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On-line Monitoring of Wet On-line Monitoring of Wet Granulation Processes using Granulation Processes using Acoustic Emission Acoustic Emission

John Gamble John Gamble Bristol-Myers Squibb Bristol-Myers Squibb Moreton, UK Moreton, UK

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Granulation - An Overview

V - Liquid bridge formation(denser)solid to Solid in Liquid IV----LiquidAbsorption liquid saturated S4 Interparticular from Liquid in III Part of wetted granules II System changes void space fill-up Better the mass is I
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How does Acoustic Emission work ?

Amplified AC signal

AC to RMS conversion

DC signal envelope

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Comparison of Impeller Torque data and Mean Acoustic Power data

600 550 500
A E P ow er/Torque

450 400 350 300 250 200 AE Data Torque Data

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Acoustic Monitoring
650 kHz Acoustic Emission sensors were applied to a Mi-Pro High Shear Granulator (900ml bowl) Acoustic data was sampled at 100Hz from 128 points (64 per sensor) Granulation conditions:
! ! ! !

120g Batch size (Placebo formulation) 800rpm impeller speed 1000rpm chopper speed 6ml/min liquid dose rate (water)
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Comparison of Impeller Torque data and Mean Acoustic Power data

Mi-Pro Placebo Granulation
1.00E+00 700.0 600.0 5.00E-01 500.0 Mean acoustic power

400.0

300.0 -5.00E-01

200.0 -1.00E+00 100.0

-1.50E+00 Time

0.0

Impeller Torque

0.00E+00

Dry Blend Water start 12-32ml 32-38ml 38-48ml Torque

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Test of Prediction Model for a Placebo Granulation

19 data points were identified as indicators of the endpoint (23 seconds of acoustic data) End-point data was then modelled using SIMCA software to create the prediction model A batch was then manufactured using the prediction model A class boundary of 3 standard deviations from the model end-point was selected

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Results for a placebo granulation using the prediction model

700.0 50.0 45.0 600.0 40.0 500.0 35.0 30.0
T o rq u e ( m N m )

400.0 25.0
Impeller Torque

300.0

Liquid Volume Prediction Class Boundary (SD)

20.0 15.0 10.0

200.0

100.0 5.0 0.0 Time 0.0

S D 'd to e ndp oin t

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Testing of Prediction model

To further test the model, batches of placebo granule were manufactured using varying dose rates, impeller and chopper speeds, and batch sizes In each case the granulation was halted at the predicted end-point (2.5 standard deviation class boundary applied) Wet and dried granule were then analysed for a range of solid state characteristics (density, particle size etc)

Dose Impeller Chopper Rate speed Batch speed Batch No. (ml/min) (rpm) Size (g) (rpm) 5 3 800 120 1000 6 9 800 120 1000 7 6 800 120 1000 8 6 1000 120 1000 9 6 600 120 1000 10 6 800 120 1000 11 6 800 120 1000 12 6 800 100 1000 13 6 800 140 1000 14 6 800 120 500 15 6 800 120 1500

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6ml/min; 800rpm
Mi-Pro 900ml placebo granulation monitored using acoustic emission in prediction mode stopping at the predicted endpoint (6ml/min dose rate; 795rpm)
500.0 450.0 400.0 30.0 350.0 Im peller Torque 300.0 250.0 200.0 150.0 10.0 100.0 50.0 0.0 10:04:48 5.0 25.0 40.0

35.0 SDs to End-point / Dosed volum e (m l)

Impeller Torque Dose Volume (ml) Prediction (SD) Class Boundary

20.0

15.0

10:06:14

10:07:41

10:09:07 Tim e

10:10:34

10:12:00

10:13:26

0.0 10:14:53

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6ml/min; 600rpm
Mi-Pro 900ml placebo granulation monitored using acoustic emission in prediction mode stopping at the predicted endpoint (6ml/min dose rate; 595rpm)
500.0 450.0 30.0 SDs to End-point / Dosed volum e (m l) 400.0 350.0 Im peller Torque 300.0 250.0 200.0 150.0 100.0 5.0 50.0 0.0 10:06:14 0.0 10:14:53 15.0 25.0 35.0

20.0

Impeller Torque Dose Volume (ml) Prediction (SD) Class Boundary

10.0

10:07:41

10:09:07

10:10:34 Tim e

10:12:00

10:13:26

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Granulation Results
The system was able to identify end-points (acoustic data passes the class boundary) for each of the batches at 800rpm, despite varying dose rates, chopper speeds and batch sizes

However, the system did not predict an end-point for the batches manufactured at 600 and 1000rpm

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Physical Characterisation Results for the Granule

Wet Mass testing Dose Impeller Rate speed Batch Batch No. (ml/min) (rpm) Size (g) 5 3 800 120 6 9 800 120 7 6 800 120 8 6 1000 120 9 6 600 120 10 6 800 120 11 6 800 120 12 6 800 100 13 6 800 140 14 6 800 120 15 6 800 120 16 6 800 120 17 6 800 120 Chopper Time to Water speed End-point content Bulk (rpm) (mins) (ml) Density 1000 09:54 29.9 0.39 1000 04:11 37.6 0.46 1000 05:48 34.8 0.4 1000 05:10 37.4 0.44 1000 05:01 30.4 0.36 1000 05:26 33.1 0.39 1000 05:50 35.4 0.4 1000 04:56 30.1 0.35 1000 06:08 37.3 0.39 500 04:13 25.6 0.31 1500 04:08 25.2 0.35 500 05:47 34.8 0.39 1500 05:14 31.8 0.39 Dry Mass Testing Specific Tapped Mean Surface Rheology Area Bulk Bulk Compressibility (m/g) Density Density (%) (mJ) 84.1 0.42 0.47 0.62 24.19 93.65 0.47 0.48 0.6 20 86.95 0.56 0.45 0.6 25 101.5 0.43 0.5 0.62 19.35 79.5 0.54 0.35 0.51 31.37 89.95 0.53 0.4 0.57 29.82 82.45 0.42 0.43 0.56 23.21 89.2 0.42 0.55 23.64 93.2 0.43 0.57 24.56 83.25 0.32 0.45 28.89 75.2 0.33 0.47 29.79 74.6 0.44 0.58 24.14 78.5 0.44 0.55 20

Rheology (mJ) 76.3 91.9 87.3 100 93.5 80.4 111 92 84.5 74.5 84.1 95.8 81.3 83.6 77.4 101 99.6 86.8 74 92.5 85.1 65.3 77.6 71.6 77.7 79.3

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Physical Characterisation Results for the Granule

600rpm Impeller speed 1000rpm Impeller speed

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Discussion of Results
Main physical differences between the granule batches manufactured using varied impeller speeds are: Particle size distribution Rheology Bulk density (Dried granule)

Factors such as particle size (and particle velocity), will have an impact on the acoustic frequencies and so affect the models predictive capability
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Conclusions
The prediction model has been demonstrated to be robust in that it is able to identify the process endpoint using differing dose rates and batch sizes The model has been able to provide granule with the same physical characteristics despite varied dose rates and batch sizes The model was affected by a change in excipient batch, highlighting the importance of control of physical properties for this technique. Acoustic emission could be a valuable addition to the PAT toolbox for the monitoring of wet granulations

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