1

Real-Time Measurement of Granule Densification

and Size in High Shear Wet Granulation:

Combined Use of Focused Beam Reflectance

Measurement with Drag Force SensorAjit S. Narang1, Brian Breza1, Kevin Macias1, Tim Stevens1,

Divyakant Desai1, Sherif Badawy1, Dilbir Bindra1,

1Bristol-Myers Squibb, Co., New Brunswick, NJVadim Stepaniuk2, Valery Sheverev2

2Lenterra, Inc., Newark, NJ

AAPS 2013

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

Drag Force Flow (DFF) 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 detectedOptical fibers

Optical strain gauges

Hollow pillar

Base

Placement of Sensors in the High Shear GranulatorDFF Sensor

• Focused beam reflectance measurement (FBRM) C35 probe for in-line

measurement of chord length distribution (CLD).

• DFF sensor for shear measurement.

DFF SensorC35 Probe

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

• Increase in DFF shear during water addition and wet massing phase evident.

1% HPC batch

DFF Sensor Raw Data with Zero Correction

• Increase in DFF shear during water addition and wet massing phase evident.• 3% HPC provides signal differentiation from 1% HPC batch

3% HPC batch

DFF Sensor Raw Data with Zero Correction

• Increase in DFF shear during water addition and wet massing phase evident.• 5% HPC batch has signal different than 1% and 3% HPC

5% HPC batch

10

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

Fast Fourier Transformation

Figure 1

DC component

Fundamental 10.56Hz

Second harmonics

Third harmonics

Impeller frequency

• High resolution data collection allows processing options such as FF transformation

Amplitude of the Fundamental Harmonic

0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 1,400 1,500-0.05

0.00

0.05

0.10

0.15

0.20

Test 1

Test 2

Test 3

Time, s

Ampl

itude

, N

Water on

Water off

• DFF sensor is ability to differentiate batches made with different HPC % w/w content as well as different stages of processing.

Highest Peak Magnitude

0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 1,400 1,5000.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Test 1

Test 2

Test 3

Time, s

High

est p

eak

mag

nitu

de, N

Water off

Water on

• 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

0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300 1,400 1,500-0.05

0.00

0.05

0.10

0.15

0.20

Time, s

Ampl

itude

, N

Water off

Water on

• 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

• 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.

1500 855

568 303

165 113

38

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

1% HPC

3% HPC

5% HPC

Part Size (Microns)

Norm

aliz

ed A

mou

nt

FBRM C35 Chord Length Distribution: 1% HPC

FBRM C35 Chord Length Distribution: 3% HPC

FBRM C35 Chord Length Distribution: 5% HPC

ResultsParticle 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.