Low-porosity solid
Time (picosecond)
Of course a roller-compacted ribbon is a porous material
whose effective RI depends on void volume, provided
scattering effects are minor. The terahertz pulse will pass
more quickly through a highly porous sample than a tightly
compacted one (Figure 3). Therefore, the effective RI,
while not an intrinsic property of the ribbon material, is
directly proportional to the ribbon’s apparent density and
solid fraction; it is inversely proportional to porosity (Table
1). Note that in transmission mode, the ribbon thickness
must be known in order to calculate the RI.
d
Copyright CSC Publishing
The RI can also be obtained from surface reflectance
using a simple expression derived from the Fresnel
equations and assuming a 90-degree angle of incidence
(Equation 3).
[1 r]
1r
and nair 1
Studies on surface-density mapping of compacts using
terahertz imaging spectrometers have shown excellent
results [6, 7]. Surface-reflectance RI measurements are
independent of ribbon thickness and therefore have no
restriction on ribbon dimensions. However, the reflectance mode is generally less accurate than the transmission mode when measuring bulk RI. This is because
factors such as surface roughness, which causes scattering,
can significantly decrease sample reflection intensity but
have little effect on phase. In addition, the surface density
may not be representative of the bulk sample.
Terahertz sampling modes
Figure 4 shows three terahertz sampling modes, each
with a different design geometry, for measuring the
density of roller-compacted ribbons. For transmission, the
emitter-detector pair is placed on opposite sides of the
ribbon (Figure 4a.) Laser micrometers may be mounted on
the terahertz elements to provide a serial reading of the
moving ribbon’s thickness, followed by a terahertz reading
at the same location. This combination allows nearly realtime density measurements. For most static samples, such
as those measured for QA/QC, ribbon thickness would be
recorded manually and the results entered into software as
a sample parameter in the calculation of RI.
Figure 4
Sampling modes for terahertz measurements
Laser micrometers
Det
ecto
r
Emitter
Detector
Ribbon
a. Transmission
r
Metallic reflector
r
itte
Em
b. Transflectance
Terahertz spectroscopy measures the RI of a solid
directly, and converting the RI results to density, solid
fraction, and percentage porosity requires calibration.
The easiest conversion entails preparing powder
compacts at different compaction forces and measuring
them with an analyzer like the one in the photo on the
next page. Apparent density is calculated from the sample
weight and envelope volume, which are easily obtained
by directly measuring the cylindrical compacts. Figure 5a
shows the linear correlation between RI and apparent
density for fresh and relaxed compacts of microcrystalline
cellulose (MCC). The plot demonstrates the sensitivity
of terahertz spectroscopy when measuring the elastic
recovery of materials after compression. It also
demonstrates the need to measure envelope volume
simultaneous to terahertz analysis of freshly made
compacts. To convert apparent density to percentage
Figure 5
Det
ecto
Single-point density measurements
r
Correlation of refractive index (RI) to apparent density and
to percentage porosity for fresh and relaxed MCC
compacts over a range of compaction forces
itte
Em
c. Surface reflectance
Depending on the roller compactor’s design and
operating conditions, material may exit the rollers as a
rigid, freestanding ribbon or it may adhere as a layer to
the roller surface until a scraper removes it, which
generally reduces the ribbon to flakes before they enter
the mill. Rigid ribbons can be analyzed by transmission,
but when they flake, density must be measured while the
ribbons adhere to the roller.
1.9
a. RI vs. apparent density
b. RI vs. percentage porosity
1.9
1.85
1.85
1.75
1.75
1.8
1.8
RI
Intensity of the sample reflection
Intensity of a reference mirror reflection
RI
where r Equation 3
Alternatively, the ribbon can be measured in transflectance mode, where the roller serves as a metallic
reflector between the angled emitter-detector pair (Figure
4b). In that case, because the terahertz waves must pass
through the ribbon twice, its path is twice as long as it is
in transmission. While that enhances sensitivity when
measuring thin ribbons, it reduces the maximum
thickness that can be measured. Because there is no
practical way to measure thickness while a ribbon
adheres to the roller, the minimum roller gap—plus a
fixed percentage increase to account for the ribbon’s
elastic recovery—can provide a reasonable gauge of
ribbon thickness for in-line applications.
The surface-reflectance sampling mode shown in
Figure 4c—essentially identical to the transflectance
geometry in the absence of a metallic reflector—is
included here for completeness. This mode is useful for
surface characterization but is generally not as accurate as
transmission or transflectance and is not a bulk
measurement.
1.7
1.7
1.65
1.6
1.65
1.1
1.2
1.3
1.4
Apparent density (g/cm3
Fresh
Linear (fresh)
Relaxed
Linear (relaxed)
1.5
1.6
0
5
10
15
% Porosity
Fresh
Linear (fresh)
20
Relaxed
Linear (relaxed)
25
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porosity, use the formula in Table 1, which also requires
knowing the true density of the powders [8]. The plot in
Figure 5b shows the correlation of RI to percentage
porosity.
Figure 7 shows the RI gradients of two sets of rollercompacted ribbon sections prepared at high and low
compaction force. While the graphics provide insight into
important qualitative spatial differences, plotting the RI
distribution as a histogram (Figure 8) enables you to apply
quantitative comparisons and quality metrics. As
expected, the ribbon sections prepared at high compaction force show a wider distribution in RI than the
ribbon sections prepared at low compaction force.
However, the latter distribution shows a longer tail at the
lowest RI values, which may indicate weaker granules and
more fines.
Figure 9 shows three different 2D spatial RI maps of a
textured ribbon section made using knurled rollers. The
Figure 6
Two-dimensional RI mapping of a roller-compacted ribbon
section
Terahertz spectroscopy measurement unit equipped with transmission module.
Inset shows placement of sample on transmission stage.
a. Raw data
Two-dimensional density mapping
35
1.7
30
Width (mm)
1.75
1.65
25
1.6
20
15
1.55
10
RI
Two-dimensional mapping of ribbon density is
accomplished by moving the sample stepwise in a grid
pattern and collecting an array of spectra (photo below).
The step size should correspond to the desired spatial
resolution and the diameter of the terahertz beam. For
example, the map of the ribbon section in Figure 6a was
constructed from steps of 10 by 4 millimeters in the
width dimension and 8 by 2 millimeters in the length
dimension. In this case, the pixels were color-coded
according to the RI, which can be converted to apparent
density, solid fraction, or porosity, as discussed above. It
is generally easier, however, to see RI gradients in a
contour map (Figure 6b). This pattern is typical of most
compacted ribbons: The RI value is highest near the
center and tapers off at the edges.
b. Contour map of
same ribbon section
1.5
5
1.45
0
0
5
10
15
20
25
-5
Length (mm)
0
5
10
15
20 25
1.4
Figure 7
Two-dimensional RI mapping of roller-compacted ribbons
35
a. Four sections of same ribbon, high compaction force
30
25
Width (mm)
20
15
1.75
10
1.7
5
0
10
15
10
15
20 5
10
15
5
10
15
b. Four sections of same ribbon, low compaction force
1.5
1.4
Width (mm)
20
15
10
5
Motorized X-Y stage platform with terahertz transmission optics for mapping the
density of roller-compacted ribbons
1.55
1.45
25
0
1.6
RI
30
1.65
5
5
10
15 5
Length (mm)
10
15
5
10
Length (mm)
15
5
10
15
Copyright CSC Publishing
data were collected using a motorized X-Y stage with
step sizes of 1 millimeter in both the width and length
dimensions. The resulting maps appear different because
of how the data were processed. The left plot was
obtained with the highest frequency and, therefore, the
smallest beam diameter. In fact, the beam diameter was
smaller than the step size, so the fine features of the
ribbon’s texture are apparent, and the map is pixelated. In
contrast, the plot on the right was obtained at the lowest
frequency using a beam diameter larger than the step size,
and the ribbon texture is smoothed out on the RI map.
Figure 8
Histograms of RI
Figure 9
Two-dimensional RI maps of a textured roller-compacted
ribbon measured using three different beam diameters
Frequency
Beam diameter
70
1.5 THz
0.76 mm
1.0 THz
1.15 mm
0.5 THz
2.29 mm
35
60
1.8
30
Frequency
Low-compaction-force ribbon
sections (Figure 7b)
30
20
1.6
20
RI
High-compaction-force ribbon
sections (Figure 7a)
40
1.78
25
Width (mm)
50
1.5
15
1.4
10
1.3
5
10
0
As noted above, RI values obtained by transmission are
directly dependent on the measurement of ribbon
thickness at the point where the beam is located. In the
case of a high-frequency observation where the beam
diameter is similar in size to the pattern of the textured
ribbon, it is impossible to measure thickness accurately.
The best compromise in that case is to conduct a lowfrequency observation using a beam diameter larger than
1.8 1.78 1.76 1.74 1.72 1.7 1.68 1.66 1.64 1.62 1.6 1.58 1.56 1.54 1.52 1.5 1.48 1.46 1.44 1.42 1.4 1.38 1.36 1.34 1.32 1.3
RI
the pattern of the textured ribbon. The more accurate
average thickness over a wider area will yield lower
spatial resolution, but the RI values will be more accurate.
Understanding the relationships between process
parameters and the critical quality attributes (CQAs) of
roller-compacted ribbons is important for small-scale
development, scale-up, and commercial manufacturing.
Figure 10 shows the results of an experiment to measure
how roll speed affects bulk density. The 2D maps (figures
10a, 10b, and 10c) show that RI decreases as roll speed
increases. In Figure 10d, the overlaid average cross-section
projection line plots of RI are averaged over 40
millimeters in the machine direction (X) versus the ribbon
width (Y) for the three roll speeds. In Figure 10e, this
average cross-section projection line plot of RI was
converted to the line plot of apparent density using the
equation for correlating between average RI and apparent
density (Figure 10f) that was established independently on
MCC compacts. The plot in Figure 10e shows that the
apparent density is highest in the middle of the ribbon’s
width and tapers off toward the edges. Ribbon density
decreases as roll speed increases, which corresponds to a
shorter dwell time in the nip region of the rollers.
Figure 11 shows the results of an experiment to measure
how the size of the roller gap affects apparent density. As
the average cross-section projection line plots in figures 11c
and 11d show, apparent density decreases as the roller gap
increases. The terahertz results (red line) are superimposed
on the density data that were obtained by cutting the
0
5
10
0
5
10
Length (mm)
0
5
10
1.2
ribbon into sections (blue line). This section-and-weigh
method generated fewer points across the ribbon because it
was difficult to cut the ribbon into small pieces. More
important, the standard deviation is high compared to that
of the terahertz results, where the standard deviation is less
than the height of the marker on the plot.
In-line density measurement
Terahertz 2D mapping of roller-compacted ribbons
yields detailed quantitative spatial density and porosity
information, which enables you to optimize process
parameters and ensure different types of equipment provide
functional equivalence. Once the process parameters are
set, the objective is to monitor the process over time, and
this can be done with an in-line terahertz analyzer (Figure
12). In production, ribbons typically travel at linear speeds
of 50 to 150 millimeters per second, which is compatible
with terahertz sampling intervals of less than 1 second.
Different sampling patterns can be used, and figures
12a and 12b illustrate how to use a small spot size to
monitor a single track and traverse the ribbon. Figure 12c
shows how a cylindrical lens is used to generate a large
elliptical spot, which provides efficient sampling over a
large area and improves the signal-to-noise ratio. This
optical arrangement is preferred for monitoring the
approach of steady-state operation at startup and to
monitor short- and long-term ribbon density variations
during operation. Ideally, this information would be fed
back to the machine to provide real-time process control.
Copyright CSC Publishing
Figure 10
Effect of process parameters on ribbon apparent density cross-section: Variable roller speed and fixed gap (0.95 mm) and
2D RI maps
a. 1 rpm
1.5
1.4
1.3
1.2
1 rpm
3 rpm
1.1
5 rpm
1
0.9
-30
-20
-10
0
Width, Y (mm)
1.4
1
0.8
0.6
1 rpm
0.4
20
0
30
5 rpm
-30
-20
-10
Effect of process parameters on ribbon apparent density
cross section: Variable gap with fixed roller speed (1 rpm)
and 2D RI maps
Length, X (mm)
Length, X (mm)
10
20
40
Terahertz
Section
0.5
0
-30
30
0.5
40
0
2
Terahertz
Section
1.5
30
-20
-10
0
10
Width, Y (mm)
1
0.5
20
30
0
-30
40
f. Calibration curve for average RI vs.
apparent density
2
1
10
20
30
0
Refractive index 0.44 (Apparent density) 1.01
0
0.5
1
Apparent density (g/cm3)
1.5
Figure 12
Terahertz sampling patterns for in-line analysis
a. Small spot
monitors single
track
b. Small spot
traverses
ribbon
c. Cylindrical lens
generates large
elliptical spot
1.5
d. Average apparent density
cross-section projection line
plot (1 mm)
Apparent density (g/cm3)
Apparent density (g/cm3)
c. Average apparent density
cross-section projection line
plot (0.8 mm)
1
20
40
0.3
1
20
30
1.5
0
10
20
0.6
30
2
10
10
Width, Y (mm)
-10
-20
20
10
0
-10
-20
Width, Y (mm)
b. 1 mm
0
Width, Y (mm)
Figure 11
a. 0.8 mm
0.9
20
0.5
3 rpm
0.2
10
1.2
10
1.5
1.2
Average RI
Apparent density (g/cm3)
1.6
Average RI
Length, X (mm)
Length, X (mm)
1.6
1.5
20
40
10
30
0
20
1.8
Width, Y (mm)
-10
10
e. Average apparent density cross-section
projection line plot for 1, 3, and 5 rpm
1.7
2
-20
40
d. Average RI cross-section projection
line plot for 1, 3, and 5 rpm
c. 5 rpm
20
30
10
20
0
10
-10
Width, Y (mm)
-20
20
10
0
-10
-20
Length, X (mm)
b. 2 rpm
Width, Y (mm)
-20
-10
0
10
Width, Y (mm)
20
30
Conclusions
Terahertz spectroscopy is a fast, non-destructive, noncontact technique for measuring density (solid fraction,
percentage porosity), which is the most important CQA
of roller-compacted ribbons. This information can be
used to optimize process parameters during development,
facilitate scale-up, and to control the process during
continuous manufacturing.
T&C
References
Copyright CSC Publishing
1. Sullivan, M.J., King, E.; Kato, E.; Heaps, D.;
McKay, R.; Zhou, X.H. Using terahertz spectroscopy to
map tablet cores and coatings. Tablets & Capsules, 2013.
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Mark Sullivan is a senior R&D scientist; David Heaps and
Richard McKay are principal scientists; Eiji Kato is a terahertz
technology expert; and Xiao Hua Zhou is an analytical
scientist at Advantest America, 508 Carnegie Center, Suite 102,
Princeton, NJ 08540. Tel. 609 897 7320. E-mail:
[email protected]. Chuan-Yu Wu is a professor
in the Department of Chemical and Process Engineering at the
University of Surrey, Guildford, GU2 7XH UK. Chun-lei
Pei, Jian-yi Zhang, and Serena Schiano are members of Wu’s
research group.