Title of Presentation

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Real-Time Measurement of Granule Densification
and Size in High Shear Wet Granulation:
Combined Use of Focused Beam Reflectance
Measurement with Drag Force Sensor
Ajit S. Narang1, Brian Breza1, Kevin Macias1, Tim Stevens1,
Divyakant Desai1, Sherif Badawy1, Dilbir Bindra1,
1Bristol-Myers Squibb, Co., New Brunswick, NJ
Vadim Stepaniuk2, Valery Sheverev2
2Lenterra, Inc., Newark, NJ
AAPS 2013
1
Purpose
• Process analytical technologies (PAT) for real time monitoring and control of
high shear wet granulation (HSWG) have achieved significant success in granule
size distribution using focused beam reflectance measurement (FBRM).
• However, granule densification is an important quality attribute that often
correlates with granule porosity and drug product dissolution.
• PAT tool to quantify granule densification, in parallel with size distribution, can
provide complete attribute-control for the granulation processes, enabling
building quality-by-design in the HSWG unit operation.
• In this study, the resolution and sensitivity of a drag force flow (DFF) sensor in
delineating granulation densification used concurrently with FBRM C35 probe
was investigated.
Methods
• A placebo formulation consisting of microcrystalline cellulose, lactose
monohydrate, croscarmellose sodium, and hydroxypropyl cellulose (HPC) was
granulated with 40% w/w water in a 30 liter Pharma Connect granulator at
impeller tip speed of 4.8 m/s and chopper speed of 1000 rpm.
• Rate of granule size growth and densification were measured using in-line
FBRM C35 probe and DFF sensor at different concentrations of HPC (1%, 3%,
and 5% w/w).
Shear Sensor
• Product of Lenterra Inc.
• Drag force on thin cylinder  shear force
• Minute deflections of the hollow pillar are
detected by two optical strain gauges
Drag Force Flow (DFF) Sensor
(Fiber Bragg Gratings) attached on the
Base
inner surface of the pillar
• Force and temperature measured
Optical strain
gauges
• No moving parts, no gaps where particles
Hollow pillar
could be trapped
• Measurement speed 500 Hz
• Force as low as 1 mN can be detected
Optical fibers
Placement of Sensors in the High Shear Granulator
DFF Sensor
C35 Probe
DFF Sensor
• Focused beam reflectance measurement (FBRM) C35 probe for in-line
measurement of chord length distribution (CLD).
• DFF sensor for shear measurement.
Experimental Conditions
• Batches:
• Test 1- HPC 1%; Test 2- HPC 3% ; Test 2- HPC 5%.
• Blade RPM: 210 (4.8 m/s), chopper RPM: 1000
• Timing:
• Test 1: Impeller starts – 9 s, water on- 259 s, water off- 439 s, impeller
stops- 1370 s.
• Test 2: Impeller starts – 10 s, water on – 250 s, water off – 432 s,
impeller stops – 1333 s
• Test 3: Impeller starts – 24 s, water on – 267 s, water off – 447 s,
impeller stops – 1368 s
• DFF Sensor
• Position: 1” above the blade.
• Acquisition rate: 500 Samples per second
• Color convention on the plots:
• Test #1 – red curve
• Test #2 – green curve
• Test #3 - blue curve
• Light blue area – duration of water addition
DFF Sensor Raw Data with Zero Correction
1% HPC batch
• Increase in DFF shear during water addition and wet massing phase evident.
DFF Sensor Raw Data with Zero Correction
3% HPC batch
• Increase in DFF shear during water addition and wet massing phase evident.
• 3% HPC provides signal differentiation from 1% HPC batch
DFF Sensor Raw Data with Zero Correction
5% HPC batch
• Increase in DFF shear during water addition and wet massing phase evident.
• 5% HPC batch has signal different than 1% and 3% HPC
DFF Sensor Time Resolved Signal
Peaks due to consolidated
granule impacts
Continuous signal due to wet
mass flow (sine fit)
• Peak amplitude is proportional to the mass of the granule
• Sine fit amplitude is proportional to the density of wet mass
10
Fast Fourier Transformation
DC component
Fundamental 10.56Hz
Second harmonics
Third harmonics
Impeller frequency
Figure 1
• High resolution data collection allows processing options such as FF
transformation
Amplitude of the Fundamental Harmonic
0.20
Water off
0.15
Amplitude, N
Water on
0.10
0.05
Test 1
0.00
Test 2
Test 3
-0.05
0
100
200
300
400
500
600
700
800
900
1,000
1,100
1,200
1,300
1,400
1,500
Time, s
• DFF sensor is ability to differentiate batches made with different HPC %
w/w content as well as different stages of processing.
Highest Peak Magnitude
1.4
Water off
Test 1
Highest peak magnitude, N
1.2
Test 2
1.0
Test 3
Water on
0.8
0.6
0.4
0.2
0.0
0
100
200
300
400
500
600
700
800
900
1,000
1,100
1,200
1,300
1,400
1,500
Time, s
• DFF sensor is able to differentiate batches made with different HPC % w/w
content as well as different stages of processing.
Time Dependent Histogram of Peak Amplitude
Distribution: 1% HPC
Time Dependent Histogram of Peak Amplitude
Distribution: 3% HPC
Time Dependent Histogram of Peak Amplitude
Distribution: 5% HPC
Sine Function Amplitude After Distribution Fitting
0.20
Water off
Amplitude, N
0.15
0.10
0.05
0.00
Water on
-0.05
0
100
200
300
400
500
600
700
800
900
1,000
1,100
1,200
1,300
1,400
Time, s
• DFF sensor is able to differentiate batches made with different HPC % w/w
content as well as different stages of processing.
1,500
Particle Size Distribution: Sieve Analysis
0.45
0.4
0.35
0.3
Normalized Amount
0.25
0.2
0.15
0.1
0.05
0
5% HPC
1500
855
3% HPC
568
303
1% HPC
165
113
Part Size (Microns)
38
• No significant difference in the particle size distribution of batches
manufactured with different % w/w HPC levels.
• Indicates the ability of DFF shear sensor to quantitate a binder-level related
in-process attribute that is not necessarily PSD dependent.
FBRM C35 Chord Length Distribution: 1% HPC
FBRM C35 Chord Length Distribution: 3% HPC
FBRM C35 Chord Length Distribution: 5% HPC
Results
Particle Size:
• Differences in the rate of granule growth with different concentrations of HPC
were evident in the FBRM measurement.
Shear:
• A high acquisition rate sensor that measures drag force on a thin cylindrical pillar
provided high resolution unipolar signal, i.e., the pillar did not oscillate but
deflect under an applied force and then quickly relaxed back into the equilibrium
position.
• Signal consisted of separate peaks, and their frequency generally synchronized in
time with blades passing below the sensor.
• The time-dependent periodic signal was clearly synchronized with the frequency
of blades passing the sensor, and included a number of peaks of variable
magnitude that may be interpreted as particle or granule impacts.
Conclusions
• The peak amplitudes were a function of the concentration of HPC used in the
batch.
• Basic statistical analysis of peak magnitudes suggested potential the development
of a procedure to quantitatively characterize such parameters of the wet mass as
densification, tackiness, and particle growth.
• The DFF sensor was able to capture anticipated differences in wet mass
consistency with different concentrations of binder.
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