Ajit S. Narang 1 , Brian Breza 1 , Kevin Macias 1 , Tim Stevens 1 ,

1. 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 Sheverev22Lenterra, Inc., Newark, NJ AAPS 2013

2. 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.

3. 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).

4. 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 Hollow pillar Optical fibers

5. 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.

6. 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

7. DFF Sensor Raw Data with Zero Correction • 1% HPC batch • Increase in DFF shear during water addition and wet massing phase evident.

8. 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

9. 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

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

11. Fast Fourier Transformation • High resolution data collection allows processing options such as FF transformation

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

13. Highest Peak Magnitude • DFF sensor is able to differentiate batches made with different HPC % w/w content as well as different stages of processing.

14. Time Dependent Histogram of Peak Amplitude Distribution: 1% HPC

15. Time Dependent Histogram of Peak Amplitude Distribution: 3% HPC

16. Time Dependent Histogram of Peak Amplitude Distribution: 5% HPC

17. Sine Function Amplitude After Distribution Fitting • DFF sensor is able to differentiate batches made with different HPC % w/w content as well as different stages of processing.

18. 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.

19. FBRM C35 Chord Length Distribution: 1% HPC

20. FBRM C35 Chord Length Distribution: 3% HPC

21. FBRM C35 Chord Length Distribution: 5% HPC

22. 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.

23. 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.