Ajit S. Narang 1 , Brian Breza 1 , Kevin Macias 1 , Tim Stevens 1 ,
Divyakant Desai 1 , Sherif Badawy 1 , Dilbir Bindra 1,
1 Bristol-Myers Squibb, Co., New Brunswick, NJ
Vadim Stepaniuk 2 , Valery Sheverev 2
2 Lenterra, 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
(Fiber Bragg Gratings) attached on the inner surface of the pillar
• Force and temperature measured
• No moving parts, no gaps where particles could be trapped
•
Measurement speed 500 Hz
• Force as low as 1 mN can be detected
Drag Force Flow (DFF) Sensor
Base
Optical strain gauges
Optical fibers
Hollow pillar

Placement of Sensors in the High Shear Granulator
DFF Sensor
DFF Sensor
C35 Probe
•
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
0,15
Water off
Water on
0,10
0,05
0,00
Test 1
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
1,0
0,8
0,6
0,4
1,4
1,2
Water on
Water off
Test 1
Test 2
Test 3
0,2
0,0
0 100 200 300 400 500 600 700 800
Time, s
900 1 000 1 100 1 200 1 300 1 400 1 500
•
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
0,15
0,10
0,05
0,00
Water on
-0,05
0 100 200 300 400 500 600 700
Time, s
800 900 1 000 1 100 1 200 1 300 1 400 1 500
•
DFF sensor is able to differentiate batches made with different HPC % w/w content as well as different stages of processing.

Particle Size Distribution: Sieve Analysis
0,45
0,4
0,35
0,3
0,25
0,2
0,15
0,1
0,05
0
1500
855
568
303
165
Part Size (Microns)
113
38
5% HPC
3% HPC
1% HPC
•
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.