2. PHARMACEUTICAL TECHNOLOGIES
Background
Dry granulation comprises three integrated steps of blending, roller-compaction (or slugging)
and milling.
The roller compaction stage produces ribbons of the blended material which are then milled
to produce granules of controlled size distribution (Inc. fines) and porosity, as these
parameters impact flow and compaction properties.
The target quality attributes of the ribbon are content uniformity and uniformity of the
porosity/density profile of the ribbon.
Content uniformity is controlled in the blending stage and porosity/density is controlled by
the RC stage.
One feedback loop for controlling the density of ribbons emerging from the RC process is to
control the roll pressure (as our surrogate for density) by adjusting auger speed to account
for inherent fluctuations in feed density.
3. PHARMACEUTICAL TECHNOLOGIES
Aim & Objectives
Aim: To research the application of THz imaging for determining the density and thickness of
RC ribbons.
There are four area of this study:
1. OEM glass slides: Initial validation of 3 time-domain terahertz methods* on.
2. Tablets: Optimising the TD analytical methods on. (A 4th frequency-domain (FD) THz method was
required**).
3. Prediction of mechanical strength (RTS) as a further use of the FD THz method**.
4. RC Ribbons: Evaluate our aim of predicting parameters of density and thickness.
* The terahertz principle time-domain methods include:
a) TD transmission optical-time-delay analysis.
b) TD reflection amplitude coefficient.
c) TD reflection optical-time delay analysis, and
A frequency domain method chiefly used as a comparator method to the TD methods
a) FD spectral extraction of RI’s.
4. PHARMACEUTICAL TECHNOLOGIES
𝑅𝐼 = 𝑐 𝑜(𝑚/𝑠) 𝑐 𝑠𝑎𝑚𝑝𝑙𝑒(𝑚/𝑠)𝐸𝑞𝑢. 1
The optical time-delay methods require:
1) A reference time delay measurement.
2) Inserting an analyte, a proportion of the signal is either transmitted,
slowing c (see Equ. 1:) , or reflected at the surface (see Fig 2. @ times <20ps).
This provides two options to measure RI:
1. Optical time-delay: see TD waveform plot in transmission; Fig 1.
• RI has a linear trend to density, and sensitive to chemical composition.
• The ref max(t) against the 1st (attenuated) silica peak (Fig 1. @ ~10 ps),
• allows Equ. 2 for RI. If a 2nd is observed, (as at ~22 ps), the signal has
bounced internally and exited the posterior to give a Fabry-Perot echo. This is
analogous to Fig 2. (at 20-30 ps).
2. The proportion of signal reflected; Fig 2 & 3.
𝑅𝐼 = 1 +
𝑐 𝑚 𝑠 × 𝑆𝐷 𝑠
)𝑇ℎ𝑘 𝑛(𝑚
𝐸𝑞𝑢. 2. 𝑅𝐼 = 1
2 ×
𝑐 𝑚 𝑠 × 𝐼𝐷 𝑠
)𝑇ℎ𝑘 𝑛(𝑚
𝐸𝑞𝑢. 3.
Summary of TD methods (demonstrated with glass
slides) to chiefly extract RI
Fig 1: TD waveform in transmissionTime-domain methods
Signal Delay, SD (t)
Internal Delay. ID (t)
-4
1
6
305 315 325 335
THzE-Field×103,a.u.
Optical Delay, ps
Silica Ref. Pulse
AUC = 1.48 I(t)
AUC = 0.48 I (t)
0
5
10
THzIntensity10,
au
Optical delay-time, ps
Ref. Intensity Silica Intensity
Fig 2: TD waveform in Reflection
• The proportion of the reflected signal surface (Fig 2 ~20ps) compared with a
ref. of full reflection is treated with the Hilbert transformation = signal intensity.
• The function simulates a B-Field for enhanced Intensity (t). Then the area
under the intensity curve (at the substrates interface: highlighted) provides
coefficients that when applied to a simplified Fresnel amplitude reflection
coefficient, yield reliable RI’s that are fit for purpose. (Equ. 4)
• Now that a RI can be generated, so can thickness. 𝑟𝑝 =
𝐴𝑈𝐶 (𝑠) (0.48)
𝐴𝑈𝐶 (𝑟) (1.48)
⟹ 𝑅𝐼 =
1 + 𝑟𝑝
1 − 𝑟𝑝
𝐸𝑞𝑢. 4
5. PHARMACEUTICAL TECHNOLOGIES
Summary of frequency-domain (transmission) RI
calculation of (demonstrated with glass slides)
Fig 1: Raw TD waveform of silica.
• Stock software supplied with the TPS-3000 includes a
routine fast Fourier transformation.
• The FD method translates the time-domain functions of the
raw transmission waveform with Equ 1.
Stable THz region
1.0
1.5
2.0
0 1 2 3 4
RI
Frequency, THz
-4
-2
0
2
4
6
8
305 315 325
THzE-Field×103,a.u.
Optical Delay, ps
Silica Ref. Pulse
FFT
𝑅𝐼 𝑣 = 1 +
𝑐(𝜙 𝑠𝑎𝑚𝑝𝑙𝑒 𝑣 − 𝜙 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒( 𝑣)
2𝜋 𝑣𝑑
𝐸𝑞𝑢 2.
𝐹𝐹𝑇: 𝐸 𝑧, 𝜔 =
1
2𝜋 −∞
∞
𝐸( )𝑧, 𝑡 𝑒−𝑖𝜔𝑡
𝜕𝜏 𝐸𝑞𝑢. 1
• The imaginary component of the complex number supplies
transmittance phase information () and is used to produce
a RI spectra with the use of Equ. 2 and then plotted (Fig 2),
whereby a stable region of RI values are used in our studies.
Fig 2: FD RI spectra of silica.
6. PHARMACEUTICAL TECHNOLOGIES
Roller Compaction
The three major units of a typical roller compactor :
A feeding system (1-4) : powder conveyance to the compaction area between the rolls.
A compaction unit (5) : powder is consolidated between 2 rollers forming ribbons by force.
A size reduction unit (6) for milling the ribbons to the desired particle size.
Importance of Process Parameters:
Force and Roll Gap
• Force is the most important
parameter in the dry granulation
process as it defines density and the
strength if the ribbon, along-side,
• The Roll Gap (as the secondary most
critical PP). The RPM is a tertiary
setting and chiefly influences ribbon
throughput
• At a given force, the powder will be
compacted to a pre-defined ribbon
thickness depending on the amount
of powder conveyed to the rolls.
A typical horizontal and diagonal feed RC unit.
7. PHARMACEUTICAL TECHNOLOGIES
RC Process Control
A Gerteis
Mini-
PolyGran
GUI
User defined GAP (2nd greatest PP
influence of ribbon quality). The adjacent
white-box reports the current parameter.
User defined Roll-speed (3nd greatest PP
influence of ribbon quality).
User defined FORCE (1st greatest PP influence of RC
quality): Set at 5 kN/cm, force-inducers monitor
resistive strain along with the defined gap. Achieved
Dynamic control of feeding system.
Material feed of augers at rate to
force the rolls apart to max GAP and met
defined FORCE
Feed rate controlled
GAP: USER DETERMINED
FORCE: USER DETERMINED
RPM: USER DETERMINED
Feed-back: Process parameters monitored
8. PHARMACEUTICAL TECHNOLOGIES
Road map of project
Ribbons Glass
slides
TabletsTHz Uses
Output
RI values agree within 5% of FD
literature values
TD methods validated for glass slides
FD RI values known from literature
RI depends on chemistry
OEM standards : Precise thickness & homogeneous
Evaluate TD methods for RI determination
(i) OD in transmission mode
(ii) OD in reflection mode
(iii) Amplitude coefficient in reflection mode
Compare TD RI vs FD RI (literature)
Unknown RI : Measure RI by FD method
RI depends on solid fraction
Precise thickness & quasi-homogeneous
Solid fraction f (depth into tablet)
Evaluate TD methods for RI determination
(i) OD in transmission mode
(ii) OD in reflection mode
(iii) Amplitude coefficient in reflection mode
Compare TD RI vs FD RI (measured)
Output
RI values agree within 5% of FD
literature values
TD methods validated for
tablets
Mechanical strength prediction:
Measure RI by FD method and RTS
RI depends on solid fraction and is
∝ to thickness
Evaluate FD method for non-destructive RTS
determination
(i) Tablets with fixed mass compressed at
greater forces
(ii) Tablets produced with equal compaction
forces will constant mass.
Compare FD RI vs RTS
Output
RI can est. RTS when fill-weight
remains constant. Less success
with others: agglomeration forces?
Unknown: RI’s, effect of machine (system/user PP’s) and
formn
RC’s: Gerteis (smooth rolls), AlexanderWerk (knurled).
RI depends on SF & character of ribbon.
Evaluate TD methods for RI determination/thkn
(i) OD in transmission mode
(ii) OD in reflection mode
(iii) Amplitude coefficient in reflection mode
Compare TD RI vs FD RI (FDT)
9. PHARMACEUTICAL TECHNOLOGIES
Identification of ribbon density profiles was illustrated by x-ray diffraction (atomic cloud
density) [Simon and Guigon, 2001]
In this case, it can be see that the density map is a consequence of the RC design
Relative quantification
Example of a non-homogeneous ribbon
10. PHARMACEUTICAL TECHNOLOGIES
Accurate RI and Thickness prediction (TD): Glasses
Glass Specifications Silica Pyrex BK7 Units
Literature RI 1.950 2.100 2.500 n
Actual Thickness 1.08 1.73 1.03 mm
Optical Delay Analysis: RI (for Signal Delay)
Δ OD 3.433 6.329 5.162 ps
RI as function of SD 1.953 2.097 2.556 n
Difference 0.003 -0.003 0.032 n
Mean & Error from Mean Lit RI 0.151 -0.155 1.289 %
Optical Delay Analysis: RI (for Internal Delay)
Δ OD 14.032 23.916 17.21 ps
RI as function of internal echoes 1.948 2.072 2.505 n
Difference -0.002 -0.028 0.054 %
Mean Percentage Error from Lit RI -0.126 -1.323 2.167 %
Reflection method
Amplitude Coefficient 0.323 0.359 0.441 rp
Reflection RI 1.953 2.119 2.580 n
Difference 0.003 0.019 0.080 n
Mean Percentage Error from Lit RI 0.18 0.90 3.21 %
Thickness Prediction (Predicted reflectance RI OD methods)
Predicted thickness 1.06 1.64 1.03 mm
Percentage Thkn error -1.34 -3.82 -0.69 %
Material RI Thickness Prediction
Limitations of methods:
• Substrate must lie in precise positioning to the
antennae.
Transmission
• Thkn or RI must be known.
• Fabry-Pérot events are not always present for ID
measure.
Reflection
• * Simplification of Fresnel coefficient reduces RI
accuracy by < 1%.
• Lit. error bars, n = 3, broad THz frequency limits, calliper degree of sensitivity.
• Combined OD error bars, n = 3, calliper degree of sensitivity.
• TPI/Reflection error bars, n=3 calliper degree of sensitivity,
• method constraints.
1.60
1.80
2.00
2.20
2.40
2.60
2.80
Silica Pyrex BK7
THzRI
Literature
Combined SD & ID TDT thkᶯ results
TPI/Reflection
Glass
slides
11. PHARMACEUTICAL TECHNOLOGIES
FD measurements of RI of tablets
37 tablets of MCC were prepared (with variable fill weights and compaction force) and
analysed with FD transmission spectroscopy to establish RI as a function of SF/density
A linear (line of best fit) extrapolation to a RI of <1, crossing the density axis at ~ 0.06
Given that the RMSE for density is 0.005 g/cm3 then measurement precision alone may not
explain the low value for the intercept. The alternative might be a non-linear relationship
For a tablet of bulk density 1.00 g/cm3 the measurement precision is 0.4%. In terms used by
the ICH Q2 guideline (Directive 75/318/EEC) this represents an LOD of 1.3%.
y = 0.586x + 0.9664
52% 57% 62% 67% 72%
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6
Solid Fraction, %
RI,ñ@0.3-1.5THz
Bulk Density, g/cm3
Fixed Force (420kg)/Var. Weight
Fixed Force (320kg)/Var. Weight
Fixed Weight (200mg)/Var. Force
Fixed Weight (295mg)/Var. Force
RMSE for density
is 0.005 g/cm3
0.06 g/cm3.
Tablets
12. PHARMACEUTICAL TECHNOLOGIES
Compare TD RI vs FD RI (measured)
10 pharmaceutical tablets of Avicel
with a constant volume (thus Thkn) &
variable densities were analysed.
The mean of FDT RI’s are calculated
between 0.3 - 1.5 THz and
transmission optical-delay &
amplitude reflection results reported.
FFT is considered as the ‘gold-
standard’ for RI’s are true at specific
EMR frequencies.
Gradient = 0.53
R² = 1.00
Gradient = 0.56
R² = 1.00
Gradient = 0.48
R² = 0.97
1.00
1.05
1.10
1.15
1.20
1.25
1.30
1.35
1.40
1.45
1.50
0.00 0.20 0.40 0.60 0.80
THzRI
Density, g/cm3
FFT RI
OD RI
rp RI
* Error bars are the result of repeat experiments (n=3), the callipers degree of
sensitivity. For FFT, broad RI ranges of are reported because of narrow region of
stable frequencies
Breadth
-0.04
-0.03
-0.02
-0.01
0.01
0.02
0.03
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
305 315 325 335
THzE-Field(×10³),a.u.
THzE-Field(×103),a.u.
Optical-delay, ps
ρ = 0.59 g/cm³
ρ = 0.66 g/cm³
ρ = 0.69 g/cm³
ρ = 0.72 g/cm³
ρ = 0.76 g/cm³
ρ = 0.79 g/cm³
ρ = 0.82 g/cm³
ρ = 0.86 g/cm³
ρ = 0.89 g/cm³ R² = 0.99
R² = 0.93
0.020
0.021
0.022
0.023
0.024
0.025
0.026
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0.0 0.2 0.4 0.6 0.8 1.0
2ndmaxE-fieldpeak(×10³),a.u.
1stmaxE-fieldpeak(×10³),au
Bulk density, g/cm3
TD Transmission time-delay
Magnified
2nd peak
E-Fieldmax (t) magnitudes
• Breadth and
detection of
Emax more
accurate than
2nd EMax .
• At greater
density,
detection of 2nd
EMax(t) is harder
to distinguish.
First max. Breadth
0.00
0.05
0.10
0.15
0.20
0.25
Amplitude,a.u.
Optical Delay, ps
ρ = 0.93 g/cm³
ρ = 0.89 g/cm³
ρ = 0.86 g/cm³
ρ = 0.79 g/cm³
ρ = 0.79 g/cm³
ρ = 0.76 g/cm³
ρ = 0.72 g/cm³
ρ = 0.69 g/cm³
ρ = 0.66 g/cm³
ρ = 0.59 g/cm³
Tablets
TD Reflection
13. PHARMACEUTICAL TECHNOLOGIES
Evaluate FD method for non-destructive RTS determination
RI correlation was first demonstrated to a degree >0.99
Four batches comprised of 2 set off MCC:
• Set 1 with 2 fill weights and variable compaction force.
• Set 2 with 2 compaction-forces and variable fill weights
Analysed with FD transmission spectroscopy and then diametrically crushed, giving RTS.
An apparent linear line of best fit (see Fig ‘a’ and ‘b’) can be drawn over both tablet batches’ while both
sets converge and cross over with increased density.
Given that the 200 & 295 mg set have a greater R2, the cross-over point indicates that the fill-weight
volume influences the resistive consolidation mechanisms produced under different duress. Set 2
highlight that particle-particle binding mechanisms are different again a function of particle volume and
temporary (i.e. elastic) and permanent forces.
As a further use of THz technology, the RTS of tablets of comparatively equal FW’s are more reliably
indicatory of RI.
RTS
R² = 0.98
R² = 0.99
0.80 0.90 1.00 1.10 1.20
0.60
1.00
1.40
1.80
2.20
2.60
3.00
0.00
0.40
0.80
1.20
1.60
2.00
2.40
2.80
3.20
0.80 0.90 1.00 1.10 1.20
RTS,MPa
(a) SET 1 Density, g/cm3
200 mg tablets
295 mg tablets
R² = 0.76
R² = 0.61
0.8 0.9 1.0 1.1
0.4
0.9
1.4
1.9
2.4
2.9
0.4
0.9
1.4
1.9
2.4
2.9
0.8 0.9 0.9 1.0 1.0 1.1 1.1
RTS,MPa
(b) SET 2 Density, g/cm3
320 kg tablets
420 kg tablets
F.W.C.F.
14. PHARMACEUTICAL TECHNOLOGIES
Multi-variant sets of RC ribbons
To elucidate varying RI lateral and longitudinal density to the key process and machine
parameters.
State Limitations.
Produced Ribbons Composition (w/w%) Equipment set-up Character
Alexandwe
rk WP-120
15 RC’s
10 Wafers
Avicel® PH-102 (78.6 %)
Anhydrous lactose (19.4 %)
Croscarmellose Na (1.5%)
Mg stearate (0.25%)
n =10
Variable: Compaction-
Force.
- Compressed at 4.79 –
6.79 kN/cm.
-Roll-gap: 2.2 mm
- Knurled roller-wheel.
- Knurled wafer press.
Ribbon SF’s / Mean
Thkn:
63 % / 2.78 mm
76 % / 2.68 mm
83 % / 2.82 mm
Wafer SF’s / Thkn
63 % / 2.32 mm
83 % / 2.27 mm
90 % / 2.28 mm
Gerteis
Micro-
Pactor
16 samples Vivapur 102 (78.0 %)
Anhydrous lactose (18.25 %)
Croscarmellose Na (3.0 %)
SiO2: Supernat 160 (½ %)
Mg stearate (¼ %)
Smooth roller-wheel.
Roller-speed: 3 mm.
Roller-force:
1/5/10/15 kN/cm
Roller-gap:
1/2/3/4 mm.
Roller-force:
1/5/10/15 kN/cm
Roller-gap:
2/4 mm.
8 samples • Avicel® PH-101 (100 %)
Ribbons
15. PHARMACEUTICAL TECHNOLOGIES
Limitation # 1: Problems with knurled wafer/ribbons
Knurled wafers and ribbons prevent either an accurate RI or thickness to be predicted
when imaged.
• (a) Reflectance waveform acquired from
both front and rear surfaces: One face
knurled.
• RI can be taken of smooth face, but then
Thkn inaccurate.
(b) Probing from knurled face is unreliable
depending on placement.
• Knurled surfaces cause unpredictable
signal propagation causing ripples.
Ribbons
16. PHARMACEUTICAL TECHNOLOGIES
Limitation # 2: Problems with non-planar ribbons
For accurate prediction of RI’s the intensity of the probe beam is contrasted to a flat
mirror, which is then removed and focused (z-dimension) on initial position before
scanning
Multiple lateral/longitudinal scans of curved ribbons give fluctuating amplitudes when
moved from the fixed reference point.
• A ribbon with a planar lateral character.
• Often the product of using smooth roll-wheels.
• A ribbon with a curved lateral character.
• The majority of curved ribbons are produced
with knurled rolls.
Ribbons
?
: reliable RI =
reliable Thkn
: specular/flat interception
17. PHARMACEUTICAL TECHNOLOGIES
Effect of Roll Force and Thkn: Examples of Blend 1: 1 mm thick ribbons
Composition 1 (w/w%) Vivapur 102 (78.0 %)
Anhydrous lactose (18.25 %)
Croscarmellose sodium (3.0 %)
SiO2: Supernat 160 (½ %)
Magnesium stearate (¼ %)
Smooth rolls/3 RPM
Variables:
Force 5/10/15 kN/cm
Roll Gap 1/2/3/4 mm
Composition 2 (w/w%) Avicel PH-101 (100%)
Variables: Force 5/10/15 kN/cm
Roll Gap 1/2 mm
40 reflection scans per ribbon were made.
(a) Histogram displaying the distribution of the all
the ribbons (points analysed/ribbon = 40),
Individual contour images are shown:
(b) 05 kN/cm
(c) 10 kN/cm
(d) 15 kN/cm
(e-g) Mean lateral I distributions are plotted, with
error bars for the minimum to maximum RI’s
along the ribbons’ length.
Ribbons
18. PHARMACEUTICAL TECHNOLOGIES
Results of the effects of Roll Force and Thickness of Composition 1
Composition 1 (w/w%) Vivapur 102 (78.0 %)
Anhydrous lactose (18.25 %)
Croscarmellose sodium (3.0 %)
SiO2: Supernat 160 (½ %)
Magnesium stearate (¼ %)
Smooth rolls/3 RPM
N = 18
Variables:
Compaction Force 5/10/15 kN
Roll Gap 1/2/3/4 mm
• Linear relation at lower forces (i.e. 5 to ~ 7.5 kN/cm)
• Material consolidation lessens as True densities approach.
• Broader ribbons report maximum SF’s at lower force.
• Agglomeration of thin ribbons remains curved over great
forces. This suggests consolidation processes (i.e. particle
rearrangement, interlocking, brittle fracture.
* The error bars show RI variance longitudinally over the 18 ribbons (points analysed/ribbon = 40).
Ribbons
Visually
linear
1mm
4mm
19. PHARMACEUTICAL TECHNOLOGIES
Results of the effects of Roll Force and Thickness of Composition 2
Composition 2 (w/w%) Avicel PH-101 (100%) n = 6
Variables: Compaction Force 5/10/15 kN
Roll Gap 1/2 mm
* The error bars show RI variance longitudinally over the 6 ribbons (points analysed/ribbon = 40).
• Linear relation at lower forces (i.e. 5 to ~ 8 kN/cm).
• Although fewer points as previous slide, the deformation
character of MCC alone (leading to similar RI’s) is less
prone to a broad number of consolidation processes in
approaching an apparent SF indicative of MCC’s true
densities
Ribbons
